Bio

Clinical Focus


  • Leukemia
  • Cancer > Hematology > Leukemia - Acute and Chronic
  • Chronic Lymphocytic Leukemia
  • Idiopathic Hypereosinophillic Syndrome
  • Plasmacytoma
  • Hematology
  • Cancer > Hematology
  • Chronic Myeloid Leukemias
  • Acute Lymphoblastic Leukemia
  • Acute Myelogenous Leukemia
  • Multiple Myeloma

Academic Appointments


Administrative Appointments


  • Vice Chair, Clinical Affairs, Department of Medicine (2011 - Present)
  • Disease Management Group Leader-Hematology, Stanford Hospital and Clinics (2010 - Present)
  • Acute Myeloid Leukemia Panel, National Comprehensive Cancer Network (1998 - Present)
  • Acute Lymphoblastic Leukemia Panel, National Comprehensive Cancer Network (2012 - Present)
  • Vice Chair, Leukemia Committee, Southwest Oncology Group (1996 - Present)
  • Director of Hematology Clinic, Stanford University (1996 - Present)
  • Associate Director, Internal Medicine Residency program, Stanford University (2009 - 2011)

Honors & Awards


  • Timothy F. Beckett, Jr. Award for Excellence in Clinical Teaching, Stanford University (1990)
  • Bernard Cohen Postdoctoral Fellowship, Stanford University (1991)
  • Division Teaching Award, Stanford University (2002)

Professional Education


  • Fellowship:Stanford University School of Medicine (1992) CA
  • Residency:Yale - New Haven Hospital (1989) CT
  • Internship:Yale - New Haven Hospital (1987) CT
  • Medical Education:Stanford University School of Medicine (1986) CA
  • BS, Northwestern University, Biochemistry (1981)
  • MD, Stanford University, Medicine (1986)
  • Internship/Residency, Yale-New Haven Hospital, Internal Medicine (1989)
  • Fellowship, Stanford University, Hematology (1992)

Research & Scholarship

Current Research and Scholarly Interests


My work emphasizes both patient care and translational research. I focus on both the hematologic malignancies as well as conditions such as anemia and blood clotting disorders. Our program offers novel treatments for many of these conditions in the context of clinical trials. We also have comprehensive laboratory services offering the most up-to-date testing for both the diagnosis and management of complex hematologic problems. Recent clinical protocols involved the treatment of acute myeloid leukemia, acute lymphoid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, prolymphocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis and heparin-induced thrombocytopenia.

Clinical Trials


  • Single Agent Lenalidomide in Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia Not Recruiting

    Primary Objective: • Determine the complete response (CR) rate, duration of remission of single agent lenalidomide in patients with relapsed/refractory Acute Lymphoblastic Leukemia (ALL), after at least one previous treatment regimen. Secondary Objective: • Establish the toxicity profile for lenalidomide in this patient population

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Efficacy and Safety of GS-6624 in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis Recruiting

    This study is to evaluate the efficacy and safety of GS-6624 on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with Primary myelofibrosis (PMF) and Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis (ET/PV MF). The study is designed as a two stage trial. In the stage 1, patients will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, patients on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

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  • A Long-Term Study of the Effects of Orally Administered SAR302503 in Patients With Myelofibrosis Not Recruiting

    The purpose of this study is to evaluate the long-term effects of orally administered SAR302503 (TG101348) in patients with myelofibrosis who have completed the MF-TG101348-001 study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Combination Chemotherapy in Treating Young Patients With Newly Diagnosed Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating young patients with newly diagnosed acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • Study to Determine the Maximum Tolerated Dose and Evaluate the Efficacy and Safety of CEP-18770 in Patients With Relapsed Multiple Myeloma Refractory to the Most Recent Therapy Not Recruiting

    The primary objective for part 1 of the study is to determine the maximum tolerated dose (MTD) of CEP-18770 in patients with relapsed and refractory multiple myeloma. The primary objective for part 2 is to evaluate the antitumor activity of CEP-18770 in patients treated at the MTD.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • To Demonstrate Superiority of Decitabine Over Azacitidine in Subjects With Intermediate- or High-risk MDS. Not Recruiting

    The purpose of this study is to compare the response of patients with Intermediate or High Risk myelodysplastic syndromes (MDS) following treatment with decitabine or azacitidine.

    Stanford is currently not accepting patients for this trial. For more information, please contact Mai Tran, (650) 723 - 8594.

