CML Newswire Archives: CMLHope.Com

CML Newswire Archives Moved To New Site

2007-02-10T14:15:00.000-05:00

All of the old blog archives of CMLNewswire have been moved to our new site at
http://cmlnewswire.wordpress.com

CML Newswire Moves To Wordpress

2006-07-26T02:19:00.000-04:00

Because of frequent problems with the Blogger/Blogspot system future articles of CML Newswire will be posted at http://cmlnewswire.wordpress.com Old articles will still be archived at http://cmlsupport.blogspot.com

Listing Of CML Clinical Trials

2006-06-03T02:05:00.000-04:00

51.RecruitingChemotherapy and Monoclonal Antibody Therapy in Treating Patients With Advanced Myeloid Cancer
Conditions: Adult Acute Myeloid Leukemia; Atypical Chronic Myeloid Leukemia; Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; ...52.RecruitingClofarabine Combinations in Relapsed/Refractory AML, MDS and Myeloid Blast Phase CML
Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome; Chronic Myeloid Leukemia53.RecruitingSafety and Efficacy of Imatinib in Chronic Myelogenous Patients in Relapse After Stem Cell Transplantation
Condition: Chronic Myeloid Leukemia54.RecruitingAdoptive Immunotherapy and Interleukin-2 in Treating Patients With Recurrent Myeloid Leukemias After Undergoing Allogeneic Stem Cell Transplantation
Conditions: Adult Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia55.RecruitingImatinib Mesylate After a Donor Stem Cell Transplant in Treating Patients With Philadelphia Chromosome-Positive Leukemia
Conditions: Adult Acute Lymphoblastic Leukemia; Childhood Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia56.RecruitingTotal-Body Irradiation, Thiotepa, and Fludarabine in Treating Young Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
Conditions: Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Chronic Myelogenous Leukemia; ...57.Not yet recruitingImatinib Mesylate and Zoledronic Acid in Patients With Chronic Myeloid Leukaemia in Cytogenetic Response Without Molecular Response
Condition: Myeloid Leukemia, Chronic58.RecruitingA Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Blood Related Cancers
Conditions: Chronic Myelogenous Leukemia; Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive); Hypereosinophilic Syndrome; Systemic Mastocytosis59.Not yet recruitingAllogeneic Tumor Cell Vaccination in Patients With Chronic Myeloid Leukemia
Condition: Chronic Myeloid Leukemia60.RecruitingDasatinib (BMS-354825) in Chronic Myelogenous Leukemia (CML)
Condition: Myelogenous Leukemia, Chronic61.RecruitingAlemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
Conditions: Diamond-Blackfan Anemia; Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; Chronic Myelogenous Leukemia; ...62.RecruitingDonor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
Conditions: Acute Lymphocytic Leukemia; Acute Myeloid Leukemia; Chronic Myelogenous Leukemia; Congenital Amegakaryocytic Thrombocytopenia; ...63.RecruitingVorinostat and Idarubicin in Treating Patients With Relapsed or Refractory Leukemia or Myelodysplastic Syndromes
Conditions: Adult Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia; Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies; ...64.RecruitingA Study of Dasatinib in Patients With Chronic Myelogenous Leukemia (Accelerated Phase, Blast Phase or Ph+ ALL) Who Are Resistant or Intolerant of Imatinib Mesylate
Conditions: Chronic Myeloid Leukemia Accelerated and Blast Phase; Leukemia, Acute, Philadelphia-Positive65.RecruitingPhase 2 Trial of a CMV Vaccine in Donors and Recipients Undergoing Allogeneic Hematopoietic Cell Transplant (HCT)
Conditions: Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Acute Myelogenous Leukemia; Hodgkins Lymphoma; Non-Hodgkin's Lymphoma; ...66.RecruitingUse of SV40 Vectors to Treat Chronic Myeloid Leukemia (CML)
Condition: Chronic Myeloid Leukemia67.RecruitingEfficacy of 400 Mg Versus 800 Mg Imatinib in Chronic Myeloid Leukemia in Chronic Phase Patients
Condition: Leukemia, Myeloid, Chronic Phase68.Not yet recruitingPhase I Study of Dasatinib (BMS-354825) and Imatinib in Subjects With Chronic Myeloid Leukemia in Chronic Phase
Condition: Chronic Phase Chronic Myelogenous Leukemia (CML)69.RecruitingStudy Comparing Standard Dose and High-Dose Imatinib Mesylate in Patients With Chronic Phase Ph+ CML
Condition: Chronic Phase Ph+ Chronic Myelogenous Leukemia70.RecruitingSTI571 ProspectIve RandomIzed Trial: SPIRIT
Condition: Chronic Myeloid Leukemia71.Not yet recruitingEfficacy and Safety of Oral AMN107 in Adults With Chronic Myelogenous Leukemia Resistant and/or Intolerant to Imatinib Mesylate Therapy
Condition: Chronic Mylogenous Leukemia (CML) Patients Resistant or Intolerant to Imatinib Mesylate Therapy72.RecruitingPilot Phase II - Synthetic Vaccine in CML
Condition: Chronic Myeloid Leukemia73.RecruitingGM-K562 Vaccination for CML Patients
Condition: Chronic Myeloid Leukemia74.RecruitingHomoharringtonine With Oral Gleevec in Chronic, Accelerated and Blast Phase Chronic Myeloid Leukemia (CML)
Conditions: Myeloid Leukemia, Chronic; Myeloid Leukemia, Chronic, Accelerated-Phase; Blast Phase; Myeloid Leukemia, Chronic, Chronic-Phase75.RecruitingBusulfan, Fludarabine, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Stem Cell Transplant for Hematologic Cancer
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; ...76.RecruitingComparing Imatinib Standard Dose With Imatinib High Dose Induction in Pretreated CML Patients in Chronic Phase
Condition: Chronic Myeloid Leukemia77.RecruitingAFR10 - Combination Therapy of Imatinib Mesylate (IM) + Alpha-2A Interferon for Chronic Phase CML Patients Resistant or Refractory to IM Used as Single Therapy for at Least One Year
Condition: Chronic Myeloid Leukemia78.RecruitingRadiolabeled Monoclonal Antibody Therapy Combined With Total-Body Irradiation, Allogeneic Peripheral Stem Cell Transplantation, and Immunosuppression Therapy in Treating Older Patients Who Have Advanced Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Chronic Myelomonocytic Leukemia
Conditions: Adult Acute Myeloid Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Graft Versus Host Disease; ...79.RecruitingVNP40101M in Treating Patients With Acute Myelogenous Leukemia or High-Risk Myelodysplasia
Conditions: Adult Acute Myeloid Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; ...80.RecruitingIntensive Compared With Nonintensive Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
Conditions: Acute Myeloid Leukemia; Adult Acute Monoblastic and Acute Monocytic Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; ...81.RecruitingArsenic Trioxide, Ascorbic Acid, Dexamethasone, and Thalidomide in Treating Patients With Chronic Idiopathic Myelofibrosis or Myelodysplastic or Myeloproliferative Disorders
Conditions: Atypical Chronic Myeloid Leukemia; Chronic Idiopathic Myelofibrosis; Chronic Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; ...82.RecruitingDonor Stem Cell Transplantation With or Without Chemotherapy in Treating Children With Primary Myelodysplastic Syndrome
Conditions: Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; ...83.RecruitingLow-Dose Decitabine Compared With Standard Supportive Care in Treating Older Patients With Myelodysplastic Syndrome
Conditions: Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; Myelodysplastic Syndromes84.RecruitingReduced-Intensity Regimen Before Donor Bone Marrow Transplantation in Treating Patients With Myelodysplastic Syndromes
Conditions: Atypical Chronic Myeloid Leukemia; Chronic Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; Myelodysplastic Syndromes85.RecruitingBone Marrow Transplantation in Treating Patients With Hematologic Cancers
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; ...86.RecruitingAlemtuzumab and Combination Chemotherapy Followed By Donor Lymphocytes in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; ...87.RecruitingAlemtuzumab Plus Fludarabine and Melphalan With or Without Cyclosporine, Mycophenolate Mofetil, and Low-Dose Total-Body Irradiation Therapy Followed by Donor Peripheral Stem Cell Transplantation in Treating Patients With Hematologic Cancer
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Leukemia; Myelodysplastic and Myeloproliferative Disease; Non-Hodgkin's Lymphoma; ...88.RecruitingTherapy of Hypereosinophilic Syndrome, Polycythemia Vera, Atypical CML or CMML With PDGF-R Fusion Genes, or Mastocytosis With Gleevec
Conditions: Chronic Myelomonocytic Leukemia; Chronic Myeloid Leukemia; Polycythemia Vera; Hypereosinophilic Syndrome; Mastocytosis89.RecruitingUmbilical Cord Blood and Placental Blood Transplantation in Treating Patients With Hematologic Cancer or Aplastic Anemia
Conditions: Langerhans Cell Histiocytosis; Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer90.RecruitingStudy Evaluating the Safety and Efficacy of AMD3100 for Transplantation of Sibling Donor Stem Cells in Patients With Hematological Malignancies
Conditions: Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome; Chronic Myelogenous Leukemia; Non-Hodgkin Lymphoma; ...91.Not yet recruitingSafety and Efficacy of Unrelated Cord Blood Transplantation for Adult Patients With Hematologic Malignancies
Conditions: Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome92.RecruitingInfusion of Specially Treated Umbilical Cord Stem Cells After Chemoradiation Treatment for Blood Cancers
Conditions: Acute Lymphocytic Leukemia; Acute Myeloid Leukemia; Myelodysplastic Syndrome; Non-Hodgkin Lymphoma; Chronic Myelogenous Leukemia93.Not yet recruitingStudy of Dasatinib in Patients With Chronic Phase CML and a Suboptimal Response to Imatinib
Condition: Leukemia, Myeloid, Chronic94.RecruitingTotal-Body Irradiation Plus Chemotherapy Followed By Donor Bone Marrow Transplantation in Treating Children With Hematologic Cancer
Conditions: Acute Leukemia; Childhood Large Cell Lymphoma; Childhood Lymphoblastic Lymphoma; Childhood Small Noncleaved Cell Lymphoma; Chronic Leukemia; ...95.RecruitingEtanercept, Mycophenolate Mofetil, Denileukin Diftitox, or Pentostatin Combined With Prednisone or Methylprednisolone in Treating Patients With Acute Graft-Versus-Host Disease Who Have Undergone a Previous Donor Stem Cell Transplant
Conditions: Graft Versus Host Disease; Accelerated Phase Chronic Myelogenous Leukemia; ...96.RecruitingAllogeneic Transplantation for Patients With Acute Leukemia or CML
Conditions: Leukemia, Lymphocytic, Acute; Leukemia, Myeloid, Acute; Leukemia, Myeloid, Chronic97.RecruitingSelective T-Cell Depletion to Reduce Graft-Versus-Host-Disease in Patients Receiving Stem Cell Transplantation to Treat Leukemia, Lymphoma or Myelodysplastic Syndromes
Conditions: Graft vs Host Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myelomonocytic, chronic; Leukemia, Lymphocytyc; Lymphoma; ...98.RecruitingTreatment Of Hematologic Malignancies With Single-Unit Or Double-Unit Cord Blood Transplantation
Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Chronic Myeloid Leukemia; Non-Hodgkin Lymphoma; Myelodysplastic Syndromes99.RecruitingVX-680, an Aurora Kinase Inhibitor, in Patients With Relapsed/Refractory Leukemia
Conditions: Myelogenous Leukemia, Acute; Lymphocytic Leukemia, B Cell, Acute; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic100.RecruitingArsenic Trioxide and Etanercept in Treating Patients With Myelodysplastic Syndromes
Conditions: De Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Secondary Myelodysplastic Syndromes; ...

101.RecruitingAzacitidine and Etanercept in Treating Patients With Myelodysplastic Syndromes
Conditions: De Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Secondary Myelodysplastic Syndromes; ...102.RecruitingDonor Peripheral Stem Cell Transplantation in Treating Patients With Myelodysplastic Syndrome, Acute Myeloid Leukemia, or Myeloproliferative Disorder
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; ...103.RecruitingMonoclonal Antibody Therapy in Treating Patients With Ovarian Epithelial Cancer, Melanoma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, or Non-Small Cell Lung Cancer
Conditions: Acute Leukemia; Atypical Chronic Myeloid Leukemia; Melanoma; Myelodysplastic and Myeloproliferative Disease; Non-Small Cell Lung Cancer; ...104.RecruitingStudy Evaluating SKI-606 in Philadelphia Chromosome Positive Leukemias
Condition: Leukemia, Myeloid, Chronic105.RecruitingDecitabine and FR901228 in Treating Patients With Relapsed or Refractory Leukemia, Myelodysplastic Syndromes, or Myeloproliferative Disorders
Conditions: Adult Acute Erythroid Leukemia; Adult Acute Monoblastic and Acute Monocytic Leukemia; Chronic Myeloproliferative Disorders; Leukemia; ...106.RecruitingFilgrastim-Mobilized Peripheral Stem Cell Transplantation Compared With Bone Marrow Transplantation From Unrelated Donors in Treating Patients With Hematologic Malignancies
Conditions: Acute Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; Myelodysplastic and Myeloproliferative Disease107.RecruitingFilgrastim-Mobilized Peripheral Stem Cell Transplantation Compared With Bone Marrow Transplantation From Unrelated Donors in Treating Patients With Hematologic Malignancies
Conditions: Acute Leukemia; Chronic Leukemia; Chronic Myeloproliferative Disorders; Myelodysplastic and Myeloproliferative Disease108.RecruitingFludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing an Umbilical Cord Blood Transplant for Hematologic Cancer
Conditions: Childhood Non-Hodgkin's Lymphoma; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...109.RecruitingCombination Chemotherapy, Tacrolimus, and Mycophenolate Mofetil in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant For Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; ...110.RecruitingDonor Umbilical Cord Blood Transplant By Injection Into the Bone Marrow in Treating Patients With Hematologic Cancer
Conditions: Childhood Non-Hodgkin's Lymphoma; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma111.RecruitingPeripheral Stem Cell Transplantation in Treating Patients With Hematologic Cancer or Aplastic Anemia
Conditions: Childhood Hodgkin's Lymphoma; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...112.RecruitingFludarabine and Total-Body Irradiation Followed By Cyclosporine and Mycophenolate Mofetil in Treating Patients Who Are Undergoing a Donor Peripheral Stem Cell Transplant for Hematologic Cancer
Conditions: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...113.RecruitingCaregiver Support in the Coping of Patients Who Are Undergoing a Donor Bone Marrow Transplant
Conditions: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...114.Not yet recruitingBusulfan and Fludarabine Before Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
Conditions: Anemia; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...115.RecruitingDonor Umbilical Cord Blood Stem Cell Transplant in Treating Patients With Hematologic Cancer
Conditions: Adult Acute Erythroid Leukemia; Childhood Non-Hodgkin's Lymphoma; Leukemia; Lymphoma116.RecruitingDonor Stem Cell Transplant Followed By Donor White Blood Cell Infusions in Treating Young Patients With Hematologic Cancer
Conditions: Acute Leukemia; Childhood Large Cell Lymphoma; Childhood Lymphoblastic Lymphoma; Childhood Small Noncleaved Cell Lymphoma; Chronic Leukemia; ...117.RecruitingTotal-Body Irradiation and Cyclophosphamide in Treating Patients Who Are Undergoing Donor Stem Cell Transplant for Hematologic Cancer and Other Diseases
Conditions: Hodgkin's Lymphoma; Acute Leukemia; Chronic Leukemia; Cutaneous T-Cell Lymphoma; Non-Hodgkin's Lymphoma118.RecruitingPentostatin in Treating Patients With Refractory Chronic Graft-Versus-Host Disease
Conditions: Breast Cancer; Endocrine Cancer; Female Reproductive Cancer; Graft Versus Host Disease; Hematopoietic and Lymphoid Cancer; Neuroblastoma119.RecruitingCombination Chemotherapy Followed By Umbilical Cord Blood Transplantation in Treating Patients With Hematologic Cancer or Severe Aplastic Anemia
Conditions: Adult Acute Erythroid Leukemia; Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer120.RecruitingClinical Evaluations and Laboratory Studies in Patients With Chronic Graft-Versus-Host Disease Who Have Undergone a Previous Donor Stem Cell Transplant
Conditions: Cancer; Graft Versus Host Disease121.RecruitingDonor Stem Cell Transplantation in Treating Patients With Hematologic Cancer
Conditions: Childhood Non-Hodgkin's Lymphoma; Leukemia; Lymphoma; Myelodysplastic and Myeloproliferative Diseases122.RecruitingImmunosuppresive Treatment Regimens With or Without Mycophenolate Mofetil in Treating Patients With Newly Diagnosed Chronic Graft-Versus-Host Disease
Conditions: Cancer; Graft Versus Host Disease123.RecruitingCyclophosphamide, Fludarabine, and Donor White Blood Cells in Treating Patients With Hematologic Cancer That Relapsed After a Previous Donor Stem Cell Transplant
Conditions: Childhood Non-Hodgkin's Lymphoma; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...124.RecruitingUmbilical Cord Blood Transplantation in Treating Patients With High-Risk Hematologic Cancer
Conditions: Childhood Non-Hodgkin's Lymphoma; Graft Versus Host Disease; Leukemia; Lymphoma; Myelodysplastic and Myeloproliferative Diseases125.RecruitingDonor Umbilical Cord Blood Transplant in Treating Patients With Advanced Hematologic Cancer
Conditions: Adult Acute Monoblastic and Acute Monocytic Leukemia; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms126.RecruitingLow-Dose Fludarabine, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Umbilical Cord Blood Transplant in Treating Patients With Advanced Hematologic Cancer
Conditions: Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms127.RecruitingPalifermin in Reducing or Preventing Mucositis in Patients Who Are Receiving Radiation Therapy and Chemotherapy Followed by an Autologous Stem Cell Transplant for Hematologic Cancer
Conditions: Drug Toxicity; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; Oral Complications of Cancer and Cancer Therapy; ...128.RecruitingFludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; ...129.RecruitingT-Cell-Depleted Allogeneic Stem Cell Transplantation After Immunoablative Induction Chemotherapy and Reduced-Intensity Transplantation Conditioning in Treating Patients With Hematologic Malignancies
Conditions: Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...130.RecruitingSirolimus in Preventing Graft-Versus-Host Disease in Patients With Hematologic Malignancies Who Are Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Conditions: Chronic Myeloproliferative Disorders; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...131.RecruitingCombining Chemotherapy, Tacrolimus, Mycophenolate Mofetil, and Radiation Therapy With Donor Bone Marrow Transplantation in Treating Patients With Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Leukemia; Lymphoma; Multiple Myeloma and Other Plasma Cell Neoplasms; ...132.RecruitingPeripheral Stem Cell Transplantation in Treating Patients With Hematologic Cancer
Conditions: Langerhans Cell Histiocytosis; Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer133.RecruitingCyproheptadine and Megestrol in Preventing Weight Loss in Children With Cachexia Caused By Cancer or Cancer Treatment
Conditions: Cachexia; Childhood Hodgkin's Lymphoma; Childhood Brain Tumor; Childhood Non-Hodgkin's Lymphoma; Childhood Solid Tumor; ...134.RecruitingLaboratory-Treated Donor Bone Marrow in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Graft Versus Host Disease; Hematopoietic and Lymphoid Cancer135.RecruitingFludarabine, Cyclophosphamide, and Total-Body Irradiation Followed By an Umbilical Cord Blood Transplant, Cyclosporine, and Mycophenolate Mofetil in Treating Patients With Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer136.RecruitingG-CSF-Treated Donor Bone Marrow Transplant in Treating Patients With Hematologic Disorders
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Childhood Rhabdomyosarcoma; Graft Versus Host Disease; ...137.RecruitingDonor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer138.RecruitingDonor Stem Cell Transplant or Donor White Blood Cell Infusions in Treating Patients With Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer; Unusual Cancers of Childhood139.RecruitingDonor Umbilical Cord Blood Transplant in Treating Patients With Hematologic Cancer
Conditions: Diamond-Blackfan Anemia; Fanconi's Anemia; Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Graft Versus Host Disease; ...140.RecruitingDonor Stem Cell Transplant in Treating Patients With Hematologic Cancer, Metastatic Kidney Cancer, or Aplastic Anemia
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer; Kidney and Urinary Cancer141.Not yet recruitingMusic Therapy or Book Discussion in Improving Quality of Life in Young Patients Undergoing Stem Cell Transplant
Conditions: Cancer; Fatigue; Pain; Psychosocial Effects and Treatment142.RecruitingMoxifloxacin Compared With Ciprofloxacin/Amoxicillin in Treating Fever and Neutropenia in Patients With Cancer
Conditions: Adult Solid Tumor; Fever, Sweats, and Hot Flashes; Hematopoietic and Lymphoid Cancer; Infection; Neutropenia143.RecruitingTacrolimus and Mycophenolate Mofetil in Preventing Graft-Versus-Host Disease in Patients Who Have Undergone Donor Stem Cell Transplantation for Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Graft Versus Host Disease; Hematopoietic and Lymphoid Cancer144.RecruitingCaspofungin Acetate in Treating Aspergillosis in Patients With Hematologic Cancer or in Patients Who Have Undergone a Stem Cell Transplant
Conditions: Cancer; Infection145.RecruitingCombination Chemotherapy and Bone Marrow Transplantation in Treating Patients With Aplastic Anemia or Hematologic Cancer
Conditions: Childhood Hodgkin's Lymphoma; Childhood Non-Hodgkin's Lymphoma; Hematopoietic and Lymphoid Cancer146.RecruitingAcupuncture in Treating Mucositis-Related Pain Caused by Chemotherapy in Patients Undergoing Stem Cell Transplantation
Conditions: Cancer; Oral Complications of Cancer and Cancer Therapy; Pain147.RecruitingLight-Emitting Diode Therapy in Preventing Mucositis in Children Receiving Chemotherapy With or Without Radiation Therapy Before Bone Marrow Transplantation
Conditions: Cancer; Oral Complications of Cancer and Cancer Therapy; Pain148.Not yet recruitingEtanercept in Treating Young Patients With Idiopathic Pneumonia Syndrome After Undergoing a Donor Stem Cell Transplant
Conditions: Cancer; Pulmonary Complications149.RecruitingRasburicase in Treating or Preventing High Levels of Uric Acid in the Blood and Tumor Lysis Syndrome in Patients With Relapsed or Refractory Lymphoma, Leukemia, or Solid Tumors
Conditions: Cancer; Hyperuricemia; Tumor Lysis Syndrome150.RecruitingImatinib Mesylate in Patients With Various Types of Malignancies Involving Activated Tyrosine Kinase Enzymes
Conditions: Hypereosinophilic Syndrome; Systemic Mastocytosis; Chronic Myelomonocytic Leukemia; Dermatofibrosarcoma

201.RecruitingDouble Cord Blood Transplant Study
Conditions: Leukemia, Lymphocytic, Acute; Leukemia, Myelocytic, Acute; Leukemia, Myeloid, Chronic; Lymphoma, Non-Hodgkin202.RecruitingVatalanib in Treating Patients With Primary or Secondary Myelodysplastic Syndromes
Conditions: Chronic Myelomonocytic Leukemia; Myelodysplastic and Myeloproliferative Disease; Myelodysplastic Syndromes203.RecruitingAzacitidine and Arsenic Trioxide in Treating Patients With Myelodysplastic Syndromes
Conditions: Chronic Myelomonocytic Leukemia; Myelodysplastic Syndromes204.RecruitingStudy of Three Different Schedules of Low-Dose Decitabine in Myelodysplastic Syndrome (MDS)
Conditions: Myelodysplastic Syndrome; Chronic Myelomonocytic Leukemia205.RecruitingIdarubicin and Cytarabine With or Without Bevacizumab in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
Conditions: Adult Acute Erythroid Leukemia; Adult Acute Monoblastic and Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia; ...206.Not yet recruitingT-Cell and B-Cell Depletion in Allogeneic Peripheral Blood Stem Cell Transplantation
Conditions: Leukemia, Myeloid; Leukemia, Lymphocytic; Myelodysplastic Syndrome; Leukemia, Myeloid, Chronic; Lymphoma207.RecruitingSibling and Unrelated Donor Hematopoietic Cell Transplant in Hematologic Malignancies
Conditions: Acute Disease; Leukemia, Myeloid, Chronic; Myelodysplastic Syndromes; Myeloproliferative Disorders208.RecruitingAutologous Peripheral Stem Cell or Bone Marrow Transplant Using Laboratory-Treated Cells in Treating Patients With Acute Leukemia
Conditions: Acute Lymphocytic Leukemia; Acute Myeloid Leukemia; Adult Acute Erythroid Leukemia; Adult Acute Monoblastic and Acute Monocytic Leukemia; ...209.RecruitingBusulfan, Cyclophosphamide, and Melphalan in Treating Young Patients Who Are Undergoing a Donor Stem Cell Transplant For Juvenile Myelomonocytic Leukemia
Condition: Juvenile Myelomonocytic Leukemia210.RecruitingCombination Chemotherapy Followed By Donor Bone Marrow or Umbilical Cord Blood Transplantation in Treating Children With Newly Diagnosed Juvenile Myelomonocytic Leukemia
Condition: Juvenile Myelomonocytic Leukemia211.RecruitingStem Cell Transplant for Juvenile Myelomonocytic Leukemia (JMML)
Condition: Juvenile Myelomonocytic Leukemia212.RecruitingLower-Dose Chemotherapy and Stem Cell Transplantation to Treat Childhood Leukemias and Lymphomas
Conditions: Hodgkin Lymphoma; Lymphocytic Leukemia; Mixed Cell Leukemia; Myelodysplastic Syndrome; Non Hodgkin's Lymphoma213.RecruitingImatinib Mesylate to Treat Myeloproliferative Hypereosinophilic Syndrome
Condition: Hypereosinophilic Syndrome214.RecruitingDecitabine and Valproic Acid in Treating Patients With Refractory or Relapsed Acute Myeloid Leukemia or Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Conditions: Adult Acute Myeloid Leukemia; Refractory Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma215.RecruitingMegadose CD34 Selected Progenitor Cells for Transplantation in Patients With Advanced Hematological Malignant Diseases
Conditions: Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Myelodysplastic Syndrome; Chronic Lymphocytic Leukemia; Non Hodgkin's Lymphoma216.RecruitingStudy of Immune Response Modifier in the Treatment of Hematologic Malignancies
Conditions: Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Non-Hodgkin's Lymphoma; Hodgkin's Lymphoma; Multiple Myeloma; Chronic Lymphocytic Leukemia217.RecruitingAnalysis of Genetic Factors Related to Predisposition and Prognosis of Hematological Malignancies in Israel
Conditions: Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia218.Recruiting17-N-Allylamino-17-Demethoxygeldanamycin and Bortezomib in Treating Patients With Relapsed or Refractory Hematologic Cancer
Conditions: Adult Acute Erythroid Leukemia; Adult Acute Monoblastic and Acute Monocytic Leukemia; Leukemia; Lymphoma; Small Intestine Cancer219.RecruitingPhase II Trial of Prophylactic Rituximab Therapy for Prevention of CGVHD
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Five years after approval, Gleevec underscores the promise of targeted therapy to provide sustained disease control

2006-05-12T02:31:00.000-04:00

EDIA RELEASE

Five years after approval, Gleevec underscores the promise of targeted

therapy to provide sustained disease control

• Unprecedented outcomes in Ph+ chronic myeloid leukemia (CML) patients validate

the targeting of a specific cancer cause to create effective and well-tolerated therapies

• First to show reduced annual progression rate with long-term use in newly diagnosed

CML patients – less than 1% progress to more advanced stages of disease in fourth

treatment year

• New data from the largest CML study ever conducted with Gleevec to be presented at

ASCO

• Nearly 15,500 patients in more than 80 countries have received Gleevec through

patient assistance program

East Hanover, May 10, 2006 – Marking an important milestone since its first approval in

May 2001, Gleevec® (imatinib mesylate) tablets,∗ has become the first oncology drug to be

validated as an effective and generally well-tolerated medicine that targets a specific cause of

a cancer.

Gleevec was first approved in May 2001 by the US Food and Drug Administration (FDA) in

an unprecedented 11 weeks – the fastest FDA review period of any cancer drug at that time –

as a treatment for patients with advanced stage Philadelphia chromosome-positive (Ph+)

chronic myeloid leukemia (CML).

Recent data marking 4.5 years of use showed that more than 90% of patients taking Gleevec

continued to survive and were free from progressing to advanced disease. A five-year update

from the IRIS study (International Randomized Interferon versus STI571), the largest clinical

trial to date for newly diagnosed adult patients with Ph+ CML, will be presented at the

American Society of Clinical Oncology meeting on June 3.

Before Gleevec was available, about 50% of patients progressed to the more advanced stages

of Ph+ CML after only three to five years, and survival was generally short for those patients.

Traditional, less-targeted treatments were associated with significant toxicities that often

limited the ability of patients to stay on therapy long-term.

“Gleevec has an unprecedented record of efficacy and safety for the treatment of patients

suffering from chronic myeloid leukemia, allowing many to resume their daily lives” said Dr.

Daniel Vasella, Chairman and CEO of Novartis. “After more than a decade of research and

clinical development as well as over 200,000 patient years of clinical treatment, we are

moving forward with confidence in the principles of rational drug design pioneered with

∗ Known as Glivec® (imatinib) outside the U.S.

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Gleevec. The success of Gleevec gives us confidence in the search for novel medicines that

offer improved treatment outcomes.”

No other drug for this disease has ever established such a proven and durable track record of

efficacy and safety. Interim 54-month data from the IRIS study showed that approximately

93% of newly diagnosed patients with Ph+ CML treated with Gleevec had not progressed to

the more advanced and terminal stages.

“What Gleevec tells us is that a precise understanding of what drives the growth of a

particular cancer allows us to target those abnormalities specifically and develop an effective,

durable and well-tolerated treatment,” said Brian Druker, MD, JELD-WEN Chair of

Leukemia Research at the Oregon Health and Science University Cancer Institute, Howard

Hughes Medical Investigator and lead investigator of the key Gleevec clinical trials. “After

five years, we know with certainty that going after the root cause of a cancer, and shutting it

down, not only makes sense – it works.”

Gleevec is the first targeted therapy for patients with Ph+ CML since it has been proven to

inhibit Bcr-Abl, the definitive cause of the disease. Following the rapid US approval on May

10, 2001, Gleevec was approved later that year in the European Union and subsequently in

other countries worldwide. Gleevec has also been approved in the meantime for all phases of

Ph+ CML.

After initial approval, Novartis led the industry in creating the Gleevec International Patient

Assistance Program (GIPAP). Nearly 15,500 patients in more than 80 countries have received

Gleevec under GIPAP and in the United States under the US Patient Assistance Program.

These programs provide Gleevec, in accordance with the drug’s specific approved use in

countries, at no cost to qualified patients who are properly diagnosed, not insured, not

reimbursed and have no other financial resources.

Novartis has continued to investigate Gleevec for use in treating patients with other types of

cancer. In 2002, Gleevec was approved worldwide for the treatment of patients with

unresectable and/or metastatic Kit (CD117)-positive gastrointestinal stromal tumors (GISTs).

In 2005, Gleevec was also submitted in the US and EU as a treatment for the solid tumor

dermatofibrosarcoma protuberans and certain forms of myeloproliferative disorders as well

as for the treatment of adult patients with Ph+ acute lymphoblastic leukemia (ALL). This

year, Novartis submitted additional applications for the use of Gleevec in treating two rare

hematologic malignancies: hypereosinophilic syndrome and systemic mastocytosis. All five of

these diseases are considered rare but may be life threatening and often have no approved

treatments.

About Gleevec Tablets

Gleevec (imatinib mesylate) tablets are indicated for the treatment of newly diagnosed adult

patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in

chronic phase. Follow-up is limited. Gleevec tablets are also indicated for the treatment of

patients with Ph+ CML in blast crisis, in accelerated phase, or in chronic phase after failure

of interferon-alpha (IFN-α) therapy. Gleevec tablets are also indicated for the treatment of

pediatric patients with Ph+ chronic phase CML whose disease has recurred after stem cell

transplant or who are resistant to IFN-α therapy. There are no controlled trials in pediatric

patients demonstrating a clinical benefit, such as improvement in disease-related symptoms

or increased survival. Gleevec tablets are also indicated for the treatment of patients with KIT

(CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

The effectiveness of Gleevec is based on objective response rate. There are no controlled trials

demonstrating a clinical benefit, such as improvement in disease-related symptoms or

increased survival.

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Important Safety Information*

Severe (NCI Grades 3/4) neutropenia (3%–48%), anemia (<1%–42%), thrombocytopenia

(<1%–33%), hemorrhage (1%–19%), fluid retention (eg, pleural effusion, pulmonary edema,

and ascites <1%–8%) and superficial edema (1%–6%), musculoskeletal pain (1%–9%), and

hepatotoxicity (3%–8%) were reported among Gleevec® recipients. Patients should be

weighed and monitored regularly for signs and symptoms of edema, which can be serious or

life-threatening. There have also been reports, including fatalities, of cardiac tamponade,

cerebral edema, increased intracranial pressure, papilledema, and gastrointestinal

perforation.

Bullous dermatologic reactions (eg, erythema multiforme and Stevens-Johnson syndrome)

have also been reported. In some cases, the reaction recurred upon rechallenge. Several

foreign postmarketing cases note a resolution or improvement of bullous reaction following

dose reduction with or without supportive care.

Dose adjustments may be necessary due to hepatotoxicity, other nonhematologic adverse

events, or hematologic adverse events. Therapy with Gleevec was discontinued for adverse

events in 3% to 5% of patients.

Patients with severe hepatic impairment should be treated at a starting dose of 300mg/day

and should be closely monitored.

Gleevec is metabolized by the CYP3A4 isoenzyme and is an inhibitor of CYP3A4, CYP2D6,

and CYP2C9. Dosage of Gleevec tablets should increase by at least 50% and clinical

response should be carefully monitored in patients receiving Gleevec tablets with a potent

CYP3A4 inducer such as rifampin or phenytoin. Examples of commonly used drugs that may

significantly interact with Gleevec include acetaminophen, warfarin, erythromycin, and

phenytoin. Please see enclosed full prescribing information for other potential drug

interactions.

For daily dosing of 800mg and above, dosing should be accomplished using the 400mg

tablets to reduce exposure to iron.

Use of Gleevec tablets is contraindicated in patients with hypersensitivity to imatinib or to

any other component of Gleevec tablets.

Women of childbearing potential should be advised to avoid becoming pregnant while taking

Gleevec tablets.

Because of the potential for serious adverse reactions in nursing infants, women should be

advised to avoid breast-feeding while taking Gleevec tablets.

* Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis

Pharmaceuticals Corporation; 2005.

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Common Side Effects of Gleevec Tablets*

The majority of the approximately 1700 adult patients who received Gleevec in clinical

studies experienced adverse events at some time, but most were mild to moderate in severity.

The most frequently reported adverse events were superficial edema (58%–81%), nausea

(47%–74%), diarrhea (39%–70%), muscle cramps (28%–62%), vomiting (21%–58%), rash

(36%–53%), fatigue (30%–53%), musculoskeletal pain (30%–49%), and abdominal pain

(30%–40%)**

Supportive care may help management of most mild-to-moderate adverse events so that

prescribed dose can be maintained whenever possible.

Gleevec tablets should be taken with food and a large glass of water to minimize

gastrointestinal (GI) irritation. Gleevec tablets should not be taken with grapefruit juice.

The foregoing release contains forward-looking statements that can be identified by

terminology such as “unprecedented outcomes”, “promise”, “durable”, “long-term use”,

“survival” or similar expressions, or by express or implied discussions regarding potential

new indications for Gleevec or potential future sales of Gleevec, or regarding the long-term

impact of a patient's use of Gleevec. Such forward-looking statements involve known and

unknown risks, uncertainties and other factors that may cause actual results with Gleevec to

be materially different from any future results, performance or achievements expressed or

implied by such statements. There can be no guarantee that Gleevec will be approved for any

additional indications in any market. Nor can there be any guarantee regarding potential

future sales of Gleevec. Neither can there be any guarantee regarding the long-term impact of

a patient's use of Gleevec. In particular, management's expectations regarding

commercialization of Gleevec could be affected by, among other things, additional analysis of

Gleevec clinical data; new clinical data; unexpected clinical trial results; unexpected

regulatory actions or delays or government regulation generally; the company's ability to

obtain or maintain patent or other proprietary intellectual property protection; competition

in general; government, industry, and general public pricing pressures; and other risks and

factors referred to in the Company's current Form 20-F on file with the US Securities and

Exchange Commission. Should one or more of these risks or uncertainties materialize, or

should underlying assumptions prove incorrect, actual results may vary materially from those

anticipated, believed, estimated or expected. Novartis is providing this information as of this

date and does not undertake any obligation to update any forward-looking statements

contained in this document as a result of new information, future events or otherwise.

About Novartis

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets

leading innovative prescription drugs used to treat a number of diseases and conditions,

including central nervous system disorders, organ transplantation, cardiovascular diseases,

dermatological diseases, respiratory disorders, cancer and arthritis. The company's mission is

to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate

of Novartis AG (NYSE: NVS) – a world leader in pharmaceuticals and consumer health. In

2005, the Group's businesses achieved sales of USD 32.2 billion and pro forma net income of

* Gleevec® (imatinib mesylate) tablets prescribing information. East Hanover, NJ: Novartis

Pharmaceuticals Corporation; 2005.

**Numbers indicate the range of percentages in 5 studies among adult patients with Phpositive

CML and KIT-positive GIST. For more detailed study information, please see the full

prescribing information for Gleevec.

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USD 6.1 billion. The Group invested approximately USD 4.8 billion in R&D. Headquartered

in Basel, Switzerland, Novartis Group companies employ approximately 91,000 people and

operate in over 140 countries around the world. For further information please consult

http://www.novartis.com.

# # #

Contacts

John Gilardi

Novartis Global Media Relations

Tel +41 61 324 3018

Mobile +41 79 596 1408

John.Gilardi@novartis.com

Geoff Cook

Novartis Oncology

Tel +1 862 778 2675 (direct)

Geoffrey.Cook@novartis.com

A Painless Donation, an Enduring Lifeline

2006-05-03T14:56:00.000-04:00

By JANE E. BRODY

Martin Mark, 33, who came to the United States from Uganda 11 years ago to get an education, is now working on a master's degree in computer systems and international business at New Mexico State University. He is also battling a disease, chronic myelogenous leukemia. Though it is now controlled by drugs, the only possible cure is a transplant of cells that would enable bone marrow to form new blood cells.

But the chances that a black person from Africa can find a suitable match for his tissue type are, as he put it, "quite slim," especially in this country, where only 23 percent of those who have signed up as volunteer donors represent minority groups.

But even Caucasians can sometimes have a hard time finding a well-matched donor of these life-giving cells. Ten years ago Stephen Sprague of New York had the same disease as Mr. Mark but at a time when there were no drugs to keep him going.

He had no relative who could help, and there was no match for him among the millions of potential donors in the National Marrow Donor Registry. On the verge of death, he was saved by a transplant of umbilical cord cells from a newborn girl, whose cell type proved to be a perfect match for him.

An Emerging Procedure

"Somewhere on the streets of New York there's an 8-year-old girl who has absolutely no idea what she's done for me," said Mr. Sprague, 58, all of whose blood cells are now female. Mr. Sprague, who works for the New York Blood Center's National Cord Blood Program, expects a bright future for cord blood transplants even though so many logistical and technical obstacles remain before it can be widely used.

Most people, and even many doctors, are unaware of the tremendous strides that have been made in the field of bone marrow transplants. They also don't realize that today it can be much easier to be a donor. No longer is it necessary to be anesthetized and have bone marrow extracted from your hips. Now blood stem cells can be removed from your blood with minimal risk to the donor. And when mothers-to-be choose to donate umbilical cord blood at a hospital equipped to process it, there is no risk at all to the donor.

Dr. Jason Aaron Sokol, then a medical intern, had no idea when he chose his profession that the first time he would try to save a life would have nothing to do with his medical training. Dr. Sokol signed up to be a marrow donor at his synagogue in New York. Nine months later he was told he was a match for a young man dying of leukemia.

Given a choice between donating marrow or peripheral blood stem cells, Dr. Sokol chose the latter. For five days he took a drug, Neupogen, that stimulates the formation of new blood cells, pushing millions of stem cells into his bloodstream. Then he sat for about six hours hooked up to a machine that extracted the stem cells from his blood and returned all the rest of his blood to his body.

Although the recipient of his cells died within a year, the transplant gave the man nine good months and, Dr. Sokol said without hesitation, he'd donate his cells again if asked.

When I signed up to be a bone marrow donor in the late 1980's, there was only one way to donate. Under anesthesia in a hospital, a large needle would be inserted into both hip bones to extract about a quart of marrow, which the body replaces. Anesthesia presents the greatest risk, followed by possible infection and unavoidable soreness at the extraction sites, as if you'd fallen hard on the ice.

Still, having witnessed a child I loved die of leukemia, I thought it was a small price to pay for the reward of possibly saving someone's life.

I am now an emeritus donor; over 60, I'm considered too old to donate to a nonrelative. But I'm not too old to call for more volunteers, especially those from minority ethnic and racial groups who are vastly underrepresented as potential donors.

Of more than six million donor volunteers in the National Registry, 1.4 million are now from ethnic groups: more than 465,000 blacks, nearly 400,000 Hispanics, 398,000 Asians and more than 73,000 American Indians. But the chances can be one in a million of finding a good patient-donor match.

Each year some 35,000 children and adults with life-threatening illnesses could benefit from marrow, stem cell or cord blood transplants. Many receive transplants from related donors, some are considered unsuitable for transplants and others die waiting for a transplant.

Today a majority of marrow transplants involve peripheral blood stem cells. Last year the national registry helped bring about transplants from unrelated donors to more than 2,800 recipients: 1,700 peripheral blood stem cells, 821 bone marrow and 324 cord blood transplants.

Matching donor and recipient is especially crucial when doctors transplant cells that produce blood cells because among them are cells that attack foreign invaders. If the match is less than perfect, the donated cells can attack the recipient as foreign — a problem called graft-versus-host, or G.V.H., disease. The closer the match, the less problem with G.V.H.

Finding the Right Match

Matching is done by analyzing the tissue types, or H.L.A. (for human leukocyte antigen) profiles, of donor and recipient. When you sign up to be a potential donor, your profile type is determined from a two-tablespoon sample of your blood. The result is filed in the donor registry. If someone in need of marrow very closely matches your type, the registry will contact you to determine if you are still willing and medically fit to be a donor.

With donations of both bone marrow and peripheral blood stem cells, very close matching is crucial. But with cord blood transplants, less than perfect matches seem to do very well, making it more likely that a patient will find a donor. "The big advantage of cord blood is you don't have to find a person who agrees to donate," Mr. Sprague noted. "The cells are frozen and ready to go."

A major stumbling block is that, while cord blood is often adequate to treat a child, too few cells are derived from an umbilical cord to help an adult. Scientists are experimenting with ways to enrich cord blood samples so that they can be used in adults. One of those methods helped Mr. Sprague. Another approach is to use two well-matched cord blood samples for one patient.

A second problem: too few hospitals are equipped to process cord blood.

Still, Mr. Sprague urges mothers-to-be to look into the possibility of donating her baby's cord blood. Others interested in becoming donors can contact the donor program at 1-800-627-7692 or marrow.org.

The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines.

2006-04-26T23:29:00.000-04:00

Timeus F, Crescenzio N, Ricotti E, Doria A, Bertin D, Saglio G, Tovo PA

Haematologica. 2006 Apr 3;

We evaluated the effect of the human immunodeficiency virus (HIV) protease inhibitor saquinavir on the imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia cell lines. Saquinavir, which is also a proteasome blocker, showed dose- and time-related anti-proliferative activity, particularly on the imatinib-resistant lines and a pro-apoptotic effect. Association with imatinib caused a significant increase of activity.

The effects of saquinavir on imatinib-resistant chronic myelogenous leukemia cell lines.

BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia.

2006-04-26T23:28:00.000-04:00

Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, Rousselot P, Tamouza R, Le Bouteiller P, Mahon FX, Steinle A, Charron D, Dombret H, Toubert A

J Immunol. 2006 Apr 15; 176(8): 5108-16

MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34+ cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL+ cell line K562, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels, but decreased MICA protein production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.

BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia.

Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples.