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  • Dose Escalation Study of CAL-101 in Select Relapsed or Refractory Hematologic Malignancies Not Recruiting

    The purpose of this study is to determine the dose that can be safely given to see what effect it may have on your cancer and to determine how the drug is distributed in the body.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Study of ABT-263 When Administered in Combination With Either Fludarabine/Cyclophosphamide/Rituximab or Bendamustine/Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia Not Recruiting

    This is a Phase 1 study evaluating the safety of ABT-263 administered in combination with either FCR or BR in subjects with relapsed or refractory chronic lymphocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • S0535, Gemtuzumab and Combination Chemotherapy in Treating Patients With Previously Untreated Acute Promyelocytic Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as gemtuzumab, can block cancer growth in different ways. Some find cancer cells and help kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Gemtuzumab may also stop the growth of promyelocytic leukemia by blocking blood flow to the cancer. Giving gemtuzumab together with combination chemotherapy may be more effective in treating promyelocytic leukemia. PURPOSE: This phase II trial is studying how well giving gemtuzumab together with combination chemotherapy works in treating patients with previously untreated promyelocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Efficacy and Safety of Midostaurin in Patients With Aggressive Systemic Mastocytosis or Mast Cell Leukemia Not Recruiting

    This study will investigate if the drug midostaurin taken orally twice daily is effective and safe in treating patients with aggressive systemic mastocytosis or mast cell leukemia with or without an additional hematological neoplasm.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Compare Bosutinib To Imatinib In Subjects With Newly Diagnosed Chronic Phase Philadelphia Chromosome Positive CML Not Recruiting

    Two-arm, randomized, open-label trial designed to evaluate the efficacy and safety of bosutinib alone compared to imatinib alone in subjects newly diagnosed with chronic phase Chronic Myelogenous Leukemia (CML). The primary endpoint is cytogenetic response rate at one year.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • A Dose Escalation Study of Lenalidomide in Relapsed or Refractory B-cell Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to evaluate the safety of lenalidomide and to define the maximum tolerated escalation dose level (MTEDL) when administered by a stepwise dose-escalation schedule in subjects with relapsed or refractory B-cell CLL.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • S0703 Azacitidine and Gemtuzumab Ozogamicin in Treating Older Patients With Previously Untreated Acute Myeloid Leukemia Not Recruiting

    This phase II trial is studying the side effects of giving azacitidine together with gemtuzumab ozogamicin to see how well it works in treating older patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Azacitidine may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as gemtuzumab ozogamicin, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving azacitidine together with gemtuzumab ozogamicin may kill more cancer cells.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joselene Sipin-Sayno, (650) 736 - 8113.

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  • COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment: The COMFORT-I Trial Not Recruiting

    This was a randomized, double-blind study comparing the efficacy and safety of ruxolitinib (INCB018424) tablets to matching placebo tablets in patients diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF).

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Vorinostat, Azacitidine, and Gemtuzumab Ozogamicin in Treating Older Patients With Relapsed or Refractory Acute Myeloid Leukemia Not Recruiting

    The purpose of this study is to test the safety of vorinostat (Zolinza) and azacitidine (Vidaza) when combined with gemtuzumab ozogamicin (GO) at different dose levels. These drugs increase the effect of GO against leukemia cells in the test tube, but we don't know yet whether they also increase the anti-leukemia effect of GO in people.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase I Bortezomib (VELCADE) in Combo With Pralatrexate in Relapsed/Refractory MM Not Recruiting

    This is an open-label Phase I dose-escalation safety study of VELCADE in combination with pralatrexate in patients with previously treated multiple myeloma. In a standard 3+3 dose escalation trial design, escalating doses of pralatrexate in combination with VELCADE will be studied sequentially, with at least 3 patients in each dose level until the MTD is determined. Dose limiting toxicity (DLT) and MTD are determined during cycle 1 of treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Vani Jain, (650) 725 - 5459.

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  • Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma Not Recruiting

    Panobinostat (LBH589) is a highly potent pan-deacetylase inhibitor (pan-DACi), inclusive of HDAC6, which disrupts aggresome function, promotes accumulation of cytotoxic misfolded protein aggregates and triggers myeloma cell death. Combination of pan-DAC and protease inhibition by co-treatment with panobinostat (PAN) and bortezomib (BTZ) has demonstrated synergistic cytotoxicity in vitro and in vivo in pre-clinical experiments. Furthermore, clinical experience in advanced multiple myeloma (MM) patients treated by oral panobinostat and i.v bortezomib ± dexamethasone showed very encouraging results for efficacy and manageable toxicity profile. Given the medical need for improved treatment strategies for patients with previously treated and relapsed MM, the purpose of this prospective, multinational, randomized, double-blind, placebo-controlled, parallel group Phase III study is to compare the results in progression-free survival of 2 combination therapies, panobinostat with bortezomib and dexamethasone or placebo with bortezomib and dexamethasone, in patients with previously treated MM whose disease has recurred or progressed.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • A Randomized, Double-Blind and Placebo-Controlled Study of Idelalisib in Combination With Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) Recruiting

    This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control. Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib or placebo. All subjects will be administered bendamustine and rituximab.

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  • Bortezomib and Dexamethasone With or Without Lenalidomide in Treating Patients With Multiple Myeloma Previously Treated With Dexamethasone Not Recruiting

    This randomized phase III trial is studying bortezomib, dexamethasone, and lenalidomide to see how well they work compared with bortezomib and dexamethasone in treating patients with multiple myeloma previously treated with dexamethasone. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. It is not yet known whether giving bortezomib together with dexamethasone is more effective with or without lenalidomide in treating multiple myeloma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nancy Mori, (650) 724 - 0201.

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  • Allogeneic HCT Using Nonmyeloablative Host Conditioning With TLI & ATG vs SOC in AML Not Recruiting

    Acute myeloid leukemia (AML) is a cancer of the bone marrow that mostly affects older adults. Even with the best chemotherapy, two-year disease-free survival is achieved in a minority of patients. Bone marrow transplantation from a sibling donor may improve cure rates; however, patients over 50 years of age have a high risk of complications and therefore generally are excluded from this treatment option. Recently our group developed a transplantation strategy for older cancer patients that protects against transplant-associated complications, yet does not interfere with the ability of the transplanted donor cells to destroy cancer cells. With this new method, we can now safely evaluate transplantation as a curative therapy for AML patients over the age of 50. We have assembled clinical and scientific researchers throughout the state of California to study and compare bone marrow transplantation using our new approach with the best standard of care chemotherapy in AML patients over the age of 50. The results of this study have the potential to establish a new treatment standard that will improve survival of older AML patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact BMT Referrals, 650-725-1647.

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  • S0919 Idarubicin, Cytarabine, and Pravastatin in Treating Patients With Relapsed Acute Myeloid Leukemia Recruiting

    RATIONALE: Drugs used in chemotherapy, such as idarubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Pravastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Pravastatin may also help idarubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Giving idarubicin and cytarabine together with pravastatin may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving idarubicin and cytarabine together with pravastatin works in treating patients with relapsed acute myeloid leukemia.

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  • Safety & Efficacy Study of Oral Panobinostat (LBH589) With Chemotherapy in Patients < 65 Years Old With Acute Myeloid Leukemia (AML) Recruiting

    This study will be conducted to assess the maximum tolerated dose (MTD) of panobinostat given 3 times a week (administered on weeks 2 and 3 of a 4 week cycle) in combination with induction chemotherapy (idarubicin and cytarabine) in newly diagnosed patients with a cytopathologically confirmed diagnosis of high-risk AML, and to investigate the safety of the combination in this regimen.

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  • S0910 Epratuzumab, Cytarabine, and Clofarabine in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia Not Recruiting

    RATIONALE: Monoclonal antibodies, such as epratuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as cytarabine and clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving epratuzumab together with cytarabine and clofarabine may kill more cancer cells. PURPOSE: This phase II trial is studying the side effects and how well giving epratuzumab together with cytarabine and clofarabine works in treating patients with relapsed or refractory acute lymphoblastic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia Recruiting

    The purpose of this study is to evaluate the safety and clinical activity of idelalisib in combination with CD20 mAb chemotherapeutic agents, Immunomodulatory Agents, mTOR inhibitors and proteasome inhibitor in participants with hematologic malignancies.