2006-04-26T23:20:00.000-04:00

Stock W, Yu D, Karrison T, Sher D, Stone RM, Larson RA, Bloomfield CD

Int J Oncol. 2006 May ; 28(5): 1099-103

Molecular monitoring of the BCR-ABL transcript in chronic myelogenous leukemia (CML) using quantitative RT-PCR provides clinicians with important diagnostic and prognostic information. To determine whether molecular detection and monitoring of CML is comparable using peripheral blood (PB) and bone marrow (BM) aspirate samples, we performed a prospective study using quantitative real-time RT-PCR (QRT-PCR) of paired PB and BM samples from 41 patients with CML entered onto a single Cancer and Leukemia Group B (CALGB) treatment study. QRT-PCR analysis of PB and BM samples was performed prior to initiation of, and during, treatment with homoharringtonine and cytarabine on a CALGB study for previously untreated CML. Statistical analyses demonstrated good agreement of PB and BM pre-treatment samples. However, using the Bland-Altman statistical method that measures true agreement between PB and BM values, we found that there was only modest agreement of BCR-ABL measurements in PB and BM for samples obtained during treatment. PB values obtained during treatment tended to be lower than the corresponding BM values [average difference = -0.37 (p<0.001) in 36 paired samples] and the 95% limits of agreement ranged from -1.23 to 0.48. Nevertheless, our study demonstrates that BM and PB QRT-PCR values followed a similar trend during treatment (Spearman correlation coefficient, 0.83; 95% CI, 0.70, 0.96). Our data suggest that, quantitatively, PB and BM measurements of BCR-ABL are frequently disparate. Since BM values tended to be higher than PB values, BM sampling provides the most accurate assessment of minimal residual disease (MRD). Based on these results, we caution against interchanging BM with PB sampling for MRD monitoring during treatment of CML since this may lead to misinterpretation of treatment results.

Quantitative real-time RT-PCR monitoring of BCR-ABL in chronic myelogenous leukemia shows lack of agreement in blood and bone marrow samples.

Generation of the BCR/ABL fusion gene in a Philadelphia chromosome-negative chronic myeloid leukaemia: insertion of 5.6 Mb of 9q34 into the BCR region

2006-04-26T23:19:00.001-04:00

Valle L, Fernández V, Pérez-Pons C, Sánchez FG, Benítez J, Urioste M

Hematol Oncol. 2006 Apr 6;

This report describes a chronic myelogenous leukaemia patient with an apparently normal bone marrow karyotype but BCR/ABL fusion-gene-positive. Commercial FISH probes showed an atypical pattern and the BCR/ABL fusion transcript was detected by RT-PCR, but not the reciprocal ABL/BCR. Consecutive FISH assays clarified the mechanism of the masked Ph. The ABL gene and the following 5.6-5.7 Mb of 9q are inserted into the BCR region of chromosome 22. There is no transference of 22q material to chromosome 9 or to any other chromosomes. Clinical features and evolution of the patient are similar to those cases with classic Ph chromosome. Copyright (c) 2006 John Wiley & Sons, Ltd.

Generation of the BCR/ABL fusion gene in a Philadelphia chromosome-negative chronic myeloid leukaemia: insertion of 5.6 Mb of 9q34 into the BCR region of chromosome 22.

Durable molecular complete remission induced by low-dose imatinib plus low-dose interferon alpha in a patient with chronic myelogenous leukaemia.

2006-04-26T23:19:00.000-04:00

Takeuchi J, Miura K, Hatta Y, Sawada U

J Int Med Res. 2006 Jan-Feb ; 34(1): 103-8

A 50-year-old male was diagnosed with chronic myelogenous leukaemia (CML) in chronic phase in March 2000. He was treated initially with hydroxyurea, administered orally. This was changed to interferon alpha (IFN) 5 million units (5 MIU) subcutaneously daily in May 2000; complete cytogenetic response was achieved 11 months later. IFN dosage was reduced to 5 MIU, alternate days, in June 2001 and a cytogenetic relapse occurred 3 months later. Since April 2002, he has received IFN 5 MIU three times weekly in combination with imatinib 200 mg/day. The Philadelphia chromosome disappeared from his peripheral blood cells in July 2002 and a complete molecular response was achieved in January 2003. Serial molecular studies between January 2004 and January 2005 showed no detectable major BCR/ABL chimeric transcript. Grade 2 neutropenia and grade 1 non-haematological adverse effects have been observed. This case report suggests the combination of low-dose imatinib and IFN would be tolerable and effective for CML patients in chronic phase.
Durable molecular complete remission induced by low-dose imatinib plus low-dose interferon alpha in a patient with chronic myelogenous leukaemia.

Blastic phase of chronic myelogenous leukemia.

2006-04-26T23:18:00.000-04:00

Karbasian Esfahani M, Morris EL, Dutcher JP, Wiernik PH

Curr Treat Options Oncol. 2006 May ; 7(3): 189-99

Chronic myelogenous leukemia (CML), also known as chronic myelocytic or chronic myeloid leukemia, is a clonal disorder of hematopoiesis that arises in a hematopoietic stem cell or early progenitor cell. This is characterized by the dysregulated production of mature nonlymphoid cells with normal differentiation. Eventually, in spite of the term chronic, there is progression to acute leukemia, usually of the myeloid variety, which is highly resistant to current therapies. Despite recent improvements in the treatment of early-stage disease, CML blast crisis (CMLBC) remains a therapeutic challenge. CMLBC is highly refractory to standard induction chemotherapy, with a response rate in myeloid blast crisis of less than 30%. Conventional chemotherapy has been much less successful in this disease compared with de novo acute leukemia, with a mean survival after diagnosis of blast crisis of only 2 to 4 months for nonresponders. Many regimens of chemotherapies have been tried in CMLBC, with minor success. Although imatinib was evaluated in patients with CMLBC, most CMLBC cases today arise in patients already on imatinib-based therapy and developing blastic phase on that therapy; thus there is no standard therapy for patients with CMLBC. Further studies of the mechanisms of transformation of chronic-phase CMLBC at a molecular level, and methods to target these molecular abnormalities, will determine the future direction of new treatment modalities. The prognosis of CML in blast crisis remains disappointing, despite great efforts. Currently, the most successful strategy for improving survival in CML is by prolonging the chronic phase and delaying the onset of blast crisis.

Blastic phase of chronic myelogenous leukemia.

Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

2006-04-26T23:17:00.001-04:00

Lee YK, Kim YR, Min HC, Oh BR, Kim TY, Kim YS, Cho HI, Kim HC, Lee YS, Lee DS

Cancer Genet Cytogenet. 2006 Apr ; 166(1): 65-73

To evaluate the prognostic significance of submicroscopic deletions of the ABL or BCR gene associated with t(9;22) in chronic myelogenous leukemia (CML), we investigated the incidence of an ABL or BCR deletion on derivative chromosome 9 using fluorescence in situ hybridization (FISH). FISH was performed using the LSI BCR/ABL dual-fusion translocation probe on bone marrow cells of 86 patients with CML. Of 86 patients, ABL deletion was detected in 13 (15.1%) patients and BCR deletion in 8 patients (9.3%). Patients with ABL deletion showed shorter event-free survival time (EFS) than those without ABL deletion (P = 0.020). Patients with BCR deletion showed significantly short overall survival time (OS; P = 0.039). Patients with ABL and/or BCR deletion (14/86 patients, 16.3%) showed significantly short OS and EFS (median OS, 43.0 months; median EFS, 40.0 months), compared to the patients without any BCR or ABL gene deletions (median OS, 94.0 months; median EFS, 90.0 months; P = 0.041 for OS, P = 0.008 for EFS). All the patients with BCR deletion, except for one, had a concomitant ABL deletion, suggesting that BCR deletion occurs in conjunction with ABL deletion. In patients with ABL deletion only, BCR/ABL rearrangement with b2a2 mRNA type tended to be more frequent than in patients without any deletion of the two genes (P = 0.073). Deletion of any of the BCR or ABL genes on derivative chromosome 9 was associated with both short OS and EFS. We conclude that deletion of not only the ABL gene, but also of the BCR gene, is a poor prognostic marker that indicates rapid disease progression in CML.
Deletion of any part of the BCR or ABL gene on the derivative chromosome 9 is a poor prognostic marker in chronic myelogenous leukemia.

A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem

2006-04-26T23:17:00.000-04:00

Weisser M, Tischer J, Schnittger S, Schoch C, Ledderose G, Kolb HJ

Haematologica. 2006 Apr 19;

Imatinib mesylate is highly effective in relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoetic stem cell transplantation (HSCT). However, it is unknown whether imatinib produces durable molecular remissions. The outcome of CML patients transplanted at our center who had received only imatinib for relapse after HSCT was compared with that of patients treated with donor lymphocyte infusions (DLI). Imatinib therapy resulted in a higher incidence of relapse and inferior leukemiafree survival (p=0.006 and p=0.016, respectively). These data suggest that imatinib alone probably does not cure relapse after HSCT.

A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation.

Survival advantage from Imatinib compared to the combination Interferon-{alpha} plus Cytarabine in chronic phase CML: historical comparison between tw

2006-04-26T23:16:00.000-04:00

Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA, O'brien SG, So C, Massimini G, Guilhot F

Blood. 2006 Apr 20;

In the multinational IRIS study comparing imatinib to interferon plus cytarabine (IFN/AraC) in patients with newly diagnosed chronic-phase chronic myelogenous leukaemia (CP CML), imatinib demonstrated significantly higher rates of complete cytogenetic responses (CCyR) and improved progression free survival (PFS). However, because of a high early cross over rate to imatinib, survival benefit was not assessable. Here we report the result of a study comparing long term outcome of patients included in two prospective randomized trials: 551 patients assigned to imatinib in the IRIS trial from 2000 to 2001 and 325 patients who received the combination IFN/AraC in the CML91 trial between 1991 and 1996 before imatinib was available. With a follow-up of 42 months for both groups of patients, estimated CCyR, survival free of transformation and overall survival were significantly higher with imatinib compared with IFN/AraC (P < .0001, P = .004, and P < .0001 respectively). Improved overall survival was also confirmed within different Sokal prognostic risk groups. Interestingly, among all patients who achieved major cytogenetic response or CCyR at 12 months, the survival rate was similar irrespective of their treatment. In conclusion, within the limitation of this historical comparison, there is a survival advantage from first line therapy with imatinib over IFN/AraC.

Survival advantage from Imatinib compared to the combination Interferon-{alpha} plus Cytarabine in chronic phase CML: historical comparison between two phase III trials.

A novel MHC-associated Proteinase 3 peptide isolated from primary chronic myeloid leukaemia cells further supports the significance of this antigen fo

2006-04-26T23:15:00.000-04:00

Knights AJ, Weinzierl AO, Flad T, Guinn BA, Mueller L, Mufti GJ, Stevanovic S, Pawelec G

Leukemia. 2006 Apr 20;

Three of the most promising antigens for immunotherapy of chronic myelogenous leukaemia (CML) include the specific fusion-protein, Bcr/Abl, and the overexpressed proteins WT1 and Proteinase 3. The clinical significance of Proteinase 3 as a target in myelogenous leukaemias has been bolstered by detection of high frequencies of cytotoxic CD8+ lymphocytes specific for this antigen in patients undergoing immune therapies. Our investigation aimed to directly identify MHC-ligands derived from these antigens and presented on CML blasts by means of affinity-purification and mass spectrometric peptide-sequencing. Although no known or potential new epitopes were discovered for Bcr/Abl or WT1, a novel peptide from Proteinase 3 was detected among the more abundant MHC-ligands. Additionally, MHC-ligands derived from known immunogenic proteins overexpressed as a result of Bcr/Abl transformation were also identified. Our investigation is the second of only a small number of studies to identify a peptide from Proteinase 3 among the more abundant MHC-associated peptides and thus implies that peptides from this antigen are among the more abundantly presented of the known leukaemic antigens. Taken in conjunction with clinical observations of functional Proteinase 3 specific CTL in patients', these data further support the application of this antigen as an immunotherapeutical target for myelogenous leukaemias.Leukemia advance online publication, 20 April 2006; doi:10.1038/sj.leu.2404234.

A novel MHC-associated Proteinase 3 peptide isolated from primary chronic myeloid leukaemia cells further supports the significance of this antigen for the immunotherapy of myeloid leukaemias.

St. Jude unlocks mystery of very aggressive leukemia

2006-04-19T19:43:00.000-04:00

Contact: Kelly Perry
media@stjude.org
901-495-3306
St. Jude Children's Research Hospital

St. Jude unlocks mystery of very aggressive leukemia

Investigators at St. Jude Children's Research Hospital have used mouse models to determine why some forms of acute lymphoblastic leukemia (ALL) are extremely aggressive and resist a drug that is effective in treating a different type of leukemia.

The investigators found that the combination of a mutation called Bcr-Abl and the loss of both copies of the tumor suppressor gene Arf in bone marrow cells triggers an aggressive form of ALL. Inactivation of both Arf genes facilitated the multiplication of leukemic cells that did not respond to the drug imatinib (Gleevec�). Imatinib is already successfully used to treat chronic myelogenous leukemia (CML), another blood cell cancer caused by the Bcr-Abl mutation.

The St. Jude study provided evidence that imatinib resistance in mouse models of ALL did not depend strictly on the presence of Bcr-Abl and the loss of Arf genes in the cancer cells themselves. Rather, drug resistance reflected an interaction of the tumor cells with specific growth-promoting factors produced in the mice. After removal of leukemic cells from mice that had failed imatinib therapy, compounds inhibiting enzymes called JAK kinases restored the cells' imatinib sensitivity.

The study's findings suggest why imatinib may fail to cause remission of ALL in patients with the Bcr-Abl mutation and point to a strategy for overcoming this resistance. A report on this work appears in the April 17 issue of Proceedings of the National Academy of Sciences.

The Bcr-Abl oncogene (a cancer-causing gene) is formed when parts of two chromosomes switch places, leading to fusion of a fragment of the Bcr gene from one chromosome to a portion of the Abl gene from the other. Bcr-Abl encodes a type of enzyme called a tyrosine kinase, which then drives the abnormal, uncontrolled multiplication of leukemic cells.

Other researchers had previously shown that inhibiting the Bcr-Abl kinase with imatinib causes durable remissions of cancer with minimal side effects in patients with CML--a finding that has revolutionized the treatment of this form of leukemia. However, imatinib has proven far less effective in treating ALL patients with the Bcr-Abl mutation, and the basis of drug resistance in this disease is unknown.

The Arf gene normally suppresses the proliferation of cells carrying cancer-causing mutations such as Bcr-Abl, according to Charles J. Sherr, M.D., Ph.D., a Howard Hughes Medical Institute investigator and co-chair of the St. Jude Department of Genetics and Tumor Cell Biology. Arf acts as a safeguard against the cancer-causing effects of Bcr-Abl, Sherr said. Sherr is senior author of the paper. The Arf gene was discovered at St. Jude in 1995 in the laboratory of Sherr and Martine F. Roussel, Ph.D., a member of the Department of Genetics and Tumor Cell Biology. Roussel is also an author of the current paper.

The St. Jude team found that Arf is not inactivated in CML patients who respond to imatinib. This is in contrast to ALL, in which Arf loss frequently occurs and imatinib treatment is far less effective. "This suggested to us that inactivation of Arf in ALL cells expressing the Bcr-Abl enzyme gives these cells a strong proliferative (cell multiplication) advantage," Sherr said. "And this advantage might contribute to imatinib resistance in some way."

To investigate this hypothesis, the researchers used a virus-like piece of DNA to carry the Bcr-Abl oncogene into bone marrow-derived lymphocytes obtained from mice that either retained Arf or were previously engineered to lack this gene. These pre-B lymphocytes represent one type of white blood cell that can become cancerous and cause ALL.

The researchers then transplanted these "transformed" cells carrying Bcr-Abl back into normal mice. Animals that received transformed pre-B cells that had both copies of the Arf gene intact were highly resistant to disease development. However, mice injected with cells that carried Bcr-Abl and lacked Arf rapidly developed an aggressive form of ALL that could not be cured with high doses of imatinib.

"Intriguingly, tumor cells removed from these resistant mice and treated with imatinib in cell cultures were still very sensitive to this drug," noted Richard T. Williams, M.D., Ph.D., a fellow in Sherr's laboratory and the paper's lead author. "This suggested to us that the failure of imatinib to cure the mice depended on some substance in the animal that stimulated tumor cell replication or survival."

Sherr's team guessed that one such factor might be the B lymphocyte stimulating protein IL-7. Normally produced in the bone marrow, IL-7 further enhanced the proliferation of cultured leukemic cells removed from the mice and made the cells resistant to imatinib's growth inhibitory effects.

IL-7 binds to receptors on the surface of lymphocytes, which triggers the activity of the JAK kinases. The activated JAK kinases then stimulate cell growth through a signaling pathway that operates alongside the one controlled by the Bcr-Abl kinase, Sherr said. Therefore, the St. Jude investigators used a chemical inhibitor of JAK kinases to block the effect of IL-7 on leukemic cells in culture. This treatment restored the ALL cells' sensitivity to imatinib.

"Our study of mice with ALL containing both Bcr-Abl and Arf mutations has provided unexpected insights into how factors in the mice--and potentially in humans--might contribute to imatinib resistance," Williams said. "Although our efforts to block IL-7 were limited to cell cultures, our mouse model provides an inexpensive and efficient way to test newly developed JAK kinase inhibitors and other drugs."

###

This work was supported in part by the Howard Hughes Medical Institute, a National Institutes of Health Cancer Center Core Grant and ALSAC.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.

St. Jude unlocks mystery of very aggressive leukemia

A Broken Stress Response System Can Contribute to Gleevec Resistance

2006-04-19T12:21:00.000-04:00

New clues to why some kinds of leukemia are more aggressive and deadly than others are coming from research examining the types of genetic damage that allow some blood cells to grow out of control, scientists report.

According to Charles J. Sherr, a Howard Hughes Medical Institute researcher at the St. Jude Children's Research Hospital in Memphis, Tennessee, his team's new findings may help doctors understand why some cancers can be controlled with drugs, at least temporarily, while others somehow resist treatment.

“The combination of the two [genetic abnormalities] makes the tumors almost 1,000 times more aggressive.”
Charles J. Sherr

Sherr and colleagues Richard T. Williams, the lead author, and Martine F. Roussel reported their research findings on April 17, 2006, in an advance online publication in the Proceedings of the National Academy of Sciences.

The investigators studied two types of leukemia: CML—chronic myelogenous leukemia, which can now be alleviated to a large extent with a drug called Gleevec (imatinib), and a subtype of ALL—acute lymphoblastic leukemia, which does not respond well to this drug. The hallmark of both diseases is a genetic alteration in an enzyme (BCR-ABL) whose activity is specifically blocked by Gleevec treatment. The work reveals that loss of a gene known as Arf, which is frequently mutated in patients with ALL, but not CML, can cause some leukemias to resist Gleevec treatment.

Patients with CML who are taking Gleevec readily go into remission, and their cancer cells stop growing while they are maintained on drug therapy. Sherr explained that Gleevec's impact has been truly revolutionary. “It's a targeted therapy that works; the results have been miraculous.”

Unfortunately, there is still a small relapse rate—about five percent per year—that doctors would like to erase. Other researchers have found that “patients who fail while on therapy have developed subsequent mutations in the BCR-ABL enzyme” that alter Gleevec's effectiveness,” Sherr said.

Further clinical trials are now under way, he said, with drugs that block these mutated forms of BCR-ABL, building upon the benefit that is offered by Gleevec and keeping CML under better control.

CML is caused by a genetic change that scientists call the Philadelphia chromosome. It results when chromosomes 9 and 22 break and reattach themselves to one another. At the point where the chromosomes meet, the joined DNA creates the BCR-ABL gene, which has the unfortunate property of causing abnormal growth of the white blood cells that leads to leukemia.

This misarranged chromosome is also seen in a subset of patients with ALL. Unfortunately, Gleevec is much less effective against this more aggressive form of the disease. Sherr's team is studying why that is true, focusing especially on a way to “re-sensitize” the tumor cells to Gleevec treatments.

Chromosomes are the long, coiled molecules on which genes—life's blueprints—reside. So when chromosomes and genes are disrupted, the damage can lead to diseases, including cancer. Nature has equipped cells with repair systems that recognize genetic damage and try to correct it. But if the damage cannot be fixed, one alternative is to kill the sickened cell by activating a built-in cell suicide system.

Trouble ensues when normal growth-control mechanisms go awry and normal repair and cell suicide mechanisms also fail. Thus cancer cells gain immortality—not dying when they should—and begin growing without restraint to form tumors. In leukemia, the problem is a severe over-supply of one type of white blood cell or another.

In their experiments with mice, Sherr and his colleagues found evidence that a mutation in one of the cell's stress response systems can contribute to tumor growth even in the presence of Gleevec. The mutation disables or erases the function of a gene called Arf, which normally helps suppress the growth of cancer cells. Mutations in the Arf gene are found in the cells of more than 30 percent of patients with ALL, whereas they have not been observed in patients with CML.

The researchers found that when the Arf gene was inactivated, BCR-ABL induced a much more aggressive form of ALL in mice. These mice “do not achieve remission on high doses of oral imatinib (Gleevec), and succumb to leukemia,” Sherr said. In other words, the drug doesn't work and the mice die soon. “The combination of the two [genetic abnormalities] makes the tumors almost 1,000 times more aggressive” in terms of their ability to induce disease, he explained.

Although the biological mechanism that underlies this form of drug resistance isn't well understood, “tumor cells removed from the drug-resistant mice remained sensitive to Gleevec treatment in cell cultures,” Williams said, “so there must be a host signaling system in the mice that makes the cells drug resistant.” The investigators provide proof of principle that additional drugs might reverse this form of drug resistance, thereby restoring Gleevec's power to control this type of leukemia.

HHMI News: A Broken Stress Response System Can Contribute to Gleevec Resistance

Researchers Seek Alternative for Leukemia Patients Resistant to Standard Therapies

2006-04-03T11:11:00.000-04:00

A study led by researchers from the Howard Hughes Medical Institute has found that dasatinib provides significant benefit in chronic myeloid leukemia (CML) patients resistant to Gleevec® (imatinib), according to a study presented today during the 97th Annual Meeting of the American Association for Cancer Research.

In an update of a phase I study initiated in November 2003, researchers looked at the use of dasatinib in imatinib resistant or intolerant patients with CML in late chronic phase (CP), accelerated phase (AP), myeloid blast crisis (MBC), or lymphoid blast crisis (LBC/Ph+ ALL). Data are available for 84 patients (40 CP, 11 AP, 23 MBC, 10 LBC/Ph+ ALL). A blast crisis is the progression of diseases to an acute advanced phase.

Imatinib – which blocks the irregular protein that allows the overproduction of abnormal white blood cells – has become a standard therapy for CML patients not undergoing stem cell transplantation. However, a number of patients have developed resistance to this treatment because their cancer cells are able to mutate and adapt.

The 40 CP patients, with five years median duration of CML, were treated with 15 to 180 mg of dasatinib either once daily (QD) or twice daily (BID) for a median of 13 months. The rate of complete hematologic response (CHR) in CP patients was 93 percent, while major cytogenetic responses (MCyR) were observed in 45 percent and complete cytogenetic response (CCyR) in 35 percent.