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  • Study of Lenalidomide to Evaluate Safety and Efficacy in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to determine the safety and effectiveness of different dose regimen of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Daunorubicin, Cytarabine, and Midostaurin in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia Not Recruiting

    RATIONALE: Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Midostaurin may help daunorubicin and cytarabine work better by making cancer cells more sensitive to the drugs. Midostaurin also may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without midostaurin in treating acute myeloid leukemia. PURPOSE: This randomized phase III trial is studying giving daunorubicin and cytarabine with or without midostaurin followed by high-dose cytarabine and midostaurin to see how well it works in treating patients with newly diagnosed acute myeloid leukemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase II Study of Atorvastatin Safety and Antitumor Effects in Non-Hodgkin's Lymphoma Not Recruiting

    The purpose of this study is to: 1. Determine changes in levels of tumor bioactivity upon treatment with atorvastatin. Secondary objective: 2. Determine validity of tumor bioactivity as a biologic endpoint by correlation with clinical response. 3. Determine whether administration of atorvastatin is tolerable and safe in low grade NHL patients. We do not anticipate any significant toxicity since this dose of atorvastatin has been FDA approved for patients with hypercholesterolemia.

    Stanford is currently not accepting patients for this trial. For more information, please contact Alice Fan, 650-736-1285.

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  • Study of Oral MLN9708 in Combination With Lenalidomide and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Not Recruiting

    This will be a phase 1/2, multicenter, open-label study using the oral formulation of MLN9708 administered twice weekly in combination with lenalidomide and low-dose dexamethasone. Both phases of the study will include patients who have newly diagnosed multiple myeloma and have not previously received systemic treatment. Both the phase 1 and the phase 2 portions of the study will include induction therapy consisting of 1 year of therapy followed by maintenance therapy that will continue until progressive disease or unacceptable toxicity. Maintenance therapy will be MLN9708 alone on Days 1,4,8, & 11 of a 21-day cycle.

    Stanford is currently not accepting patients for this trial. For more information, please contact Vani Jain, (650) 725 - 5459.

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  • Safety, Efficacy, & Pharmacokinetic Study of Tamibarotene to Treat Patients With Relapsed or Refractory APL Not Recruiting

    This is a Phase II, open-label, non-randomized study to evaluate the safety, efficacy, and pharmacokinetics of tamibarotene in adult patients with relapsed or refractory acute promyelocytic leukemia (APL) following treatment with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Patients must have received and failed therapy with ATRA and ATO. Treatment may have been administered either as combination therapy or sequentially as single agents. Patients who are intolerant to either drug are eligible for this study.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • A Randomized, Double-Blind and Placebo-Controlled Study of Idelalisib in Combination With Rituximab for Previously Treated Chronic Lymphocytic Leukemia (CLL) Not Recruiting

    This Phase 3, randomized, double-blind, placebo-controlled study is to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control, combined with rituximab, in participants previously treated for chronic lymphocytic leukemia (CLL). Eligible patients will be randomized with a 1:1 ratio into 1 of the 2 treatment arms to receive either idelalisib or placebo and rituximab. Participants who are tolerating primary study therapy but experience definitive CLL progression are eligible to receive active idelalisib therapy in the extension study, GS-US-312-0117.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Extension Study of Idelalisib for Patients With Chronic Lymphocytic Leukemia Who Participated in GS-US-312-0116 Not Recruiting

    This study (GS-US-312-0117) is a multicenter, 2-arm, double-blind, parallel-group extension study that is a companion study to Study GS-US-312-0116, to evaluate the effect of idelalisib on the onset, magnitude, and duration of tumor control.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa Hunter, (650) 736 - 4032.

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  • Phase I/II Amrubicin in Combo With Lenalidomide + Weekly Dexamethasone in Relapsed/Refractory Multiple Myeloma Recruiting

    PRIMARY OBJECTIVES - Establish the maximum tolerated dose (MTD) and toxicity profile for the combination of amrubicin with lenalidomide and dexamethasone in previously treated adult patients with multiple myeloma during Phase I - Determine the combined rate of complete response (CR) and very good partial response (VGPR) for this combination in this population as defined by the International Myeloma Working Group Uniform Response Criteria (IMWGURC) SECONDARY OBJECTIVES - Determine the overall response rate (CR, VGPR and PR) - Assess additional evidence of ant-tumor activity as measured by duration of response (DOR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS)

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  • Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia Not Recruiting

    This phase II trial is studying the side effects of giving combination chemotherapy together with or without donor stem cell transplant and to see how well it works in treating patients with acute lymphoblastic leukemia. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect).

    Stanford is currently not accepting patients for this trial. For more information, please contact Vani Jain, (650) 725 - 5459.

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  • A Phase 3 Study of Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of the study is to evaluate whether treatment with ibrutinib as a monotherapy results in a clinically significant improvement in progression free survival (PFS) as compared to treatment with ofatumumab in patients with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa St. Rose, 650-736-4032.

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  • Phase II Study of VELCADE for Relapsed or Refractory T-cell Prolymphocytic Leukemia Not Recruiting

    We hope to learn more about the clinical efficacy of bortezomib in T-cell prolymphocytic leukemia. Patients will be selected as a possible participant in this study because they have a bone marrow disorder known as T-cell prolymphocytic leukemia (T-cell PLL) which does not tend to respond well to conventional treatment with chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • START Rollover Study Not Recruiting

    Chronic Myelogenous Leukemia or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemic Subjects who were previously enrolled and treated with dasatinib or imatinib in the START or CA180039 protocols who are experiencing clinical benefit. The primary objective is to determine the long term safety and tolerability of treatment with dasatinib

    Stanford is currently not accepting patients for this trial. For more information, please contact Dana Supan, (650) 725 - 8538.

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  • Phase I, Open Label, Dose Escalation Study of NEOD001 in Subjects With Light Chain (AL) Amyloidosis Recruiting

    Dose escalation study to determine the maximum tolerated dose of NEOD001 in approximately 30 subjects with AL amyloidosis. Expansion phase to evaluate safety, efficacy and pharmacokinetics of NEOD001 in 20 additional subjects at the maximum tolerated dose.

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  • Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma Not Recruiting

    To compare progression-free survival in subjects with relapsed multiple myeloma who are receiving CRd vs subjects receiving Rd in a randomized multicenter setting.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • A Multicenter Phase 2 Study of PCI-32765 (Ibrutinib) in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) With 17p Deletion Not Recruiting

    An Open-label, Single arm, Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 (Ibrutinib) in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma with 17p Deletion

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, 650-725-4041.

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  • Phase II Temozolomide + Vorinostat in Patients (>60) w/ Newly Diagnosed or Relapse/Refractory AML Recruiting

    The primary endpoint of the study is to determine the clinical efficacy as determined by the rate of morphological complete remission, of 2 different treatment regimens of temozolomide and vorinostat in patients with AML and poor prognostic features.

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  • Safety Study of CAT-8015 Immunooxin in Patients With HCL With Advance Disease Not Recruiting

    RATIONALE: The CAT-8015 immunotoxin can bind tumor cells and kill them without harming normal cells. This may be an effective treatment for hairy cell leukemia(HCL) that has not responded to chemotherapy, surgery or radiation therapy. PURPOSE: Phase I dose escalation study to determine the maximum tolerated dose of CAT-8015 immunotoxin in treating patients who have hairy cell leukemia (HCL) that has not responded to treatment.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Efficacy and Safety Study of Idelalisib in Patients With Indolent B-Cell Non-Hodgkin Lymphoma Not Recruiting

    The purpose of this study is to evaluate the efficacy and safety of idelalisib in patients with previously treated indolent Non-Hodgkin Lymphoma (iNHL) that is refractory both to rituximab and to alkylating-agent-containing chemotherapy. The primary objective will be to assess the overall response rate. Eligible patients will initiate oral therapy with idelalisib at a starting dose of 150 mg taken twice per day. Treatment with idelalisib can continue in compliant patients as long as the study is still ongoing and the patients appear to be benefiting from treatment with acceptable safety.

    Stanford is currently not accepting patients for this trial. For more information, please contact Tessa St.Rose, (650) 736 - 4032.

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  • Phase II PKC412 in Aggressive Systemic Mastocytosis and Mast Cell Leukemia Not Recruiting

    To evaluate the efficacy of twice-daily oral doses of PKC412 when administered to patients with ASM/MCL and AHNMD (associated hematological clonal non-mast cell lineage disease) by measuring response rate.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Extension Study Evaluating the Long Term Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This extension protocol to the core study CCL09101 allows patients who have tolerated the drug and derived a clinical benefit, to continue to receive treatment beyond the 9 cycles of the core protocol. Long term safety and efficacy of CYT387 will be evaluated.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4027.

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  • Efficacy Study of Oral Sapacitabine to Treat Acute Myeloid Leukemia in Elderly Patients Not Recruiting

    The main objective of this study is to learn which sapacitabine treatment is more likely to keep the cancer in check for at least one year in AML patients who are at least 70 years of age or older and in MDS patients who are at least 60 years of age.

    Stanford is currently not accepting patients for this trial. For more information, please contact Michelle Takahashi, (650) 736 - 4032.