In advanced disease, 44 patients have been treated with dasatinib (50 to 240 mg BID) for a median of 37 months. The rate of major hematologic response (MHR) is 81 percent in AP, 61 percent in MBC, and 80 percent in LBC/Ph+ ALL. The overall rates of MCyR and CCyR in advanced disease were 43 percent and 25 percent, respectively. Responses were durable in CP and AP patients, but relapses have occurred in the MBC and LBC/Ph+ ALL groups, often due to dasatinib-resistant BCR-ABL mutations.

CML is usually diagnosed by finding what is called the Philadelphia chromosome (Ph chromosome). The Ph chromosome is the result of a genetic abnormality among portions of chromosomes 9 and 22. In this, part of the BCR (breakpoint cluster region) gene from chromosome 22 is merged with part of the ABL (abelson leukemia virus) gene on chromosome 9. The irregularity takes place in a single bone marrow cell and – through the process of cell division and expansion – results in leukemia, including some cases of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

Imatinib resistance in CML and Ph chromosome positive ALL is frequently associated with BCR-ABL mutations that interfere with the ability of imatinib to stop BCR-ABL overproduction. Dasatinib (BMS-354825), which targets BCR-ABL, is 325-fold stronger than imatinib in cells with normal BCR-ABL genes and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants.

*Abstract No. CP-2: Development of the ABL Kinase Inhibitor, Dasatinib (BMS-354825), in Imatinib-Resistant Philadelphia Chromosome Positive Leukemias

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 60 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 16,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

Newswise | Researchers Seek Alternative for Leukemia Patients Resistant to Standard Therapies

SGX Pharmaceuticals Announces Strategic Collaboration to Develop and Commercialize BCR-ABL Inhibitors for the Treatment of Chronic Myelogenous Leukemi

2006-03-28T01:14:00.000-05:00

 SAN DIEGO, March 27 /PRNewswire-FirstCall/ -- SGX Pharmaceuticals, Inc.
(Nasdaq: SGXP) announced today that it has entered into a license and
collaboration agreement with Novartis focused on the development and
commercialization of BCR-ABL inhibitors for the treatment of drug resistant
Chronic Myelogenous Leukemia (CML).
   Under the terms of the agreement, SGX will receive from Novartis $25
million in upfront payments and the purchase of SGX common stock.  Along with
success-based milestones, but excluding royalties, total payments to SGX could
exceed $515 million, including a minimum of two years of research funding.
   The success of Gleevec(TM) (imatinib), the first targeted therapy in
Philadelphia Positive (Ph+CML) proven to inhibit BCR-ABL, has fundamentally
changed the treatment of Ph+CML.  However, a subset of patients develops
resistance to Gleevec or cannot tolerate therapy.  For these patients there
are currently no other approved treatment options.  Drug candidates from SGX's
lead series, developed from its FAST(TM) proprietary drug discovery platform,
have exhibited activity against wild-type and drug resistant BCR-ABL mutants,
including the most challenging T315I mutant.
   "Novartis is the leader in developing novel targeted therapies to treat
CML," said Mike Grey, president and chief executive officer of SGX
Pharmaceuticals.  "With their extensive experience developing and
commercializing Gleevec as well as development of the novel investigational
compound, nilotinib/AMN107, we believe they are the ideal partner with whom to
develop our series of next-generation BCR-ABL inhibitors.  This is a
tremendous validation of our FAST technology for generation of novel lead
molecules for key therapeutic targets."

   Background on the Agreement
   SGX will be responsible for completing preclinical development of the lead
candidate and submitting an Investigational New Drug application with the Food
and Drug Administration.  SGX will also be responsible for the completion of
an initial phase I clinical study, after which time Novartis will be
responsible for conducting further clinical development and commercialization
of the compound.
   In addition to the upfront and milestone payments, SGX will receive
royalty payments upon successful commercialization of products developed under
the collaboration.  SGX retains an option to co-commercialize, in the U.S.,
oncology products developed under the agreement.  If exercised, the option
would enable SGX to reinforce the commercial presence in the North American
hematology markets which the company plans to establish with the potential
launch of Troxatyl(TM) in the second half of 2007, assuming the successful
completion of the ongoing Phase II/III clinical trial for the treatment of
third-line acute myelogenous leukemia and regulatory approval of Troxatyl for
this initial indication in 2007.

   Background on CML: Prognosis and Treatments
   Chronic myelogenous leukemia is a malignant cancer of the bone marrow
causing rapid and abnormal growth of white blood cells.  According to the
National Institutes of Health, approximately 4,600 new cases of CML are
diagnosed annually, accounting for 7 to 20 percent of leukemia cases.  CML is
associated with a chromosome abnormality called the Philadelphia chromosome.
Since its approval in 2001, Gleevec has become the standard of care for Ph+
CML.  Results from the IRIS study (International Randomized Interferon versus
STI571), the largest clinical trial to date for newly diagnosed adult patients
with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in
chronic phase, show that 90.3 percent of patients who were initially
randomized to take Gleevec were still alive after 54 months.
   The prevalence of CML has increased substantially because Gleevec therapy
makes it possible for patients with CML to live with the disease much longer
than possible with previously used treatments.  Gleevec works directly on
leukemic cells by inhibiting the action of BCR-ABL tyrosine kinase, the enzyme
responsible for uncontrolled growth of leukemic cells.  Despite this clinical
success, resistance to Gleevec has emerged in a subset of patients.  Once
patients lose response to optimized doses of Gleevec, the only currently
approved treatment is bone marrow transplantation preceded by high-dose
chemotherapy and radiation, for which many CML patients are not eligible.
   "We believe that a BCR-ABL inhibitor developed through this collaboration
could have the potential to be used both as a monotherapy in second-line
treatment of refractory or relapsed CML, and in combination with Gleevec or
another agent in first-line treatment of CML," added Dr. Stephen Burley, chief
scientific officer of SGX Pharmaceuticals.

   About FAST(TM) Drug Discovery
   FAST, short for Fragments of Active Structures, is SGX's proprietary
fragment-based drug discovery platform for rapid identification of novel,
potent and selective small molecule inhibitors of drug targets.  FAST
addresses many of the limitations of traditional approaches utilized by large
pharmaceutical companies to find lead compounds, making it an attractive
technology for targets that have not yielded promising leads from
high-throughput screening.
   FAST is based on a proprietary fragment library of approximately 1,000
structurally diverse, low molecular weight compounds.  FAST integrates a
series of technologies, including:

   *  A high-throughput capability to generate many different crystal
      structures of a target protein in parallel;
   *  The evaluation of the library of fragments and direct visualization of
      bound fragments utilizing X-ray crystallography; and
   *  The use of novel computational and structure-based design methods and
      iterative synthetic chemistry to optimize these fragments into drug
      candidates.

   SGX believes these combined technologies generate an efficient platform
for drug discovery that delivers lead compounds active against a wide range of
targets, while accessing high chemical diversity and the potential for good
drug-like properties.

   About SGX Pharmaceuticals
   SGX Pharmaceuticals is a biotechnology company focused on the discovery,
development and commercialization of innovative cancer therapeutics.  The
Company's lead product candidate, Troxatyl(TM), is currently being evaluated
in a pivotal phase II/III trial for the treatment of third-line acute
myelogenous leukemia, an indication for which there is currently no approved
therapy or standard of care.  SGX has developed a pipeline of oncology drug
candidates based on its enabling, proprietary FAST(TM) drug discovery
platform, including a portfolio of next generation BCR-ABL inhibitors.  FAST
allows for the rapid identification of novel, potent and selective small
molecule compounds for well validated but challenging targets.  More
information on SGX's pipeline and drug discovery platform can be found at
http://www.sgxpharma.com .

   SGX Pharmaceuticals Forward-Looking Statements
   Statements in this press release that are not strictly historical in
nature are forward-looking statements.  These statements include but are not
limited to statements related to SGX's research and drug discovery and
development programs and statements regarding the potential value and scope of
the collaboration with Novartis, SGX's receipt of potential research and
milestone payments, royalty payments or profits from sales of products
developed under the collaboration, SGX's co-commercialization options and
commercialization strategies, expectations regarding the timing of initiation
and completion of development, including clinical trials, and product launch
milestones with respect to drug candidates under the collaboration,
expectations with respect to the further development and potential regulatory
approval of Troxatyl, the activity of BCR-ABL inhibitors, the potential of
BCR-ABL-based therapies as treatments for CML alone or in combination with
other treatments, the expansion of treatment options available to patients
with CML, future plans and activities regarding the collaboration and SGX's
BCR-ABL program, the effectiveness and efficiency of SGX's FAST technology to
generate novel lead molecules for key therapeutic targets and SGX's ability to
discover, develop and commercialize cancer therapeutics.  These statements are
only predictions based on current information and expectations and involve a
number of risks and uncertainties.  Actual events or results may differ
materially from those projected in any of such statements due to various
factors, including the risks and uncertainties inherent in drug discovery,
development and commercialization, collaborations with others, and litigation.
In particular, the results of early clinical trials may not be predictive of
future results, and SGX cannot provide any assurances that any of its product
candidates will have favorable results in future clinical trials or receive
regulatory approval.  In addition, SGX's results may be affected by risks that
the required regulatory approvals will be received in a timely manner, or at
all, risks related to the implementation of its collaboration with Novartis,
competition from other biotechnology and pharmaceutical companies, its
effectiveness at managing its financial resources, its ability to successfully
develop and market products, the level of efforts that its collaborative
partners devote to development and commercialization of its product
candidates, difficulties or delays in its clinical trials, difficulties or
delays in manufacturing its clinical trials materials, the scope and validity
of patent protection for its products, regulatory developments involving
future products and its ability to obtain additional funding to support its
operations.  For a discussion of these and other factors, please refer to the
risk factors section of the final prospectus from SGX's initial public
offering filed with the United States Securities and Exchange Commission on
February 1, 2006 as well as other subsequent filings with the Securities and
Exchange Commission.  You are cautioned not to place undue reliance on these
forward-looking statements, which speak only as of the date hereof.  This
caution is made under the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995.  All forward-looking statements are qualified
in their entirety by this cautionary statement and SGX undertakes no
obligation to revise or update this press release to reflect events or
circumstances after the date hereof.

SGX Pharmaceuticals Announces Strategic Collaboration to Develop and Commercialize BCR-ABL Inhibitors for the Treatment of Chronic Myelogenous Leukemia (CML)

Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells.

2006-03-23T00:13:00.000-05:00

Pluskalová M, Pešlová G, Grebeňová D, Halada P, Hrkal Z

J Photochem Photobiol B. 2006 Feb 20;

K562 is the chronic myelogenous leukemia (CML)-derived cell line that expresses high levels of chimeric oncoprotein Bcr-Abl. The deregulated (permanent) kinase activity of Bcr-Abl leads to continuous proliferation of K562 cells and their resistance to the apoptosis promotion by conventional drugs. The photodynamic treatment (PDT) based on the application of 5-aminolevulinic acid (ALA) and irradiation with blue light (ALA-PDT) resulted in the suppression of K562 cells proliferation. It was followed by a necrosis-like cell death [K. Kuzelová, D. Grebenová, M. Pluskalová, I. Marinov, Z. Hrkal, J. Photochem. Photobiol. B 73 (2004) 67-78]. ALA-PDT led to the perturbation of the Hsp90/p23 multichaperone complex of which the Bcr-Abl is the client protein. Bcr-Abl protein was suppressed whereas the bcr-abl mRNA level was not affected. Further on, we observed several changes in the cytoskeleton organization. We detected ALA-PDT-mediated disruption of filamental actin structure using FITC-Phalloidin staining. In connection with this we uncovered certain cytoskeleton organizing proteins involved in the cell response to the treatment. Among these proteins, Septin2, which plays a role in maintaining actin bundles, was suppressed. Another one, PDZ-LIM domain protein 1 (CLP36) was altered. This protein acts as an adaptor molecule for LIM-kinase which phosphorylates and thus inactivates cofilin. Cofilin was indeed dephosphorylated and could thus be activated and operate as an actin-depolymerizing factor. We propose the scheme of molecular response of K562 cells to ALA-PDT.

Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells.

New Assignments for Multi-tasking Signal Transduction Inhibitors (Relates to Article by Chen, et al. FastForward 25 January 2006).

2006-03-23T00:12:00.000-05:00

Zhang Z, Meier KE

Mol Pharmacol. 2006 Feb 23;

An article presented in this issue of Molecular Pharmacology (p. ...) provides an intriguing example of how tyrosine kinase inhibitors can be put to many uses. In this article, the action of dasatinib (BMS-354825) is contrasted to that of imatinib, a kinase inhibitor that is currently being used to treat chronic myelogenous leukemia and other disorders. Both inhibitors target several tyrosine kinases, including Bcr-Abl and the platelet-derived growth factor receptor (PDGFR). Up to this point, the PDGFR has not been a primary therapeutic target for these agents. The work of Chen and colleagues shows that BMS-354825 is a particularly potent inhibitor of PDGFR, and that the compound also targets Src kinase. The authors suggest that this combination of activities could be useful in the treatment of vascular obstructive diseases. While a lack of absolute specificity has classically been regarded as a pharmacologic drawback, this study exemplifies that drugs with multiple molecular targets can potentially provide a very beneficial spectrum of therapeutic activities in multiple disease states.
New Assignments for Multi-tasking Signal Transduction Inhibitors (Relates to Article by Chen, et al. FastForward 25 January 2006).

Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or rel

2006-03-23T00:10:00.000-05:00

Robien K, Schubert MM, Yasui Y, Martin P, Storb R, Potter JD, Ulrich CM

Bone Marrow Transplant. 2006 Apr ; 37(7): 687-92

Methotrexate (MTX) is used as an immunosuppressive agent for acute graft-versus-host disease (GVHD) prophylaxis following hematopoietic cell transplantation (HCT). Concerns that folate intake may impair MTX effectiveness or selectively rescue leukemic cells have led to variations in clinical practice regarding supplemental folic acid during MTX administration. A retrospective, observational study was undertaken to determine the association between folic acid intake (days 0-18 post transplant) and MTX toxicity and efficacy following HCT. The study population consisted of 311 adult patients who received a myeloablative HCT for chronic myelogenous leukemia, all four scheduled doses of MTX, and did not require leucovorin rescue. Multiple linear regression models were used to assess the relationships between folic acid intake (days 0-18 post-HCT) and oral mucositis index (OMI) scores, time to engraftment and risk of detectable acute GVHD. No statistically significant differences in mean OMI scores, time to engraftment, risk of acute GVHD, days to acute GVHD, risk of relapse or survival were observed when comparing patients taking, on average, 400 mug (28%) folic acid per day. Our results suggest that concurrent folic acid supplementation does not change MTX effectiveness or toxicity in this patient population.Bone Marrow Transplantation (2006) 37, 687-692. doi:10.1038/sj.bmt.1705303; published online 27 February 2006.
Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation.

Analysis of membrane proteins from human chronic myelogenous leukemia cells: comparison of extraction methods for multidimensional LC-MS/MS.

2006-03-23T00:09:00.000-05:00

Ruth MC, Old WM, Emrick MA, Meyer-Arendt K, Aveline-Wolf LD, Pierce KG, Mendoza AM, Sevinsky JR, Hamady M, Knight RD, Resing KA, Ahn NG

J Proteome Res. 2006 Mar ; 5(3): 709-19

An important strategy for "shotgun proteomics" profiling involves solution proteolysis of proteins, followed by peptide separation using multidimensional liquid chromatography and automated sequencing by mass spectrometry (LC-MS/MS). Several protocols for extracting and handling membrane proteins for shotgun proteomics experiments have been reported, but few direct comparisons of different protocols have been reported. We compare four methods for preparing membrane proteins from human cells, using acid labile surfactants (ALS), urea, and mixed organic-aqueous solvents. These methods were compared with respect to their efficiency of protein solubilization and proteolysis, peptide and protein recovery, membrane protein enrichment, and peptide coverage of transmembrane proteins. Overall, approximately 50-60% of proteins recovered were membrane-associated, identified from Gene Ontology annotations and transmembrane prediction software. Samples extracted with ALS, extracted with urea followed by dilution, or extracted with urea followed by desalting yielded comparable peptide recoveries and sequence coverage of transmembrane proteins. In contrast, suboptimal proteolysis was observed with organic solvent. Urea extraction followed by desalting may be a particularly useful approach, as it is less costly than ALS and yields satisfactory protein denaturation and proteolysis under conditions that minimize reactivity with urea-derived cyanate. Spectral counting was used to compare datasets of proteins from membrane samples with those of soluble proteins from K562 cells, and to estimate fold differences in protein abundances. Proteins most highly abundant in the membrane samples showed enrichment of integral membrane protein identifications, consistent with their isolation by differential centrifugation.
Analysis of membrane proteins from human chronic myelogenous leukemia cells: comparison of extraction methods for multidimensional LC-MS/MS.

Current status of hematopoietic cell transplantation for adult patients with hematologic diseases and solid tumors in Japan.

2006-03-23T00:08:00.000-05:00

Int J Hematol. 2006 Feb ; 83(2): 164-78

A nationwide survey of hematopoietic cell transplantation (HCT) was started in Japan in 1991, and the analyzed survey data have been presented as the annual report of the Japan Society for Hematopoietic Cell Transplantation. The 10-year overall survival (OS) rates after HCT for each disease are as follows: acute myelogenous leukemia, 44.2%; acute lymphocytic leukemia, 33.7%; adult T-cell leukemia, 24.6%; chronic myelogenous leukemia, 53.3%; myelodysplastic syndrome, 37.3%; non-Hodgkin's lymphoma, 41.5%; Hodgkin's lymphoma, 50.8%; aplastic anemia, 72.5%; breast cancer, 37.1%; germ cell tumor, 52.6%; and ovarian cancer, 44.2%. The 5-year OS rates for multiple myeloma and lung cancer were 40.6% and 23.6%, respectively. Except in cord blood transplantation, engraftment was accomplished in more than 90% of patients. The respective frequencies of acute graft-versus-host disease (GVHD) and chronic GVHD were 41.1% and 34.9% for related bone marrow transplantation (BMT), 66.8% and 34.5% for unrelated BMT, 52.9% and 36.0% for allogeneic peripheral blood stem cell transplantation, and 53.3% and 32.1% for allogeneic cord blood transplantation. OS for each disease was analyzed by patient age, stem cell source, donor type, disease status, and disease type. These data provide objective and valuable information for hematologists as well as for patients who need HCT.
Current status of hematopoietic cell transplantation for adult patients with hematologic diseases and solid tumors in Japan.

STAT5 signaling is required for the efficient induction and maintenance of CML in mice.

2006-03-23T00:06:00.000-05:00

Ye D, Wolff N, Li L, Zhang S, Ilaria Jr RL

Blood. 2006 Mar 7;

The role of signal transducers and activators of transcription (STAT)5 in chronic myelogenous leukemia (CML) is controversial. To clarify the role of STAT5 signaling in P210(BCR/ABL) leukemogenesis, P210 was introduced into primary murine STAT5A-deficient (-/-) bone marrow (BM) cells, which unlike STAT5A/5B double knockout BM cells, have no major intrinsic hematopoietic defects. Interestingly, only 21% of mice reconstituted with P210-transduced STAT5A (-/-) BM cells developed classic CML, compared to 80-100% of P210/STAT5A (+/+) and P210/STAT5A (+/-)-reconstituted animals. The remainder of P210/STAT5A (-/-) animals died from an acute B-cell lymphoblastic leukemia (ALL)-like disease (32%) or a CML/ALL mix (47%), reflecting impairment in the induction and maintenance of CML, which normally predominates in this mouse model. Of mice that ultimately developed CML, P210/STAT5A (-/-) animals had prolonged survival and increased myeloid immaturity. Importantly, reconstitution of wild-type mice with BM cells co-expressing P210 and dominant negative STAT5 also profoundly reduced the incidence of CML, without impairing the induction of ALL. Altogether, these findings indicate that STAT5 and STAT5A play an important role in the pathogenesis of the CML-like disease in mice. A greater understanding of the STAT5 target genes involved in CML induction may lead to new therapeutic targets that influence CML progenitor cell biology.
STAT5 signaling is required for the efficient induction and maintenance of CML in mice.

Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies.

2006-03-23T00:03:00.000-05:00

Correll PH, Paulson RF, Wei X

Gene. 2006 Mar 6;

Dysregulation of receptor tyrosine kinase (RTK) activity has been implicated in the progression of a variety of human leukemias. Most notably, mutations and chromosomal translocations affecting regulation of tyrosine kinase activity in the Kit receptor, the Flt3 receptor, and the PDGFbeta/FGF1 receptors have been demonstrated in mast cell leukemia, acute myeloid leukemia (AML), and chronic myelogenous leukemias (CML), respectively. In addition, critical but non-overlapping roles for the Ron and Kit receptor tyrosine kinases in the progression of animal models of erythroleukemia have been demonstrated [Persons, D., Paulson, R., Loyd, M., Herley, M., Bodner, S., Bernstein, A., Correll, P. and Ney, P., 1999. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Gen. 23, 159-165.; .]. The various classes of RTKs implicated in the progression of leukemia have been recently reviewed ]. Here, we will discuss the mechanism by which alterations in these receptors result in transformation of hematopoietic cells, in the context of what is known about the molecular regulation of RTK activity, with a focus on our recent studies of the Ron receptor tyrosine kinase.
Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies.

Circulating myeloid dendritic cell directly isolated from patients with chronic myelogenous leukemia are functional and carry the bcr-abl translocatio

2006-03-23T00:01:00.000-05:00

Orsini E, Calabrese E, Maggio R, Pasquale A, Nanni M, Trasarti S, Tafuri A, Guarini A, Foa R

Leuk Res. 2006 Mar 6;

Leukemic bcr-abl positive dendritic cells (DCs) are likely to be present in vivo in chronic myelogenous leukemia (CML) patients, but no data are available on their functional qualities. We analyzed the circulating BDCA-1+ myeloid DC compartment in 15 chronic phase CML patients. Phenotypic features of CML DCs were comparable with that of normal DCs, except for the CD80 and CD40 antigens, significantly under-represented in CML patients. Nonetheless, no differences were found between normal samples and leukemic DCs in the allostimulatory ability, as well as in the production of cytokines and polarization of T cell responses. CML DCs were analyzed by fluorescence in situ hybridization (FISH) and found positive for the bcr-abl translocation. However, when bcr-abl+ DCs were tested for their ability to stimulate an autologous T-cell response in vitro, we could not detect a specific recognition. We conclude that an apparently normal circulating DC compartment carrying the Ph+ chromosome can be identified in CML patients; however, these cells appear unable to trigger a protective anti-leukemic immune response in autologous T cells.
Circulating myeloid dendritic cell directly isolated from patients with chronic myelogenous leukemia are functional and carry the bcr-abl translocation.

Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts.

2006-03-22T23:57:00.000-05:00

Arocho A, Chen B, Ladanyi M, Pan Q

Diagn Mol Pathol. 2006 Mar ; 15(1): 56-61

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of a reciprocal translocation between chromosomes 9 and 22 and results in the formation of the Philadelphia (Ph1) chromosome and is present in most of CML patients. The Ph1 chromosome forms a chimeric gene that encodes an abnormal P210 mRNA transcript in most CML patients. Surveillance for minimal residual disease by detection of BCR/ABL transcripts is currently done mostly by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Quantitation of BCR/ABL transcripts can monitor tumor load and the outcome of therapy. Absolute quantification determines the input copy number of the transcript of interest, usually by plotting the amount of PCR product onto a standard curve based on serial dilutions of the same product cloned in plasmids. Relative quantification describes the change in expression of the target gene in the patient sample relative to that of a control transcript by using the 2-DeltaDeltaCt calculation. The results of real-time RT-PCR for BCR/ABL transcripts are often analyzed by using plasmid DNA standard curves. In the present study, 79 BCR/ABL transcript-positive samples from CML patients who were being monitored for minimal residual disease by real-time quantitative RT-PCR were studied to determine whether the 2-DeltaDeltaCt approach was equivalent to the plasmid standard curve method. BCR/ABL P210 transcripts were quantitated using both the plasmid standard curve method and the 2-DeltaDeltaCt calculation. The comparison of both methods revealed a highly significant and linear correlation between the plasmid standard curve method and the 2-DeltaDeltaCt calculation (R2=0.98, P<0.0001). Furthermore, there was a reduction of preparation time, contamination risk, and reagent usage. The 2-DeltaDeltaCt calculation is a convenient alternative method to derive accurate quantitative information from real time PCR assays.
Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts.

t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.

2006-03-22T23:56:00.000-05:00

Cameron Yin C, Cortes J, Barkoh B, Hayes K, Kantarjian H, Jones D

Cancer. 2006 Mar 10;

BACKGROUND: The t(3;21)(q26;q22) translocation is associated with myeloid leukemias and results in a chimeric oncoprotein containing AML1/RUNX1 variably fused to EAP, MDS1, and/or EVI1. METHODS: The current study describes what to the authors' knowledge is the first large case series reported to date of 26 t(3;21)(q26;q22)-associated leukemias, in which 24 cases arose after chemotherapy. Conventional G-band karyotyping and flow cytometry immunophenotyping were performed. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect fusion transcripts between AML1 and EAP, MDS1, or EVI1, followed by DNA sequencing. RESULTS: In all 16 patients with chronic myeloproliferative disorders, including 14 with chronic myelogenous leukemia (CML), the occurrence of t(3;21) heralded myeloid blast transformation. Fifteen (93%) patients had been previously treated with hydroxyurea. Eight patients with chronic myeloproliferative disorders (CMPD) were found to have t(3;21) with t(9;22) as the sole cytogenetic abnormality; in 5 other patients this was accompanied by trisomy 8. Among 10 cases of t(3;21)-associated acute myeloid leukemia, 8 were secondary tumors after chemotherapy for other neoplasms that had been treated with regimens including fludarabine and 5-fluorouracil in 3 patients each and etoposide in 2 patients. The immunophenotype of the blasts in all 22 tested cases was similar, with uniform expression of myeloid markers and CD34 and variable expression of CD7 and CD9, but minimal morphological myeloid maturation. Dysplastic micromegakaryocytes and bone marrow fibrosis were observed predominantly in CMPD cases. RT-PCR followed by DNA sequencing showed that the AML1-/MDS1-/EVI1 (AME) fusion transcript was detected in all 5 cases assessed. Among the patients with CMPD, 8 died of disease (at a median of 6.5 mos) and 5 achieved disease remission with bone marrow transplantation. Among patients with acute myeloid leukemia/myelodysplastic syndrome, 7 died of disease (at a median of 2 mos) and 2 had persistent leukemia with short follow-up. CONCLUSIONS: Activation of AME through t(3;21) defines a highly aggressive, therapy-related leukemic blast syndrome. Prior treatment with hydroxyurea or other antimetabolites is implicated as a contributory cause. Cancer 2006. (c) 2006 American Cancer Society.

t(3;21)(q26;q22) in myeloid leukemia: an aggressive syndrome of blast transformation associated with hydroxyurea or antimetabolite therapy.

Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28.

2006-03-22T23:55:00.000-05:00

Han JF, Zhao TT, Liu HL, Lin ZH, Wang HM, Ruan ZH, Zou LY, Wu YZ

Cancer Immunol Immunother. 2006 Mar 14;

Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. CML28, a recently discovered cancer-testis (CT) antigen from chronic myelogenous leukemia, is considered to be a promising target of tumor-specific immunotherapy. Because HLA-A*0201 is one of the most common histocompatibility molecule in Chinese, we aim at identifying CML28 peptides presented by HLA-A*0201. A panel of CML28-derived antigenic peptides was predicted using a computer-based program. Four peptides with highest predicted score were synthesized and tested for their binding affinities to HLA-A*0201 molecule. Then these peptides were assessed for their immunogenicity to elicit specific immune responses mediated by CTLs both in vitro, from PBMCs sourced from four healthy HLA-A*0201(+) donors, and in vivo, in HLA-A*0201 transgenic mice. One of the tested peptides, CML28((173-181)), induced peptide-specific CTLs in vitro as well as in vivo, which could specifically secrete IFN-gamma and lyse major histocompatibility complex (MHC)-matched tumor cell lines endogenously expressing CML28 antigen and CML28((173-181) )pulsed Jurkat-A2/Kb cells, respectively. These results demonstrate that CML28((173-181) )is a naturally processed and presented CTL epitope with HLA-A*0201 motif and has a promising immunogenicity both in vitro and in vivo. As CML28 is expressed in a large variety of histological tumors besides chronic myelogenous leukemia, we propose that the newly identified epitope, CML28((173-181)), would be of potential use in peptide-based, cancer-specific immunotherapy against a broad spectrum of tumors.
Identification of a new HLA-A*0201-restricted cytotoxic T lymphocyte epitope from CML28.

Dasatinib: BMS 354825.

2006-03-22T23:54:00.000-05:00

Drugs R D. 2006; 7(2): 129-32

Dasatinib [BMS 354825] is an orally active, small molecule, dual inhibitor of both SRC and ABL kinases that is under development with Bristol-Myers Squibb for the treatment of patients with chronic myelogenous leukaemia (CML) and imatinib-acquired resistance/intolerance. While imatinib remains a frontline therapy for CML, patients with advanced disease frequently develop resistance to imatinib therapy through multiple mechanisms. These mechanisms include insufficient potency at therapeutic doses, activation of alternate oncogenic pathways, and overexpression of the multidrug-resistant gene. One of the possible causes of imatinib-acquired resistance is associated with increased expression of the SRC-related kinase Lyn and loss of BCR-ABL dependence arising from sequence mutations. In December 2005, Bristol-Myers Squibb announced that it has completed the rolling NDA submission to the US FDA for dasatinib in the treatment of CML in chronic, accelerated or blast phases, as well as Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in patients with resistance or intolerance to prior treatment. At the Bristol-Myers Squibb R&D Day in May 2005, the company stated that it plans to evaluate dasatinib in solid tumours. In in vitro assays, dasatinib induced apoptosis and had potent activity in the imatinib-resistant tumour cells lines and CML patient specimens. It effectively inhibited the proliferation of cells expressing nearly all imatinib-resistant isoforms. In vivo, dasatinib has shown efficacy, with no apparent toxicity, when administered orally in SCID mice with xenografts of imatinib-sensitive and resistant human CML cells lines. Dasatinib is also undergoing preclinical evaluation for its potential as a therapy against multiple myeloma. Bristol-Myers Squibb has a composition-of-matter patent covering this research approach that will expire in 2020.
Dasatinib: BMS 354825.

In vitro and in vivo reversal of MDR1-mediated multidrug resistance by KT-5720: Implications on hematological malignancies.

2006-03-22T23:53:00.000-05:00

Galski H, Sivan H, Lazarovici P, Nagler A

Leuk Res. 2006 Mar 14;

Multidrug resistance (MDR) due to over-expression of the MDR1 (ABCB1) gene and its P-glycoprotein (Pgp) product is an obstacle in the treatment of hematological malignancies. In this study, we have evaluated the potency of KT-5720 to reverse Pgp-dependent MDR in vitro and in vivo. KT-5720 (but not its close derivatives, K252a and K252b) reversed multidrug resistance of LM1/MDR cell line at non-toxic concentrations and increased accumulation of rhodamine 123 (Rh123). KT-5720 significantly reversed MDR1-dependent resistance of primary malignant cells from patients with chronic myelogenous leukemia in blast crisis (CML-BC) and advanced multiple myeloma (MM). Moreover, KT-5720 (at 5mg/kg) sensitized the bone marrow of MDR1 transgenic mice model towards daunorubicin (at 8mg/kg) without general toxic effects. Therefore, KT-5720 can be considered as candidate for combination therapy in various hematological malignancies where Pgp activity is a major impediment for cure.
In vitro and in vivo reversal of MDR1-mediated multidrug resistance by KT-5720: Implications on hematological malignancies.

Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in my

2006-03-22T23:52:00.000-05:00

Tang R, Faussat AM, Majdak P, Marzac C, Dubrulle S, Marjanovic Z, Legrand O, Marie JP

Mol Cancer Ther. 2006 Mar ; 5(3): 723-31

Semisynthetic homoharringtonine (ssHHT) is now being evaluated in phase II clinical trials for the treatment of chronic myelogenous leukemia and acute myelogenous leukemia patients. Here, we examined the mechanism of the apoptosis induced by ssHHT in myeloid leukemia cells. First, we have shown that ssHHT induces apoptosis in HL60 and HL60/MRP cell lines in a time- and dose-dependent manner, and independently of the expression of Bax. The decrease of mitochondrial membrane potential and the release of cytochrome c were observed in the apoptotic cells induced by ssHHT. To unveil the relationship between ssHHT and the mitochondrial disruption, we have shown that ssHHT decreased myeloid cell leukemia-1 (Mcl-1) expression and induced Bcl-2 cleavage in HL60 and HL60/MRP cell lines. The Bcl-2 cleavage could be inhibited by the Z-VAD.fmk caspase inhibitor. However, Mcl-1 turnover was very rapid and occurred before caspase activation. The Mcl-1 turnover was only induced by ssHHT and cycloheximide, but not by daunorubicin and cytosine arabinoside, and could be restored by proteasome inhibitors. Second, we confirmed that ssHHT rapidly induced massive apoptosis in acute myelogenous leukemia patient cells. We have also confirmed the release of cytochrome c and a rapid turnover of Mcl-1 in these patient cells, taking place only in apoptotic cells induced by ssHHT but not in cells undergoing spontaneous apoptosis. Finally, we have shown that ssHHT inhibits protein synthesis in both cell line and patient cells. We suggest that the inhibition of protein synthesis and resulting Mcl-1 turnover play a key role in the apoptosis induced by ssHHT. Our results encourage further clinical trials for the use of ssHHT in acute myelogenous leukemia. [Mol Cancer Ther 2006;5(3):723-31].
Semisynthetic homoharringtonine induces apoptosis via inhibition of protein synthesis and triggers rapid myeloid cell leukemia-1 down-regulation in myeloid leukemia cells.

Quality of life, reproduction and sexuality after stem cell transplantation with partially T-cell-depleted grafts and after conditioning with a regime

2006-03-22T23:51:00.000-05:00

Claessens JJ, Beerendonk CC, Schattenberg AV

Bone Marrow Transplant. 2006 Mar 20;

Thirty-four men and 36 women (median age 43 and 45 years, respectively) underwent stem cell transplantation (SCT) for acute leukaemia in first complete remission or chronic myelogenous leukaemia in first chronic phase between 1981 and 2001 from HLA-identical siblings. The conditioning regimen included TBI and all grafts were partially depleted of T cells. Changes in quality of life (QOL), reproduction and sexuality were studied using a questionnaire, and the previously given information related to these problems was assessed. In addition, endocrine status was assessed and semen analysis was performed. After SCT, patients reported less energy (n=50) and a deterioration in the job situation (n=31). Patients experienced a negative change in sexual relations (n=41). Important problems of sexual dysfunction were vaginal dryness in women (n=19) and erectile dysfunction in men (n=16). None of the patients was fertile based on their gonadotrophin levels, sperm concentrations and reproductive outcomes. Women experienced climacteric symptoms (n=24). Quality of life was negatively influenced by these changes. One-fifth of the patients were not satisfied with the information given with regard to reproduction, premature menopause and sexual problems.Bone Marrow Transplantation advance online publication, 20 March 2006; doi:10.1038/sj.bmt.1705350.
Quality of life, reproduction and sexuality after stem cell transplantation with partially T-cell-depleted grafts and after conditioning with a regimen including total body irradiation.

Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia.

2006-03-22T23:49:00.000-05:00

Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia.

Moore JC, Dennehey CF, Anavim A, Kong KM, Tiong Ong S

Eur J Haematol. 2006 Mar 17;

Imatinib mesylate is a small molecule tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukaemia (CML). However, it is likely that patients with CML will require prolonged and perhaps life-long therapy. In general, the side-effects of imatinib therapy have been mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side-effects. Here, we describe a novel form of fluid retention presenting as multiple joint effusions in a patient with advanced phase CML on high-dose imatinib, as well as successful measures that were undertaken to control this adverse event. Although fluid retention, including periorbital oedema, pleural and pericardial effusions, as well as life-threatening cerebral oedema have been previously described and attributed to imatinib, this is the first case of imatinib-associated polyarticular effusions that we are aware of. Further work will be required to confirm a casual relationship between imatinib therapy and this novel side-effect, as well as to determine the underlying pathophysiologic mechanisms.
Multiple joint effusions associated with high-dose imatinib therapy in a patient with chronic myelogenous leukaemia.

Foods dense in nutrients can boost the energy levels of cancer patients

2006-03-22T12:31:00.000-05:00

By JUDITH W. WINNE
Courier-Post Staff

It's not hard to imagine the crippling stress in Teresa Kao's life.

Diagnosed with breast cancer in December 2004, the Voorhees patient underwent chemotherapy, surgery and radiation. The deaths of her mother and brother, within six months of her diagnosis, deepened her sorrow, as well as the worry line in her brow.

Now, Kao's spirits have lifted, helped in great part by a free, local program that emphasizes nontraditional therapies and practices -- meditation, restorative yoga, massage, acupuncture and nutrition.

"I think I feel much more serene and much more positive now," said the 56-year-old Kao. "It made a big difference in my life."

Next month, the Dr. Diane Barton Complementary Medicine Program at the Cancer Institute of New Jersey at Cooper kicks off a series of nutrition workshops in Voorhees called Fighting Cancer With Food.

The first topic, called Nutrition and Cancer, is April 4. Other sessions for cancer patients will spotlight fatigue-fighting, organic and fiber-rich foods, as well as other nutrition-related subjects.

Alicia Michaux, the cancer institute's oncology dietitian, noted that for patients who have had treatment for their cancer, there are special problems.

"Fatigue is a common side effect," said Michaux. "Some of the foods that are more energizing are the foods that are nutrient-dense. For example, foods that have an adequate amount of protein in them, chicken, fish, eggs, low-fat cheese.

"Things that are nutrient-dense aren't filled with empty calories. I try not to encourage a lot of sugar and processed foods just because they contain a lot of empty calories, and they fill patients up. Protein in the body helps rebuild and replenish muscle mass, so it can actually help patients in their strengthening process, and continue with the treatment and help them fight fatigue."

Michaux, 30, said a diet of well-balanced, whole foods is the goal. Such meals are obviously a smart choice for everyone, whether they have cancer or not.

The emphasis is on sensible, rather than fad or oddball, diets. Advocates in the program stress the word complementary, rather than alternative, medicine.

Their point is that the medicine is meant as an adjunct to surgery, radiation and chemotherapy, not an alternative to them.

Indeed, the program is named for Dr. Diane Barton of Moorestown, a beloved physician who died of ovarian cancer last summer.

"This was her dream," said Bonnie Mehr, who heads the complementary medicine program and was Barton's friend for a decade. "Diane believed in the mind/body connection."

Dr. Generosa Grana, Barton's friend and oncologist, said Barton had pushed her to get a program going. Grana, the director of Cooper's cancer institute, noted that patients find practices like restorative yoga useful and healing.

"It helps them deal, not just with the physical, but the emotional, aspects of the disease," said Grana.

Food is woven into the fabric of the complementary medicine program. At Live, Lunch and Learn sessions, participants munch on healthy, free lunches as Cindy Faust leads members in discussions that range from anger to sexuality. (The next session is 11:30 a.m. March 30 .)

"Food has to become a lifestyle," said Faust, a Cherry Hill clinical social worker who battled breast cancer more than a quarter century ago.

"Eating healthy is fun," said Faust. "It's creative. It doesn't have to be difficult at all. And it helps you take responsibility for your own health. It's something you can do."

Faust, now 56, turned to vegetarianism.

"I believe it helped keep me alive," she said.

Good nutrition is often a priority, or should be, for those battling a serious illness and those who want to prevent cancer. The American Institute for Cancer Research, an organization that fosters research on diet and cancer prevention, notes that the majority of research on diet and cancer suggests eating fruit, vegetables, whole grains and beans will lower the risk of developing cancer.

Antioxidants in blueberries and tomatoes have been tagged as cancer-fighting foods. Of course, patients have no guarantees that a diet rich in fruits, vegetables and whole grains will prevent cancer or its reoccurrence. But like any insurance policy consumers buy, a good diet is surely a sound investment.

"I'm very conscious of food and nutrition," said Mary McCall of Deptford. McCall received a grim diagnosis of Stage Four bladder cancer seven years ago. Remarkably, she recovered. Three years ago, she was diagnosed with chronic myelogenous leukemia. There is no cure, but her treatment is an oral form of chemotherapy, said the 64-year-old McCall.

McCall, 64, has found yoga helpful in coping with pain and swelling in her legs, a result of cancer surgery.

A huge fan of the complementary medicine program, she nevertheless noted the toll cancer has taken.

"You're a wounded warrior," she said.

Barton, the complementary medicine program's namesake, a woman who died too young at 46, would have likely understood.

"She was one gutsy lady who tried everything and fought for what she believed in," said Faust. "It (the program) is a fitting tribute to her."

Reach Judith W. Winne at (856) 486-2441 or jwinne@courierpostonline.com
Published: March 22. 2006 3:00AM

CourierPostOnline - South Jersey's Web Site

Orphan Drug Designation Granted by the U.S. FDA for Ceflatonin(R)

2006-03-20T12:12:00.000-05:00

    MELBOURNE, Australia and MENLO PARK, Calif., March 19 /PRNewswire-
FirstCall/ -- ChemGenex Pharmaceuticals Limited (Nasdaq: CXSP; ASX: CXS)
announced today that the United States Food and Drug Administration (FDA) has
granted Orphan Drug status for the company's most advanced drug, Ceflatonin,
for the treatment of chronic myeloid leukemia (CML). Ceflatonin is the first
of a new class of novel drugs that induces apoptosis (programmed cell death)
and inhibits angiogenesis (new blood vessel formation). Ongoing or soon to be
initiated clinical trials are and will be evaluating Ceflatonin in a broad
range of conditions, including: chronic myeloid leukemia (CML),
myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
   Orphan drug status is granted by the FDA to promote the development of
drugs for diseases affecting less than 200,000 people in the United States.
Orphan drug status entitles ChemGenex to seven years of market exclusivity for
the use of Ceflatonin in the treatment of CML; protocol assistance by the FDA
to optimize drug development in the preparation of a dossier that will meet
regulatory requirements; and reduced fees associated with applying for market
approval.
   A similar designation for Ceflatonin in the European market, with similar
advantages, was granted by the European Union on September 9, 2004, based on a
positive recommendation by the Committee for Orphan Medicinal Products (COMP)
of the European Medicines Agency (EMEA). The European Union granted Ceflatonin
orphan status on October 20, 2004 for the treatment of acute myeloid leukemia
(AML).
   "The decision by the U.S. FDA to grant Ceflatonin orphan drug status for
CML is further incentive to move Ceflatonin as quickly as possible through the
clinical development and regulatory approval process worldwide," said Greg
Collier, ChemGenex chief executive officer and managing director. "We are very
encouraged by the growing body of clinical data on Ceflatonin in resistant
CML, MDS and AML, and by the ongoing support of key opinion leaders in the
field. Now with the granting of Orphan Drug status by the FDA, we are fully
committed to accelerate our development efforts to help address the unmet
medical needs of CML patients worldwide."

   About Ceflatonin(R)
   Ceflatonin (HHT) is a potent inducer of apoptosis (programmed cell death)
in myeloid cells and inhibits angiogenesis (blood vessel formation).
Ceflatonin has confirmed Phase 2 clinical activity in resistant CML, both as a
single agent and in combination with other approved drugs. ChemGenex is
developing Ceflatonin for the treatment of CML, myelodysplastic syndrome (MDS)
and acute myeloid leukemia (AML).

   Recent studies have demonstrated that Ceflatonin has potential in CML
patients who are developing resistance to tyrosine kinase inhibitor (TKI)
therapy, including Gleevec(R), and in-combination with TKI's in early stage
CML to increase the cytogenetic and molecular response rate.
   A summary of recent clinical data on Ceflatonin includes the following
studies:

   *  In a nine patient single-agent Phase 1/2 study in accelerated-phase CML
      who had become resistant to Gleevec, seven (80%) patients returned to
      chronic-phase and 6 (67%) achieved a complete hematologic response.

   *  In a separate five patient single-agent Phase 2 study in late
      chronic-phase CML, five (100%) achieved a complete hematologic response
      and two (40%) achieved a cytogenetic response. Two patients with
      detectable resistance mutations achieved a complete hematologic
      response and their mutations (p-loop) were not longer detectable after
      Ceflatonin treatment.

   *  In another recent 10 patient Phase 1/2 study, Ceflatonin was added to
      Gleevec in patients who had a partial or complete cytogenetic response,
      in order to reduce bcr-abl transcript counts further. Seven (70%)
      patients had a significant decrease in bcr-abl counts. Two patients
      with partial cytogenetic responses achieved complete cytogenetic
      responses. Two patients achieved a complete molecular response, or not
      detectable evidence of residual disease.

   *  Pre-clinical studies on Ceflatonin have shown both additive and
      synergistic activity when combined with Gleevec, as measured by a
      reduction in the marker (bcr-abl protein expression) that is a hallmark
      of resistance in CML.

   A multinational Phase 2/3 study in CML patients harboring the T315I point
mutation, known to confer complete resistance to tyrosine kinase (TKI)
inhibitors like Gleevec, is scheduled to begin in Q2, 2006. A second
multinational Phase 2/3 study in CML patients resistant to TKI inhibitors is
scheduled to begin soon thereafter. Each study will include centers in the
United States, Germany, France and Italy.
   Ceflatonin is not approved by the FDA as a treatment in any indication and
is currently being evaluated in clinical trials for efficacy and safety for
future regulatory applications.
   Gleevec(R) is a registered trademark of the Novartis Pharmaceuticals
Corporation.

   About Chronic Myeloid Leukemia
   Chronic Myeloid Leukemia (CML) is a cancer of the blood cells caused by an
acquired genetic defect called the bcr-abl mutation. This defect occurs when
genetic material from two chromosomes (9 and 22) swaps places, creating the
so-called Philadelphia chromosome. The bcr-abl mutation interferes with normal
cell replication processes, leading to an abnormal proliferation of white
blood cells.
   CML usually occurs in adults and typically progresses through three
phases. Patients generally are diagnosed in 'chronic phase', progress through
an 'accelerated phase' and then may die if the disease progresses to 'blast
phase'. CML incidence is relatively consistent occurring at about 1 to 2 per
100,000 people and the global CML market for therapeutics is estimated at in
excess of US$2 billion.
   Patients with chronic phase CML have been effectively treated in recent
years by the drug Gleevec. However, over time many patients become resistant
to the therapeutic effects of the drug and the disease progresses.

   About ChemGenex Pharmaceuticals Limited (http://www.chemgenex.com)
   ChemGenex Pharmaceuticals is a pharmaceutical development company
dedicated to improving the lives of patients by developing therapeutics in the
areas of oncology, diabetes, obesity, and depression. ChemGenex harnesses the
power of genomics for target discovery and validation, and in clinical trials
to develop more individualized therapeutic outcomes. ChemGenex's lead
compound, Ceflatonin(R), is currently in phase 2/3 clinical trials for
leukemia and Quinamed(R) is in phase 2 clinical trials for prostate, breast
and ovarian cancers. The company has a significant portfolio of anti-cancer,
diabetes, obesity and depression programs, several of which have been
partnered with international pharmaceutical companies. ChemGenex currently
trades on the Australian Stock Exchange under the symbol "CXS" and on NASDAQ
under the symbol "CXSP".

   Safe Harbor Statement
   Certain statements made herein that use the words "estimate," "project,"
"intend," "expect," "believe," and similar expressions are intended to
identify forward-looking statements within the meaning of the US Private
Securities Litigation Reform Act of 1995. These forward-looking statements
involve known and unknown risks and uncertainties which could cause the actual
results, performance or achievements of the company to be materially different
from those which may be expressed or implied by such statements, including,
among others, risks or uncertainties associated with the development of the
company's technology, the ability to successfully market products in the
clinical pipeline, the ability to advance promising therapeutics through
clinical trials, the ability to establish our fully integrated technologies,
the ability to enter into additional collaborations and strategic alliances
and expand current collaborations and obtain milestone payments, the
suitability of internally discovered genes for drug development , the ability
of the company to meet its financial requirements, the ability of the company
to protect its proprietary technology, potential limitations on the company's
technology, the market for the company's products, government regulation in
Australia and the United States, changes in tax and other laws, changes in
competition and the loss of key personnel. These statements are based on our
management's current expectations and are subject to a number of uncertainties
that could change the results described in the forward-looking statements.
Investors should be aware that there are no assurances that results will not
differ from those projected.

SOURCE ChemGenex Pharmaceuticals Limited
Web Site: http://www.chemgenex.com
Orphan Drug Designation Granted by the U.S. FDA for Ceflatonin(R)

Cancer cells lose drug resistance following electrical stimulation in vitro

2006-03-19T12:11:00.000-05:00

Contact: Juliette Savin
press@biomedcentral.com
44-207-631-9931
BioMed Central

Cancer cells lose drug resistance following electrical stimulation in vitro

Drug-resistant tumour cells lose their drug resistance when exposed to low intensity, low frequency electric pulses for three days. A study published today in the open access journal BMC Cancer reveals that treating drug-resistant tumour cells with electric pulses in vitro restores the cells' ability to take up the anti-cancer drug doxorubicin.

The research group led by Luca Cucullo and Damir Janigro from the Cleveland Clinic Lerner College of Medicine, Ohio, USA exposed rat and human tumour cells to very low intensity (7.5 microamps) 50 Hertz alternating current pulses, with a ten-second interval, for three days in vitro. Such electrical stimulation is known not to damage cells but to decrease the proliferation of tumour cells. The tumour cell lines used overexpress the MDR1 protein, which makes them resistant to anti-cancer drugs such as doxorubicin. Following the three days of electrical stimulation, the cells were exposed to increasing concentrations of doxorubicin for three hours.

Janigro et al.'s results show that electrical stimulation led to an increased uptake of doxorubicin, which caused the cells to die, even at low doxorubicin concentrations. Exposing the cells to an electric current was more effective than treating the cells with an MDR1 inhibitor. These findings suggest the potential application of electrical stimulation to improve the efficacy of existing chemotherapeutic treatments.

###

Article:
Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells
Damir DJ Janigro, Catalin CP Perju, Vincent VF Fazio, Kerri KLH Hallene, Gabriele GD Dini, Mukesh MKA Agarwal and Luca LC Cucullo
BMC Cancer 2006, (in press)

Cancer cells lose drug resistance following electrical stimulation in vitro

TradingMarkets.com - Daytrading, Eminis, Forex trading, Swing Trading

2006-03-16T11:29:00.000-05:00

(RTTNews) - Wednesday, Praecis Pharmaceuticals Inc. (PRCS | charts | news | Powerrating), a biopharmaceutical company, presented an update on the development of its DirectSelect technology, a facilitator of drug discovery process, at the Drug Discovery Technology Europe 2006 meeting in London.

The DirectSelect technology is based on the creation of multiple, numerically, encoded libraries of drug-like structures that can be screened quickly to identify individual or families of structures, with affinity for a macromolecular target.

Dr. Morgan, VP, Chemistry, during the presentation, discussed the generation of a set of libraries having more than five billion compounds ready to identify small molecule drug candidates, as well as the application of these libraries in the identification of hit families to four well-known targets in proof-of-concept studies.

In the presentation, Dr. Morgan described proof-of-concept screening of the DirectSelect libraries against three kinase and one protease target, including the cancer targets Aurora A kinase and Gleevec-resistant mutant Abl T315I kinase, the inflammation target p38 map kinase, and the Alzheimer's target beta secretase. In each case, new hit families were identified and hits were validated through re-synthesis, without tags used during the library screening, and testing in biochemical and cell-based assays, proving DirectSelect's ability to rapidly identify and validate new hit families to pharmaceutical targets in a period of nearly a month. The technology was developed based on the line that the odds of identifying hits with higher affinity and enhanced selectivity for a macromolecular target can be improved by increasing the numeric size and "chemical space" interrogated by the target. In addition, access to multiple, structurally diverse families should improve the likelihood of identifying a lead molecule with a favorable safety profile in vivo. Praecis focused on combining validated chemistry methods with unique screening and deconvolution steps, the company stated.

The company revealed that it initiated activities to screen for new compounds against therapeutic targets of interest. The Company intends to use the DirectSelect technology to engage in advance research collaborations and pharmaceutical partnerships in drug discovery and development. The Company said it plans to use this technology to expand its own proprietary development pipeline.

PRCS is currently trading at $5.81, up $0.14, on 28,847 shares.

TradingMarkets.com - Daytrading, Eminis, Forex trading, Swing Trading

New strategy developed to study disease: Reveals insights into cancer and treatment leads

2006-03-08T01:02:00.001-05:00

Public release date: 7-Mar-2006
[ Print Article | E-mail Article | Close Window ]

Contact: Eric Vohr
evohr1@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions

New strategy developed to study disease: Reveals insights into cancer and treatment leads

For the first time, Johns Hopkins researchers were able to easily jumpstart the activity of a well-known cancer protein in live cells with a small molecule, a strategy that pinpointed key players in the cancer process and can be used to determine new therapeutic targets. What's more, the scientists' study, published in the March 3 issue of Science, identifies a simple method to further understand the complex mechanisms that underlie cancer as well as other diseases and may provide an easy model to screen for new cancer drugs.

"Our study reveals a new way to study proteins in live cells, in this case, a tyrosine kinase implicated in causing cancer," says the study's lead author, Philip A. Cole, M.D., Ph.D., director of the Department of Pharmacology and Molecular Sciences at The Johns Hopkins University School of Medicine. "This approach helped identify potentially important therapeutic targets and in the future may provide a method to easily screen cancer treatments."

In the study, Cole and his colleagues examined the tyrosine kinase Src (pronounced SARK), a clinically important cancer protein that scientists have heavily studied but do not completely understand. The Johns Hopkins researchers developed a special mutated version of the Src protein and incorporated it into live animal cells. The mutated version was inactive but contained an "ignition switch" that would turn it back on. They determined that the small molecule, imidazole, could act as the key. Imidazole fit into a pocket in the mutated structure of the Src protein, which mended the structure and reinstated Src's activity. Removal of imidazole quickly shut the protein off again.

"This strategy provided a controlled environment to study Src," says Cole. "This helped us uncover some new and unexpected insights into how the cancer protein creates its havoc, as well as new treatment leads." For one, the model provided evidence that Src interacts with CrkL, a signaling protein not previously known to be targeted by Src's actions. The study also found direct evidence that Src activates MAP kinase pathways, which help transfer information from growth factors, molecules that aid in the development of cancer cells. Previously the role of Src in these pathways was controversial.

"Understanding the functions of different proteins in normal states and disease states is crucial for treatment development because it can help identify new therapeutic targets," says Cole. Insights into tyrosine kinases could be particularly important for determining new cancer treatments, since scientists think that many different types are involved. "For example, Gleevec, which is used to treat gastrointestinal stromal tumors and chronic myeloid leukemia, is the most successful magic bullet against cancer in many years and works by blocking tyrosine kinase activity," Cole says.

As a next step, Cole and his colleagues plan to further examine the role of Src in cancer using their new model. They also plan to adapt the approach to develop a drug screen.

In the future, it also may be possible to use their chemical technique to mend mutated proteins found in people with certain genetic diseases, according to Cole. For example, the immune system disorder agammaglobulinemia involves mutated tyrosine kinases. Possibly researchers could identify a small molecule that rescues the activity of the mutated tyrosine kinases in the same way that imidazole corrected the structure of the mutated Src and jumpstarted its activity.

###

Other contributors to this study include Akhilesh Pandey, M.D., Ph.D., an assistant professor in the Institute of Genetic Medicine; Jin Zhang, Ph.D., an assistant professor in the Department of Pharmacology and Molecular Science, and Henrik Molina, M.S., a lab manager in the Institute of Genetic Medicine
New strategy developed to study disease: Reveals insights into cancer and treatment leads

New strategy developed to study disease: Reveals insights into cancer and treatment leads

2006-03-08T01:02:00.000-05:00

Public release date: 7-Mar-2006
[ Print Article | E-mail Article | Close Window ]

Contact: Eric Vohr
evohr1@jhmi.edu
410-955-8665
Johns Hopkins Medical Institutions

New strategy developed to study disease: Reveals insights into cancer and treatment leads

As a next step, Cole and his colleagues plan to further examine the role of Src in cancer using their new model. They also plan to adapt the approach to develop a drug screen.

###

FDA Gives Fast Track Status To Dasatinib | CMLHope.Com | Bringing Hope To CML

2006-03-07T15:29:00.000-05:00

FDA Gives Fast Track Status To Dasatinib | CMLHope.Com | Bringing Hope To CML

Retired couple seen with $200,000 health need - Yahoo! News

2006-03-06T22:57:00.000-05:00

By Herbert Lash Mon Mar 6, 11:54 AM ET

NEW YORK (Reuters) - An American couple that retires at age 65 will, on average, need $200,000 in retirement to cover out-of-pocket medical costs, Fidelity Investments, the No. 1 mutual fund firm, said on Monday.
ADVERTISEMENT
[0]

That amount, considered the biggest single expense for most people in retirement, increased 5.3 percent from $190,000 last year, said Brad Kimler, a senior vice president of Fidelity Employer Services Co., a company division.

The increase mostly resulted from the rising cost of health care and has gone up an average 5.8 percent a year since Fidelity began releasing the estimate in 2002, the company said.

The number is important as Fidelity has found that most people don't take into account health care when planning for their retirement, and because the number of companies offering health benefits to retirees is declining, Kimler said.

Health-care costs have the potential to significantly erode retirement savings, he said.

"This is the one most frequently overlooked by people when they're doing their retirement planning," he said.

The amount people will need in retirement to cover out-of-pocket health costs will vary because of the medical needs they may encounter, he said. Being healthy before retirement will likely lesson medical costs later, he said.

Fidelity at first didn't provide an estimate for individuals but later said the cost for males would be $90,000 over 17 years, and $110,000 for females over 20 years. The estimate for health-care costs assumes that retirees do not have employer-sponsored retiree health care, but includes three typical costs: expenses associated with Medicare part B and D premiums, Medicare cost-sharing provisions -- co-payments, coinsurance, deductibles and excluded benefits -- and prescription drug out-of-pocket costs.

It does not include other health expenses, such as over-the-counter medications, most dental services and long-term care.

Retired couple seen with $200,000 health need - Yahoo! News

Internet research builds cancer patients' confidence

2006-03-06T14:28:00.000-05:00

Contact: Tory Harris
tah@temple.edu
215-707-1731
Temple University

Internet research builds cancer patients' confidence

Newly diagnosed cancer patients who use the Internet to gather information about their disease have a more positive outlook and are more active participants in their treatment, according to a new Temple University study published in the March 2006 issue of the Journal of Health Communication.

"This is the first study to look at the relationship between Internet use and patient behaviors," said principal investigator and public health professor Sarah Bass, Ph.D. "We wanted to see if access to readily available information about their condition helped patients to cope with issues such as hair loss and other treatment side effects."

For this study, the researchers recruited patients who called a National Cancer Institute-funded 1-800 number, where trained specialists answered questions about the disease and directed callers to cancer-related resources in their area. Once selected, the 442 participants were broken into "direct user, indirect user and non user" categories based on their Internet usage patterns.

According to Bass, direct and indirect users tended to be females between the ages of 50 and 60 who had graduated from college and made more than $60,000 a year.

During the survey, Bass and her colleagues began to see strong parallels between Internet use and the patients' feelings about their treatment. Those who used the Internet and those who received Internet information from family members or friends were more likely to view their relationship with their doctors as a partnership, and were more comfortable asking questions and challenging treatment alternatives.

"They saw the Internet as a powerful tool that enhanced their decision-making ability," Bass said.

Moreover, Bass and her team were pleasantly surprised by the number of early non-users who after eight weeks turned to the Internet for information. When asked about the change, approximately 75 percent said that either family/friend encouragement or the cancer diagnosis itself prompted them to increase their Internet use.

"They didn't want to feel powerless or have to rely on the doctor to make all of the decisions," Bass said.

Bass warns that as more and more funding is cut for medical phone hotlines, now is the time for doctors and health workers to encourage patients to do their own research on the Web. "But as with most things, let the buyer beware. Stick to Web sites that are associated with large, well-recognized non-profit groups, or get recommendations from your physician."

###

The complete study can be viewed @ http://www.temple.edu/news_media/bass_study.html

Internet research builds cancer patients' confidence

A novel triple purge strategy for eliminating chronic myelogenous leukemia (CML) cells from autografts

2006-03-05T23:05:00.000-05:00

Yang H, Eaves C, de Lima M, Lee MS, Champlin RE, McMannis JD, Robinson SN, Niu T, Decker WK, Xing D, Ng J, Li S, Yao X, Eaves AC, Jones R, Andersson BS, Shpall EJ.

1Department of Blood and Marrow Transplantation, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Imatinib-refractory chronic myelogenous leukemia (CML) patients can experience long-term disease-free survival with myeloablative therapy and allogeneic hematopoietic cell transplantation; however, associated complications carry a significant risk of mortality. Transplantation of autologous hematopoietic cells has a reduced risk of complications, but residual tumor cells in the autograft may contribute to relapse. Development of methods for purging tumor cells that do not compromise the engraftment potential of the normal hematopoietic cells in the autograft has been a long-standing goal. Since primitive CML cells differentiate more rapidly in vitro than their normal counterparts and are also preferentially killed by mafosfamide and imatinib, we examined the purging effectiveness on CD34(+) CML cells using a strategy that combines a brief exposure to imatinib (0.5-1.0 muM for 72 h) and then mafosfamide (30-90 mug/ml for 30 min) followed by 2 weeks in culture with cytokines (100 ng/ml each of stem cell factor, granulocyte colony-stimulating factor and thrombopoietin). Treatment with 1.0 muM imatinib, 60 mug/ml mafosfamide and 14 days of culture with cytokines eliminated BCR-ABL(+) cells from chronic phase CML patient aphereses, while preserving normal progenitors. This novel purging strategy may offer a new approach to improving the effectiveness of autologous transplantation in imatinib-refractory CML patients.Bone Marrow Transplantation advance online publication, 23 January 2006; doi:10.1038/sj.bmt.1705284.

PMID: 16435011 [PubMed - as supplied by publisher]
Entrez PubMed

Epidemiological analysis of second primary malignancies in more than 9500 patients treated with imatinib

2006-03-05T23:04:00.000-05:00

P R Pilot¹, K Sablinska², S Owen¹ and A Hatfield¹

¹Novartis Pharmaceuticals Corporation, East Hanover,New Jersey, USA
²Novartis Pharma AG, Basel, Switzerland E-mail: Samantha_jane.owen@novartis.com

Reply to Roy et al. Leukemia advance online publication, 14 July 2005. Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia. In their correspondence,¹ Roy et al. report that six among 189 CML patients treated with imatinib at their Institution developed a second malignancy. All of the patients had received interferon-based therapy before beginning imatinib therapy. The study reported that the appearance of second malignancies was potentially in accordance with the incidence of cancer in the French population, with the exception of prostate cancer, which was found in three patients. They reported this incidence to be higher than the expected incidence in a French population.

In November 2004 Novartis performed an epidemiological analysis of second primary malignancies among 9518 patients in our global database treated with imatinib during Novartis sponsored clinical trials as well as spontaneous adverse reports from approximately 124 000 patient years (PY) of treatment (unpublished observations, data on file Novartis). The objective was to compare the incidence rates of second cancers among patients treated with imatinib with the expected incidence based on the rates among the general population. In addition, the frequency of spontaneous reports of cancer associated with imatinib was analyzed based on cases collected in the clinical safety database. This analysis did not provide evidence for an increased overall incidence of malignancies or in the incidence of bladder, kidney or prostate tumors in patients treated with imatinib compared to that of an age adjusted general population.

In May 2005 Novartis updated the information on second malignancies as part of ongoing safety surveillance (unpublished observations, data on file Novartis). In all, 110 malignant neoplasms including 16 prostate ca, two urinary bladder ca and three kidney carcinomas, were reported up to May 10, 2005 in Novartis sponsored clinical trials of imatinib. The observed incidence rates were: 720.34 per 100 000 PY for all malignant cancers (excluding nonmelanoma skin cancer and malignancies representing progression of the underlying disease) and 262.01 per 100 000 PY for prostate cancer. To compare these with the incidence of cancer in the general population, standardized incidence ratios (SIRs) (i.e., ratios of observed to expected cases) standardized for gender and 5-year age groups were estimated, based on Surveillance, Epidemiology, and End Results (SEER) data (Surveillance, Epidemiology and End Results (SEER) Program (http://www.seer.cancer.gov)). The SIRs were 0.87 (95% CI 0.69–1.08) and 0.86 (95% CI 0.49–1.39) for all cancers and prostate cancer, respectively, showing that the numbers of cancers in the Novartis sponsored clinical trials are similar to those expected based on the rates in general population. This database continues to mature with a mean time-at-risk for the trial population of 1.16 years (0–4.91 years), defined as a period starting 4 weeks after the beginning of imatinib until the end of follow-up.

Roy et al. report that each of six patients at their Institution with a second malignancy was at least 60 years old. Specifically, among three patients who developed prostate cancer, two were 65 and one 69 years old. The authors calculated the incidence rate as 478.5 per 100 000 PY, compared it with incidence rates for age group 40–69 in France (region Bas-Rhin) for 1975–1977 (35.0 per 100 000) and for 1995–1997 (110.6 per 100 000) and concluded that the frequency of prostate cancer on imatinib is at least four times higher than expected. As stated in Quaglia et al.² prostate ca 'usually affects elderly subjects aged 65 years or more and is a rare disease before 50 years of age'. Incidence rates for prostate carcinoma increase dramatically with age: from 10.4 per 100 000 PY for the age group 40–49, through 118.7 for 50–59, and 507.5 for 60–69 years old men (average annual age-adjusted incidence rates in the US based on year of diagnosis 1992–2001: SEER) (Surveillance, Epidemiology and End Results (SEER) Program (http://www.seer.cancer.gov)). Thus, only a comparison of rates within relatively narrow age groups is scientifically justified. Although the majority of imatinib patients (69%) observed by Roy et al. were between 40 and 69 years old, the differentiation of incidence rates of prostate cancer in this age group precludes any valid comparison.

We would like to congratulate Roy et al. for monitoring their patient populations for ongoing and late side effects of therapy. Given the remarkable success imatinib has had in patients with CML, coupled with the necessity to continue therapy based on current results, we concur with the need for long-term monitoring of patients on imatinib for late effects. They also made reference to the investigator notification letter, which was sent on September 24, 2004 following the preliminary results coming from our 2 year preclinical carcinogenicity study performed in rats. To date, this preclinical information has not translated to a signal, we can detect in patients, but imatinib has been available to patients for less than a decade and close monitoring is called for. In keeping with the Company's commitment to ensure patient health and safety, Novartis will continue to monitor the long-term effects of treatment with imatinib, such as second malignancies, through ongoing clinical trials, as well as spontaneous reports from researchers and physicians. To date, no increased incidence of prostate cancer or any other type of human malignancy has been detected by Novartis in patients exposed to imatinib.

Top

References

Roy L, Guilhot J, Martineau G, Larchee R, Guilhot F. Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia. Leukemia 2005, Jul 14; [E-pub ahead of print].
Quaglia A, Parodi S, Grosclaude P, Martinez-Gracia C, Coebergh JW, Vercelli M. Differences in the epidemic rise and decrease of prostate cancer among geographical areas in Southern Europe: an analysis of differential trends in incidence and mortality in France, Italy and Spain. Eur J Cancer 2003; 39: 654–665. | Article | PubMed | ISI | ChemPort

Leukemia - Epidemiological analysis of second primary malignancies in more than 9500 patients treated with imatinib: "P R Pilot1, K Sablinska2, S Owen1 and A Hatfield1

1. 1Novartis Pharmaceuticals Corporation, East Hanover,New Jersey, USA
2. 2Novartis Pharma AG, Basel, Switzerland E-mail: Samantha_jane.owen@novartis.com

Reply to Roy et al. Leukemia advance online publication, 14 July 2005. Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia. In their correspondence,1 Roy et al. report that six among 189 CML patients treated with imatinib at their Institution developed a second malignancy. All of the patients had received interferon-based therapy before beginning imatinib therapy. The study reported that the appearance of second malignancies was potentially in accordance with the incidence of cancer in the French population, with the exception of prostate cancer, which was found in three patients. They reported this incidence to be higher than the expected incidence in a French population.

In November 2004 Novartis performed an epidemiological analysis of second primary malignancies among 9518 patients in our global database treated with imatinib during Novartis sponsored clinical trials as well as spontaneous adverse reports from approximately 124 000 patient years (PY) of treatment (unpublished observations, data "

Rheumatic diseases and chronic myelogenous leukemia, presentation of four cases and review of the literature

2006-03-05T23:03:00.000-05:00

Senel S, Kaya E, Aydogdu I, Erkurt MA, Kuku I.

Department of Internal Medicine Turgut Ozal Medical Center, Inonu University Faculty of Medicine, 44069, Malatya, Turkey, ssenel@inonu.edu.tr.

We report four patients with rheumatic disease (RD) and chronic myelogenous leukemia (CML). In two patients with Behcet's disease (BD) and rheumatoid arthritis (RA), CML developed after RD, in two patients with diffuse cutaneous systemic sclerosis and spondyloarthropathy, RD was diagnosed after CML. A variety of interactions have been described between hematological malignancies and RD. Nevertheless, few cases of RD have been documented associated with CML. It is unclear whether the development of CML in patients with RD and RD development after CML occurs by chance alone, is due to the underlying disease, or is facilitated by drugs. Whatever the cause is, it should be kept in mind that CML may develop in the course of RD and RD may be seen in CML patients.

Entrez PubMed

Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?

2006-03-05T23:02:00.000-05:00

John Goldman ^A1 and Myrtle Gordon ^A2

^A1 Hematology Branch, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA
^A2 Department of Haematology, Imperial College, London, UK

Abstract:

It is generally accepted that allogeneic stem cell transplantation can ‘cure’ chronic myelogenous leukemia (CML), although occasional patients relapse more than 10 years after the transplant procedure. Such cures presumably result from the combined effects of leukemia stem cells (LSCs) of the conditioning regimen and the graft-vs.-leukemia (GvL) effect mediated by donor-derived T lymphocytes. The advent of imatinib has revolutionized the management of patients with CML, but much evidence suggests that it does not eradicate all LSCs, which theoretically remain a potential source of relapse to chronic phase or advanced phase disease. Moreover, sub-clones of Philadelphia-positive cells bearing mutations that code for amino-acid substitutions in the Bcr-Abl kinase domain can be identified in patients receiving treatment with imatinib and are associated with varying degrees of resistance to this agent. In the present review, we postulate that LSCs, similar to their normal counterparts, may alternate between cycling and quiescent modes. In the cycling mode, they may express Bcr-Abl protein and be susceptible to the acquisition of additional mutations, whereas, in the quiescent mode, they may express little or no Bcr-Abl oncoprotein, cannot acquire additional mutations and are unaffected by imatinib. Thus, a patient who starts treatment early in the natural history of CML, and who responds to imatinib clinically, may not have had the opportunity to acquire additional mutations in LSCs. In this case, the persistence long-term of quiescent ‘non-mutated’ LSCs despite imatinib treatment might be consistent with freedom from relapse to chronic or advanced phase disease, provided that they remain vulnerable to imatinib when they are recruited into cycle. Conversely, when imatinib resistant Philadelphia-positive sub-clones predominate, this is likely to be due to the recruitment to hematopoiesis of quiescent stem cells that had been in cycle before administration of imatinib and that had acquired additional mutations; in such cases, the best approach to eradication of residual LSCs might be to target expressed proteins thought to be targets for the GvL effect.

Keywords:

CML, stem cells, SCT, imatinib, mutations

Taylor & Francis Group - Article

Blake MacDiarmid makes the rounds of political circles

2006-03-05T02:17:00.000-05:00

by Dale King, Julia Hebert

In Palm Beach County political circles, Blake MacDiarmid gets around.

He is passionate about politics, yet doesn’t aspire to elective office.

But those who do find his assistance most helpful.

MacDiarmid, 39, who calls Delray Beach home, though he also has lived in Maine and California, is one of those tough-to-define people called a political consultant.

“I fell into it,” said MacDiarmid, who has guided the campaigns of Boca Raton Mayor Steven Abrams, Delray Beach Mayor Jeff Perlman and Boynton Beach Mayor Jerry Taylor, among others.

He would have been the consultant for both Boca Raton City Councilman Bill Hager and for M.J. “Mike” Arts, who succeeds incumbent Councilwoman Susan Haynie this year.

But neither is opposed – and no election is needed.

MacDiarmid is working with Fred Fetzer and Brenda Montague, who are running for the Delray Beach City Commission March 14.

This tall, lanky Floridian isn’t consultant-like. He is comfortable in jeans and shorts, enjoys playing with his son, Ian, and spending time with his wife, Dorothy, who he calls “a professional volunteer.” She is president of the Junior League of Boca Raton and serves on the Heart Ball and Palm Beach County Historical Centennial committees.

They are also soul mates with much in common. “She is my rock,” he said of his wife of nearly 13 years. “We met in Delray Beach, we got married and then lived in Mizner Park. We were among the first urban dwellers. I had a consulting business, and she was a senior at Lynn University. She graduated summa cum laude,” he said with pride.

The veteran political consultant said it’s hard to define his job. “It’s the art of taking complicated matters and making them clear and concise for people to understand,” he said.

“Government is not simple,” he said. “And people prefer to live their own lives.” Most don’t have time to delve into such issues as taxes, growth and traffic.”

“I try to make things simple without making them too simple,” he said. “And that’s the challenge – not to make them too simple.”

“People don’t want to hear about politics or politicians,” he noted. “But when they do pay attention, they deserve straight talk.”

MacDiarmid thinks he’s done that. He’s been involved in some four-dozen campaigns – and only two didn’t hit the mark.

Unlike consulting firms, MacDiarmid works alone. “It’s me, my cell phone and my Blackberry. I am truly a mobile professional.”

MacDiarmid attended schools in Gulfstream; St. Andrews High School and Florida Atlantic University, earning a degree in political science. “I went right into politics,” he said. “But I was burned out by age 25.”

“I thought I would go into the family business,” innkeeping,” he said. He did – for a while. In fact, his parents and brother run a family-style, bed-and-breakfast-type inn in Maine.

For the MacDiarmids, 1997 was a critical time. “I was diagnosed with leukemia,” he said. Specifically, Chronic Myelogenous Leukemia.

“I was visiting here for Thanksgiving,” he recalled. And after being diagnosed, he said, “I was told to get my affairs in order.”

The MacDiarmids went to Dana Farber Cancer Institute in Boston – without positive results.

In 1998, they discovered a new drug in San Diego, Calif. It was called Gleevec – and “was one of the first truly targeted DNA drugs.”

He took a couple of years off to recover – and has been in remission for three years.

MacDiarmid is also into sailing – and has become a seaman of note. He skippered his Melges 24 to victory in the San Diego Volvo Leukemia Cup Regatta, beating America’s Cup winner Dennis Connor in the process.

“I remember sitting on the patio overlooking Del Mar and talking to a friend. He said, ‘What are you going to do now?’ He asked me about sailing, and I said I can’t make money sailing.”

So he returned to politics. “We packed up the Suburban and headed back to Palm Beach County.”

Meeting Steven and Debbie Abrams in the mid-1990s helped him get back his political sea legs.

He said he prefers to work on local elections. He has been a consultant for Palm Beach County Commissioners Karen Marcus and Mary McCarty, state Sen. Jeff Atwater, state Rep. Ellen Bogdanoff and U.S. Rep. E. Clay Shaw, to name a few.

Right now, he is working – gratis -- for passage of two referendum questions on the March 14 ballot in Boca Raton. One is a pay raise for the mayor and council members; the other a change from two-year to three-years terms for office holders. He said he believes in both – even though the latter will cut into his pay because Boca would not have to hold a municipal election every year.

MacDiarmid admits that he tries to “shut the cell phone off” every now and then to enjoy a private life.

He does in the summer. For eight weeks each year, he sheds his political consultant trappings to run a sailing program in Southport, Maine. It gives him time to relax and reflect – and to share time with 7-year-old son, Ian, a budding filmmaker – and whose knowledge of movies seems bottomless. “He loves to watch the ‘making-of’ segments at the end of DVDs,” said Ian’s dad.

MacDiarmid sees politics coming back into vogue. “Ten years ago, no one knew what a political consultant was,” he said. “Now, they do. And they want to be engaged in politics.”

If anything, the consultant added, politics – and his life -- “is never boring.”

Dale M. King can be reached at 561-549-0832 or at dking@bocanews.com.

Boca Raton News - The Leader in Local News Online

Newly Discovered Killer Cell Fights Cancer

2006-03-04T12:27:00.000-05:00

BALTIMORE, March 3 (AScribe Newswire) -- A mouse immune cell that plays dual roles as both assassin and messenger, normally the job of two separate cells, has been discovered by an international team of researchers from the United States and France. The discovery has triggered a race among scientists to find a human equivalent of the multitasking cell, which could one day be a target for therapies that seek out and destroy cancer.

"In the same way that intelligence and law enforcement agencies can face deadly threats together instead of separately, this one cell combines the ability to kill foreign pathogens and distribute information about that experience," says Drew Pardoll, M.D., Ph.D., the Seraph Professor of Oncology at the Johns Hopkins Kimmel Cancer Center.

"We think this hybrid cell speeds up immune reactions and makes the system more efficient," adds Pardoll, whose findings are reported in the February issue of Nature Medicine.

The Hopkins investigators speculate that the hybrid, dubbed "IKDC" for interferon-producing killer dendritic cell, has been missed by cancer biologists because it is rare, making up one-tenth of cells in the spleen with similar features, such as other dendritic cells, according to Frank Housseau, Ph.D., research associate at Hopkins' Kimmel Cancer Center and member of Pardoll's immunology laboratory.

Most of the immune system typically works through a web of cross-talk and signaling among a variety of cells. One of the first immune cells that invading bacteria or cancer cells - both of which carry antigens that alert the immune system - may encounter is a natural killer (NK) cell. As its name implies, NK cells deliver a deadly blow by poking holes in the invader's outer membrane. Then, NK cells secrete molecules that reach other immune cells, including dendritic cells, known as the main messenger for the immune system. Dendritic cells spread "look here" information about foreign invaders to other immune cells, but do not actually kill the invaders.

It was while investigating a particular type of dendritic cell that Housseau noticed the outer membranes of these cells were studded with what were supposed to be hallmarks of NK cells, akin to finding feathers on a dog.

"We thought we were looking at dendritic cells, but we were wrong - they were some type of NK-dendritic cell blend," says Housseau. The blended cell turned out to be a newly identified actor on the immune system stage that retains all the molecular characteristics of both NK and dendritic cells.

Probing further, Housseau scoured the surface of IKDCs to create a sketch of its molecular profile. He found that it produces both types of interferon proteins, normally secreted independently by NK and dendritic cells. He also found both NK and dendriticlike molecules on the surface of IKDCs. Housseau calculated that they account for about 10 percent of conventional dendritic cells in the spleen.

IKDCs begin their lives behaving like an NK cell. After the cell encounters a pathogen, the cell switches roles from killer to dendriticlike messenger, and, according to the researchers, the swap occurs only once. Then, the cell dies and is replenished by the bone marrow.

"When an IKDC cell switches to its messenger function, the transformation is quite astonishing," says Pardoll. The cell sprouts long, hairy tentacles called dendrites. It uses its "arms" to increase the amount of surface area it reaches to communicate and interact with other immune cells.

In the next step of their investigation, the scientists tracked the location of fluorescent-tagged IKDCs and their corresponding stage of transformation after infecting mice with bacteria called listeria. In assassin-mode, the IKDCs were found in the blood, lining of the gut, liver and other organs - all areas where there is close contact with environmental pathogens. "Here, IKDCs are ready to sense invaders and spring into action," says Housseau.

Then, the group tracked the cells to the main messenger center of the immune system - the lymph nodes. Here, they found approximately 35 percent of the original group of IKDCs now secreting communication molecules signaling a switch to messenger-mode.

Simultaneously, Housseau's colleagues in France, led by Laurence Zitvogel at the Institut Gustave Roussy, tested whether IKDCs are culprits in killing cancer by injecting mice with a cancer drug called Gleevec, which blocks an abnormal protein produced by cancer cells, and a growth factor for NK cells. The drug-growth factor combo served as a lure, leading the IKDCs to tumors implanted in the mice. The results were that tumors shrunk in mice, which received injections of IKDCs, but not in those receiving conventional NK cells only. Evidence from the shrunken tumors revealed certain "cell-killing" proteins that could be traced to IKDCs. These results are published separately in Nature Medicine.

Housseau's group is conducting further studies to verify the role of IKDC cells in infection and cancer. Meanwhile, the group is profiling IKDC genes to find a specific marker that could help them identify a human counterpart.

The Hopkins research was funded by the National Institutes of Health, the Janney Fund and Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle.

Participants in the research include Camie W. Chan, Emily Crafton, Hong-Ni Fan, James Flook, Kiyoshi Yoshimura, Mario Skarica, and Monique F. Stins from Johns Hopkins; Dirk Brockstedt and Thomas W. Dubensky from Cerus Corporation; and Lewis L. Lanier from the University of California, San Francisco.

"Interferon-producing killer dendritic cells provide a link between innate and adaptive immunity." Nature Medicine 12, 167 - 168 (2006).

- - - -

CONTACT: Vanessa Wasta, Johns Hopkins Kimmel Cancer Center Office of Public Affairs, 410-955-1287, wastava@jhmi.edu

VIDEO FOOTAGE AVAILABLE: IKDC cell killing a cancer cell. Courtesy of the Institut Gustave Roussy.

ON THE WEB: http://www.hopkinskimmelcancercenter.org

Media Contact: See above.
Untitled Document

Irrepressible Marsden back again

2006-03-04T12:26:00.000-05:00

STUART BATHGATE

SOMETIMES gold medallists retire immediately, eager to quit at the top. Sometimes they hang on to defend their title, and then go if they fail to retain it. Only rarely do they keep coming back time after time - but that is precisely what Ian Marsden will be doing at the Commonwealth Games in Melbourne.

Now 46, Marsden, who competes in the skeet shotgun event, was the gold medallist in Auckland in 1990. Even then he was pretty experienced, having first participated in the Games in 1986, when they were held for the second time in Edinburgh, and having won his first cap for Scotland five years before that.

So he would have been forgiven if he had wanted to bow out at the top, or even four years later when he took bronze in Victoria. Yet he kept going in the most adverse of circumstances.

It was a year or so after the 1998 Games in Kuala Lumpur that Marsden, the manager of a Perthshire estate, was diagnosed with leukaemia. The players and staff at St Johnstone immediately volunteered for blood tests to see if they were suitable bone-marrow donors: the tests proved negative, but the footballers' gesture was an indication of the support offered by the local community, and Marsden was in no way dismayed. "You have to hold out hope, and as a sportsman I'm using my determination to help stay strong," he said then.

That determination was vindicated two years later, when treatment with a drug called Gleevec cured him of his potentially fatal condition. Having kept relatively fit throughout his illness, Marsden again represented Scotland in the Commonwealth Games of 2002, held in Manchester.

Twenty years on from his first Games, he is looking forward just as eagerly to competing in Australia as he was back then to shooting in his own country.

"It's a bit out of season for us, my sport especially, but training has been good and the weather's been kind recently, so we're well prepared," he said. "Shooting is an outdoor sport, so my season is basically April till September.

"It couldn't be more out of season than we are now, but things are looking well. In the off season we just try to train whenever possible, when the weather suits and the daylight is adequate."

While he patently has an aptitude for and an enjoyment of shooting, Marsden feels a particular affinity for the competitive environment. Try as he might, he has never quite been able to give of his best in training, which makes it hard to work out exactly what form he might be in.

"I'm the type of animal who is lifted by the event," he explained. "I probably only function at 95 per cent in training. It's all very tight. You need to be 100 per cent on form, and you need a bit of luck as well. It's only one target that will split those medals after 150, so it's very, very close.

"I wouldn't say I get nervous, but when the pressure is on I get aware of it. You can't afford to be blase at that level. Being a shotgun shooter it's not so vital that I keep absolutely still. It's a moving game. But you certainly don't want your knees banging together. That wouldn't help."

Something else that does not help is the isolation often imposed on the shooting competition. At the Manchester Games, for instance, the shooting went ahead in Bisley, Oxfordshire; as a result, the publicity it received was considerably less than the other so-called minority sports.

This time, however, is different, and Marsden's memories of Melbourne make him particularly glad that he and his colleagues will be less detached this time.

"Our venue is about an hour's drive from the village, which is nearer than Bisley was to Manchester. And previously, in 1998 [in Kuala Lumpur], we were detached as well, because we were on an island. So it will be nice to be back in the main village and feel more attached to the event as a whole.

The relative lack of publicity in the past, however, has never prevented Marsden from feeling under pressure to do well. Some of that comes from within, from his own high standards, but a lot also comes from a general public presumption that Scotland's shooters will always be good for a couple of medals.

"There is pressure on us here, because we've always been very successful at shooting," he explained. "So there are expectations made of us. It's a pity that we don't get the media exposure that some other sports get, but we've learned to live with that. We'll enjoy it just the same."

And like his team-mates, Marsden will enjoy it all the more because he is representing Scotland. "At world championships you're always under the GB flag," he said. "It's nice to represent Scotland, and this is the highest level under that flag."

Scotsman.com Sport - Irrepressible Marsden back again

Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction -- Copland

2006-03-04T12:23:00.000-05:00

Mhairi Copland, Ashley Hamilton, Lucy J Elrick, Janet W Baird, Elaine K Allan, Niove Jordanides, Martin Barow, Joanne C Mountford, and Tessa L Holyoake*

Section of Experimental Haematology and Haemopoietic Stem Cells, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, Scotland, United Kingdom
Department of Haematology, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom

* Corresponding author; email: tlh1g@clinmed.gla.ac.uk.

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukaemia (CML). We have previously demonstrated that IM reversibly blocks proliferation, but does not induce apoptosis, of primitive CML cells. Here we have attempted to overcome this resistance with Dasatinib. Primitive IM-resistant CML cells showed only single copy BCR-ABL, but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared to more mature CML cells (p=0.031). In addition CrKL phosphorylation (P-CrKL) was higher in the primitive CD34+38- than the total CD34+ population (P=0.002). In total CD34+ CML cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population. CD34+38- CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas Dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or Dasatinib-resistant primitive CML cells. These data confirm that Dasatinib is more effective than IM within the CML stem cell compartment, however the most primitive quiescent CML cells appear to be inherently resistant to both drugs.
Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction -- Copland et al., 10.1182/blood-2005-07-2947 -- Blood

Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction -- Copland

2006-03-04T12:22:00.000-05:00

Mhairi Copland, Ashley Hamilton, Lucy J Elrick, Janet W Baird, Elaine K Allan, Niove Jordanides, Martin Barow, Joanne C Mountford, and Tessa L Holyoake^*

Section of Experimental Haematology and Haemopoietic Stem Cells, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, Scotland, United Kingdom
Department of Haematology, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom

^* Corresponding author; email: tlh1g@clinmed.gla.ac.uk.

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitorexhibits greater potency than imatinib mesylate (IM) and inhibitsthe majority of kinase mutations in IM-resistant chronic myeloidleukaemia (CML). We have previously demonstrated that IM reversiblyblocks proliferation, but does not induce apoptosis, of primitiveCML cells. Here we have attempted to overcome this resistancewith Dasatinib. Primitive IM-resistant CML cells showed onlysingle copy BCR-ABL, but expressed significantly higher BCR-ABLtranscript levels and BCR-ABL protein compared to more matureCML cells (p=0.031). In addition CrKL phosphorylation (P-CrKL)was higher in the primitive CD34⁺38^- than the total CD34⁺ population(P=0.002). In total CD34⁺ CML cells, IM inhibited phosphorylationof CrKL at 16 but not 72 hours, consistent with enrichment ofan IM-resistant primitive population. CD34⁺38^- CML cells provedresistant to IM-induced inhibition of CrKL phosphorylation andapoptosis, whereas Dasatinib led to significant inhibition ofCrKL phosphorylation. Kinase domain mutations were not detectablein either IM or Dasatinib-resistant primitive CML cells. Thesedata confirm that Dasatinib is more effective than IM withinthe CML stem cell compartment, however the most primitive quiescentCML cells appear to be inherently resistant to both drugs.

Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction -- Copland et al., 10.1182/blood-2005-07-2947 -- Blood

Patients turn to Internet to battle illness

2006-02-27T01:01:00.000-05:00

When a blood test in 2000 showed he had chronic myelogenous leukemia, Bryce Morgan first called a doctor friend.

Next, he went online.

Morgan used the Internet to check out his oncologist's qualifications, to decide where to undergo his bone-marrow transplant and to learn what to expect during his recovery.

"It took the fear out," said Morgan, 51, a computer consultant from Buffalo. "I felt like I was in control of my destiny, as much as I could be."

Morgan is one of a growing number of people in Western New York and across the country using the Internet to research diseases, alternative treatments and new drugs.

Patients say this online research makes them feel like a partner with their doctor.

"It helps me have a conversation with an educated partner, even if some of that information is a little askew," said Dr. Thomas C. Rosenthal, chairman of the family medicine department at the University at Buffalo School of Medicine and Biomedical Sciences.

Internet surfing replaced the digging that patients had to do in libraries 10 or 20 years ago.

Those not able to devote the time to search a library's shelves had to rely on anecdotal information from a relative or co-worker. But people back then were more reluctant to talk about an illness such as cancer, doctors noted.

For the most part, only doctors had access to journal articles or data from clinical trials, so the doctor-patient relationship tended to be paternalistic.

That has changed, in large part as a result of the Internet.

Seventy-nine percent of Internet users say they have gone online to research at least one health topic, according to a 2005 survey by the Pew Internet & American Life Project.

Researchers in UB's School of Nursing surveyed 20 female cancer patients about how they used the Internet.

"[Internet research] changes it from a death sentence to an idea that it's a chronic illness, something to be dealt with," said Suzanne S. Dickerson, a UB associate professor of nursing and principal investigator on the study, published in the Oncology Nursing Forum.

Dr. Irene S. Snow, medical director of the Buffalo Medical Group, said that, five years ago, only one of the 20 patients she saw each day in her Williamsville office would ask a question based on online research. Today, it's at least one in four, she said.

Doctors' reluctance

Not every doctor is thrilled when patients bring up a second opinion from a Web site.

"Some doctors resent the patients coming in with this information. We see that," said Bill McLaughlin, 77, a Clarence resident and leader of the Buffalo metro area chapter of Us TOO, a prostate cancer education and support network.

Marcia Heaney, diagnosed with breast cancer in 2001, said the first oncologist she consulted simply told her what to do.

She sought a second opinion from another oncologist, who urged her to take her time in researching and considering all the possible treatments.

"There are a number of different options for treatment, and you need to be an educated consumer," said Heaney, president of the Breast Cancer Network of Western New York.

Patients tend to ask more and better questions after online searches, said Dr. Judy L. Smith, a surgical oncologist and medical director at Roswell Park.

"It makes the physician's job easier," she said.

With thousands of medical Web sites, how reliable is the information available online?

Physicians and medical experts said the Web sites vary considerably, so patients need to consider the source of the information on each site.

Those experts said reputable sites include WebMD.com,
Family-Doctor.org and MedLinePlus.gov, as well as the disease-specific sites of groups like the American Diabetes Association.

One feature on the WebMD site allows visitors to indicate their symptoms - using a model of a human body - and to get a possible diagnosis in response. But, a note cautions: "This information is not intended to replace the advice of a doctor."

Dr. James G. Corasanti said the Internet is useful as long as patients don't use it to self-diagnose their ailment.

"[Patients] know what's being done at [the Mayo Clinic], Cleveland Clinic. They demand excellence, which is good," said Corasanti, medical director of the gastrointestinal laboratory at Buffalo General Hospital.

Caution urged

Morgan, the computer consultant, said his search showed that his oncologist had published 15 papers in the previous nine years.

"I read them all," Morgan said.

Joan Morrissey moved to Snyder two years ago from Atlanta, where she worked as a health communicator for the Centers for Disease Control. Her job involved steering callers to credible online sources of information.

On Easter Sunday 2004, Morrissey awoke to find her right breast red and painfully swollen. She soon learned she had inflammatory breast cancer, a rare form of the illness.

Her cancer is now at the advanced stage 4, and further options for treatment are limited.

At the online recommendation of another patient, Morrissey is taking Avastin, a drug that limits the growth of cancer cells by stopping the production of new blood vessels, and Taxol, a traditional chemotherapy drug.

She said she uses the Internet judiciously.

"Sometimes I get on there, and it gives me encouragement. And sometimes you get trapped, just by reading [patient diaries], and I get depressed," said Morrissey, 42.

Nancy Kelly also said she avoided reading patient diaries, preferring to get hard information that will help her with her own fight against melanoma.

"The Internet is incredibly frank, not that you need all that information every day," said Kelly, 57, a South Buffalo resident and retired county worker who volunteers at Roswell Park.

A number of well-meaning sites also might have inaccurate information.

Patients also need to be cautious with sites that have a financial motivation, all agreed.

Rosenthal, the chairman of UB's family medicine department, recalled a pediatric patient whose mother initially wanted to treat her son's condition with a natural supplement instead of prescription medicine. The same site recommended and sold the supplements, Rosenthal said.

The digital divide between those who can afford access to the Internet and those who can't also remains an issue.

Doctors with primarily suburban practices said their patients regularly use the Internet.

Dr. Chester H. Fox, a physician with the Jefferson Family Medicine Clinic in Buffalo, said his patients largely do not, and he is unable to recommend Web sites where they can do research.

Other doctors note patients have access to computers in area public libraries. And Roswell Park, for example, offers Internet access at a cancer resource center and on laptops that patients can take to their rooms.

The hospital also has set up three computer kiosks where patients can look up and print out information provided by the National Cancer Institute.

e-mail: swatson@buffnews.com

Buffalo News - Patients turn to Internet to battle illness

Photodynamic treatment (ALA-PDT) suppresses the expression of the oncogenic Bcr-Abl kinase and affects the cytoskeleton organization in K562 cells.

2006-02-24T23:57:00.000-05:00

Pluskalová M, Pešlová G, Grebeňová D, Halada P, Hrkal Z

J Photochem Photobiol B. 2006 Feb 20;

Monolateral renal infarction and erythromelalgia in a case of chronic myelogenous leukemia.

2006-02-24T23:56:00.000-05:00

Bernardini K, Lanthaler AJ, Buratti T, Mitterer M

Am J Hematol. 2006 Feb 21; 81(3): 224-225

No Abstract.

Monolateral renal infarction and erythromelalgia in a case of chronic myelogenous leukemia.

The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by rea

2006-02-24T23:55:00.001-05:00

Han JY, Theil KS

Cancer Genet Cytogenet. 2006 Feb ; 165(1): 70-4

The Philadelphia chromosome (Ph) as a secondary cytogenetic abnormality is a rare event. It is observed mostly as an additional, late-appearing cytogenetic change during the evolution of acute leukemia and its presentation as a secondary change at the onset of disease is much rarer. We describe here a patient with acute myelogenous leukemia (AML) who had Ph as a secondary chromosome abnormality at diagnosis. Cytogenetic analysis showed an abnormal karyotype, 45,XY,inv(3)(q21q26),-7[4]/45,idem, t(9;22)(q34;q11.2)[16]. The p190 variety of BCR-ABL rearrangements was confirmed by a real-time reverse-transcriptase polymerase chain reaction using fluorescent probes. To our knowledge, the minor BCR-ABL fusion gene involving a secondary Ph superimposed on inv(3) and monosomy 7 has not been reported in AML at diagnosis. Along with the identification of more cases, it will be possible to understand the exact role of this secondary Ph in a multistep leukemogenesis.

The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by real-time quantitative polymerase chain reaction.

Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.

2006-02-24T23:55:00.000-05:00

Heinonen KM, Dubé N, Bourdeau A, Lapp WS, Tremblay ML

Proc Natl Acad Sci U S A. 2006 Feb 13;

Protein tyrosine phosphatase 1B (PTP-1B) is a ubiquitously expressed cytosolic phosphatase with the ability to dephosphorylate JAK2 and TYK2, and thereby down-regulate cytokine receptor signaling. Furthermore, PTP-1B levels are up-regulated in certain chronic myelogenous leukemia patients, which points to a potential role for PTP-1B in myeloid development. The results presented here show that the absence of PTP-1B affects murine myelopoiesis by modifying the ratio of monocytes to granulocytes in vivo. This bias toward monocytic development is at least in part due to a decreased threshold of response to CSF-1, because the PTP-1B -/- bone marrow presents no abnormalities at the granulocyte-monocyte progenitor level but produces significantly more monocytic colonies in the presence of CSF-1. This phenomenon is not due to an increase in receptor levels but rather to enhanced phosphorylation of the activation loop tyrosine. PTP-1B -/- cells display increased inflammatory activity in vitro and in vivo through the constitutive up-regulation of activation markers as well as increased sensitivity to endotoxin. Collectively, our data indicate that PTP-1B is an important modulator of myeloid differentiation and macrophage activation in vivo and provide a demonstration of a physiological role for PTP-1B in immune regulation.
Protein tyrosine phosphatase 1B negatively regulates macrophage development through CSF-1 signaling.

Gleevec is out of patent loop in India

2006-02-24T10:46:00.000-05:00

NEW DELHI: The controversy over the introduction of product patents for drugs has come full circle. Gleevec, the much sought-after cancer drug that has been the face of the campaign against the new WTO-compliant patent law, can now be made and sold at more affordable rates by Indian companies.

In its latest journal of February 17, the Indian Patent Office notified the termination of exclusive marketing right (EMR) granted two years ago to Swiss major Novartis for Gleevec.

This follows its decision on January 25, rejecting the application of Novartis for what could have been the first-ever product patent in India for a pharmaceutical drug. It was only last year that product patents were introduced in India for drugs and chemicals complying with the deadline imposed by Trade Related Intellectual Property Rights (TRIPS).

Novartis had been granted EMR for Gleevec in November 2003 in anticipation of the product patent regime that was due to be installed in India by January 1, 2005.

Relief: Cancer drug is out of patent loop- The Times of India

Test Now Available to Detect Resistance to Gleevec® in Chronic Myeloid Leukemia

2006-02-23T12:29:00.000-05:00

Genzyme Corporation has announced that they have just made a test available to the public that can detect whether a patient with chronic myeloid leukemia (CML) is resistant to treatment with Gleevec® (imatinib mesylate).

Gleevec is the standard treatment for patients with newly diagnosed CML. Over 90% of patients respond well to initial treatment with long-term benefit. However, 5-10% ultimately develop resistance, which is apparently due to secondary mutations of BCR-ABL. The new BCR-ABL Mutation Analysis test may help determine whether a patient is resistant to Gleevec. It tests for specific mutations that are present when a patient does not respond to Gleevec.

Comments: At the present time it is not clear how clinically useful the determination of specific mutations will be in the treatment of Gleevec resistant CML. Understanding of the mechanisms of resistance has led to the development of agents such as dasatinib and AMN107. However, the current paucity of agents available for the treatment of Gleevec resistant disease may limit the clinical utility of specific tests. AT the present time empiric treatment with available drugs is probably the only way to manage Gleevec resistant patients. The BCR-ABL Mutation Analysis may, however, provide insight into disease resistance.

Reference: Genzyme Corporation. Genzyme Launches Key Test To Monitor Gleevec® Resistance. Available at: http://www.genzyme.com/corp/media/GENZ%20PR-020906.asp#TopOfPage. Accessed February 2006.

Sick S-burg student has school spirit

2006-02-23T12:26:00.000-05:00

Dan Berrett
Pocono Record Writer
February 23, 2006

STROUDSBURG — Salli Chacon knew something was wrong with her daughter, Danica.

The girl had been sleeping more than usual. Her mother thought that Danica's fatigue was due to her earlier wake-up time now that she was attending Stroudsburg Middle School.

By December, Chacon grew worried enough that she got some blood work done for her daughter. The white blood cell count was abnormally high. She had leukemia.

Chacon wrestled with how to break the news to her daughter. The 13-year-old cut to the chase.

"Mommy, I have cancer," she said, according to her mother. "Am I going to die?"

Since then, the Chacons' lives have been occupied with the battle against the disease: taking medication and searching for a bone marrow donor.

But they also tried to maintain life as usual. "She hasn't missed a day of school," said Chacon. "We're trying to keep everything normal for her."

Considering the situation, the family has been fortunate; Danica has responded to her medicine, Gleevec, and her brother, Jayson, 15, is a perfect match for a transplant. She is one of about 2,200 young people in America who are afflicted with leukemia each year; it accounts for about 25 percent of all childhood cancers, according to the National Institutes of Health.

Her classmates and teachers at the middle school have pitched in, too. The student government launched a lollipop sale fundraiser that brought in over $4,400.

The family will likely use the money to defray income it will lose this summer, when Chacon will stop working to stay by her daughter's bedside after her bone marrow transplant at Children's Hospital of Philadelphia. The surgery hasn't been scheduled yet, but the recovery period can take up to three months.

"I really don't know what to expect," said Chacon.

The class that raised the most money in each grade received a few prizes. On Tuesday, the winning sixth-grade class had an ice cream party. On Wednesday morning, it got an extra bonus: being taught by the school's principal, Ray Scarpantonio.

"This is one of the things that you miss the most," Scarpantonio said to Andrea Link's social studies class. He led the 24 sixth-graders in a lesson that combined math and American history.

They plotted points on pieces of graph paper while Scarpantonio taught them ordinal and cardinal directions on an overhead projector.

After connecting the dots that they plotted, the students saw that it formed a portrait of George Washington. The rest of the class was spent on a lesson about the first president.

"It was funner than the usual class," said Ciara Banks, 11, as she gathered her books.

The school's efforts for Danica Chacon will continue. On April 8, it's planning to host a bone marrow registry. A blood drive is also in the works.

"This will be a way to show my thanks," said Chacon. "My daughter was so fortunate because her brother was a perfect match."

Pocono Record - Sick S-burg student has school spirit

Acute Graft Versus Host Disease Activity Index Can Be Used to Predict Non-Relapse Mortality: Presented at ASBMT

2006-02-21T23:39:00.000-05:00

By Alan McClelland

HONOLULU, HI -- February 21, 2006 -- Researchers have developed an evidence based real-time scoring system for quantitative assessment of acute graft versus host disease (GvHD) activity.

According to George McDonald, MD, Fred Hutchinson Cancer Research Center in Seattle, Washington, United States, presented the acute GVHD activity index model at the 2006 Blood and Marrow Transplantation Tandem meetings (ASBMT).

Current scoring systems for acute GvHD are inadequate due to retrospective assignment of scores, failure to take efficacy of treatment into account and variability between observers, Dr. McDonald explained during his presentation on February 17^th.

An improved grading system would help determine prognosis in individual patients and quantify the burden of GvHD over time, he said.

Dr. McDonald and colleagues developed the system by examining and scoring the severity of GvHD symptoms and abnormalities, use of immunosuppressive drugs, and performance status in 386 patients with chronic myelogenous leukemia (CML) who underwent allogeneic hematopoietic stem cell transplantation.

The researchers scored patients at 10 day intervals from the onset of GvHD until day 100 and used data from 191 randomly selected patients to generate an activity index that they say predicts non-relapse mortality at day 200.

Parameters that they found contribute to the predictive value of the model include liver dysfunction (serum bilirubin levels), upper gastrointestinal tract abnormalities (reduced caloric intake, nausea, vomiting), immunosuppressive therapy and performance status.

The investigators tested the accuracy of the model in predicting day 200 non-relapse related mortality against an independent data set of 193 patients and obtained good predictive values comparable to those obtained with the initial data set used to develop the model (area under receiver operator curve of 0.87), Dr. McDonald said.

Advantages of the activity index are that it is evidence based, easy to calculate, can be used in real time and has good predictive value for non-relapse related mortality, he said.

"This score puts an objective number on a subjective clinical observation," Dr. McDonald said. As such, it should be a useful tool to help clinicians determine when to initiate more aggressive therapy for GvHD and might also be of use for stratification of patients according to risk of mortality in therapeutic trials, he added.

[Presentation title: Determining Prognosis for Patients with Acute GVHD in Real Time; Development and Testing of an Acute GVHD Activity Index. Abstract 29]
News - Acute Graft Versus Host Disease Activity Index Can Be Used to Predict Non-Relapse Mortality: Presented at ASBMT

The Hindu Business Line : Exclusive marketing rights for Novartis' cancer drug cancelled

2006-02-21T17:41:00.000-05:00

C.R. Sukumar

Natco Pharma had challenged the grant of EMRs to Novartis. The grant of EMRs to Novartis had forced several Indian pharmaceutical companies such as Ranbaxy, Cipla, Sun, Hetero, Torrent and Emcure to withdraw their generics from the market.

Hyderabad , Feb. 21

IN yet another blow to the Swiss pharmaceutical giant Novartis AG in the Indian pharmaceuticals market, the Indian Patents Office has terminated the exclusive marketing rights (EMRs) granted to the company on November 10, 2003 for Gleevac (Imatinib Mesylate), a life saving anti-cancer drug, with effect from January 25, 2006.

Interestingly, on January 25 this year, the Swiss company had lost a patent claim for the anti-cancer drug — Imatinib Mesylate — before the office of the Indian Controller of Patents & Designs, following serious objections through pre-grant opposition route raised by Natco Pharma Ltd, a Hyderabad-based pharma company.

The Controller of Patents had refused to proceed further with Novartis patent application for Gleevac, which is used in the treatment of chronic myeloid leukaemia.

Interestingly, the Indian Patents Office has now decided to cancel the EMRs granted to Novartis based on the same grounds raised by the Office of Controller of Patents & Designs.

Citing the order of Office of the Controller of Patents & Designs dated January 25 in a notification dated February 17, the Indian Patents Office said, "Therefore, as per Section 78 of the Patents (Amendment) Act 2005 read with Section 24B of the Patents Act 1970 as amended by the Patents (Amendment) Act 2002, the said Exclusive Marketing Right granted to Novartis AG is hereby terminated with effect from January 25, 2006."

Natco Pharma, which launched a generic version of Gleevac under the brand `Veenat', had challenged the grant of EMRs to Novartis.

The grant of EMRs to Novartis had forced several Indian pharmaceutical companies such as Ranbaxy, Cipla, Sun, Hetero, Torrent and Emcure to withdraw their generics from the market.

Though the price difference between Gleevec and its clones was around twelve-fold, the domestic pharmaceutical companies were restrained from manufacturing and marketing the cheaper clones due to a Court order.

This case is currently pending before the Supreme Court.

The Office of Controller of Patents on January 25 ruled that the patent applied for by Novartis AG did not qualify as an invention on the grounds that it was merely a modification of the key component in the drug, for which a patent had already been filed in 1993.

Therefore, according to the Controller of Patents, this key component can not be eligible for protection under new patent regime of India that was introduced in March 2005 to comply with the WTO agreement on trade related aspects of intellectual property rights (TRIPS) that recognises patents for chemical products filed there after 1995, the year the WTO came into existence.

The Hindu Business Line : Exclusive marketing rights for Novartis' cancer drug cancelled

Stem cells might be key to cancer

2006-02-21T11:57:00.000-05:00

Research could shape new treatments
By NICHOLAS WADE
New York Times
Posted: Feb. 20, 2006

One day, perhaps in the distant future, stem cells may help repair diseased tissues. But there is a far more pressing reason to study them: Stem cells are the source of at least some, and perhaps all, cancers.

At the heart of every tumor, some researchers believe, lie a handful of aberrant stem cells that maintain the malignant tissue.

The idea, if right, could explain why tumors often regenerate even after being almost destroyed by anti-cancer drugs. It also points to a different strategy for developing anti-cancer drugs, suggesting they should be selected for lethality to cancer stem cells and not, as at present, for their ability to kill just any cells and shrink tumors.

"I think this is one of the most interesting developments in cancer research in the last five years," said Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Mass. "I think more and more people are accepting it, and evidence is accumulating that cancer stem cells exist in a variety of tumors."
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The idea that cancer cells possess the same properties as stem cells has been around for many years. Only recently have biologists developed techniques for identifying stem cells and their presence in tumors.

Cancer stem cells were first identified in certain types of leukemia in 1997 by John Dick and colleagues at the University of Toronto. They were harder to spot in solid tumors because biologists did not possess the means of recognizing the markers - characteristic proteins on the surface of a cell - that had been developed for a stem cell that makes red and white blood cells.

But in 2003, Michael Clarke, now of Stanford University, succeeded in finding cancer stem cells in breast tumors. Clarke showed that a vast majority of cells in a human breast tumor were incapable of further growth. Only a handful were able to seed new cancers, and these resembled stem cells in their ability to proliferate and generate mature cells.

In 2004, Peter Dirks of the University of Toronto identified similar stemlike cells in human brain tumors, and last year C. Parker Gibbs of the University of Florida reported seeing stemlike cells in bone cancer.

"It's a very challenging population of cells to identify, but thus far in every cancer in which cells have been carefully screened they have been found," said Gary Gilliland of Harvard University.
Process is unclear

Biologists are not yet sure how cancer stem cells are generated. It may be that the stem cells themselves suffer a mutation, or a change in their DNA instructions, that deranges the strict controls on their self-renewal. Or possibly their immediate progeny, known as progenitor cells, suffer some genetic damage after which, instead of developing into mature cells, they regain the power of self-renewal.

Self-renewal, the key property of stem cells, refers to their ability to divide unevenly. Other cells divide into two daughter cells, just as the parent cell does, but a stem cell can divide into a new stem cell and a progenitor cell. The progenitor cell loses the power of self-renewal but gains the ability to change or differentiate into the mature cell types of the tissue served by the stem cell.

After such a division, the number of stem cells in the tissue remains unchanged because one stem cell has been lost and one created. The stem cell population thus renews itself as it generates new cells.

The stem cells responsible for maintaining a tissue or an organ can presumably regulate their own numbers, perhaps by sensing through an exchange of chemicals when they have a quorum. Cancer stem cells differ in that they have lost control over their own population size.

The hypothesis explains several otherwise puzzling facts about cancer. Many of the body's tissues that are most prone to cancer, like the blood, skin and lining of the gut, are composed of short-lived cells that suffer high wear and tear.

Yet cells are believed to become malignant only after a series of mutations has disabled their genetic control systems. How can a skin cell, which lives only a few weeks, survive long enough to accumulate the right sequence of mutations?

It is more plausible to suppose that mutations build up in the self-renewing population of stem cells that maintains the skin.

Pathologists have long recognized that tumors contain a variety of cells, including some that are characteristic of the tissue in which the cancer originates. But not all these cells are equally cancerous. If the cells from a tumor are injected back into a patient at a different site, as was done in a 1961 experiment that would now be considered unethical, more than a million cells must be used before a new tumor will form.

This supports the idea that only a tiny minority of the cells in a cancer have the ability to maintain it.

An amazingly successful anti-cancer drug is Gleevec, used to treat chronic myelogenous leukemia and three rarer cancers. Many patients who take Gleevec experience complete remission. But the drug does not cure the disease, which sometimes returns. It seems Gleevec is attacking not the cancer stem cells but the progenitor cells from which the cancerous white blood cells are generated.

Though many biologists believe that the cancer stem cell idea is interesting, not all think that it will lead to new therapies. In the view of Bert Vogelstein, a leading cancer researcher at Johns Hopkins University, everything depends on how much of a tumor consists of cancer stem cells.
Targeting tumors

If the proportion is large, as several experiments suggest, then current anti-cancer drugs must already be killing them, since they can kill up to 99% of the cells in a tumor. In which case, the idea is not so helpful.

"So the real attractiveness of the cancer stem cell hypothesis, in my view, is that if the 1 percent of cells that are left after successful chemotherapy are really cancer stem cells, then obviously that provides the rationale for different forms of therapy that target them," Vogelstein said.

Gilliland, an advocate of the idea, acknowledged that 20% of cells in the solid tumors analyzed so far had stemlike properties. But with better markers, he said, it may turn out that a much smaller proportion are true cancer stem cells.

"If the growth of solid cancers were driven by cancer stem cells, it would have profound implications for cancer therapy," Irving Weissman of Stanford has written. "Therapies that are more specifically directed against cancer stem cells might result in much more durable responses and even cures of metastatic tumors," he and colleagues said.

Pharmaceutical companies are "waiting for more academic research before they take a clear view on how to proceed," geneticist Weinberg said.

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