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  • Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm Not Recruiting

    This phase II trial is studying how well giving clofarabine and cytarabine together with filgrastim works in treating patients with newly diagnosed acute myeloid leukemia (AML), advanced myelodysplastic syndrome (MDS), and/or advanced myeloproliferative neoplasm. Drugs used in chemotherapy, such as clofarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving the drugs in different doses may kill more cancer cells. Colony stimulating factors, such as filgrastim, may increase the number of immune cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia Not Recruiting

    An open-label, multicenter, phase 1, dose escalation study of MLN4924 in adult patients with acute myelogenous leukemia (AML), high-grade myelodysplastic syndrome (MDS). The patient population will consist of adults previously diagnosed with AML including high-grade MDS for which standard curative, life-prolonging treatment does not exist or is no longer effective.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leonel Gallegos, (650) 723 - 2781.

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  • Phase II Fludarabine, Cytoxan and FCCAM in Untreated B-Cell Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of the study is to evaluate the safety and efficacy of fludarabine and cyclophosphamide followed by subcutaneous Campath® in previously untreated CLL patients. Another goal is to prospectively evaluate the influence of pre-treatment CD38 expression, immunoglobulin VH gene mutation status, Zap70 expression, and cytogenetic abnormalities on outcome. In addition, the study hopes to further evaluate treatment efficacy with quantitative assessments of minimal residual disease by flow cytometry for the CLL-specific CD19+/CD5+/CD20+/CD79b+ population.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • Phase 2 Study of Temozolomide to Treat Poor Risk / Refractory Acute Myeloid Leukemia Not Recruiting

    Open-label, non-randomized, parallel assignment, phase 2 trial assessing the safety and efficacy of distinct temozolomide treatment regimens for patients with AML and poor prognosis

    Stanford is currently not accepting patients for this trial. For more information, please contact Richa Rajwanshi, (650) 736 - 4031.

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  • Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET) Not Recruiting

    This study seeks to (i) determine a safe and tolerated dose of CYT387 given to patients with PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a treatment for PMF, post-PV or post-ET.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrea Linder, (650) 725 - 4047.

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  • Safety of PCI-32765 in Chronic Lymphocytic Leukemia Not Recruiting

    The purpose of this study is to establish the safety and efficacy of orally administered PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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  • A Study of Idelalisib and Rituximab in Elderly Patients With Untreated CLL or SLL Recruiting

    This study is to evaluate the safety and clinical activity of idelalisib alone and in combination with rituximab in patients with CLL or SLL. This Phase 2 study will be the first time that idelalisib is administered to previously untreated patients with hematologic malignancies. Idelalisib has demonstrated clinical activity as a single agent in relapsed or refractory CLL and SLL with acceptable toxicity, which supports its evaluation in previously untreated patients. The study population is limited to patients over 65 years of age because younger patients are generally appropriate for standard immunochemotherapy regimens that are highly active. Since the mechanism of action of idelalisib is distinct from rituximab, it is hypothesized that the combination will be more active than either agent alone. This study will establish initial safety and clinical activity of idelalisib in combination with rituximab in patients with CLL or SLL. Cohort 2 of this study will establish safety and clinical activity of idelalisib alone in subjects with untreated CLL or SLL.

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  • Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia Recruiting

    The purpose of this study is to determine the long-term safety of a fixed-dose, daily regimen of PCI-32765 PO in subjects with B cell lymphoma or chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL).

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  • An Open-label Extension Study in Patients 65 Years or Older With Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA (PCI-32765 Versus Chlorambucil) Recruiting

    An Open-label Extension Study in Patients 65 Years or Older with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA (PCI-32765 versus Chlorambucil)

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  • A Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (RESONATE™-2) Not Recruiting

    A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor PCI-32765 versus Chlorambucil in Patients 65 Years or Older with Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.

    Stanford is currently not accepting patients for this trial. For more information, please contact Muhammad Latif, 650-725-0437.

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  • A Study of the Efficacy of ABT-199 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia With the 17p Deletion Recruiting

    This is a Phase 2, open label, multicenter, study evaluating the efficacy of ABT-199 in approximately 100 relapsed or refractory subjects with CLL harboring 17p13 (TP53 locus) deletion.

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  • Efficacy and Safety of Idelalisib (GS-1101; CAL-101) in Combination With Ofatumumab for Previously Treated Chronic Lymphocytic Leukemia Not Recruiting

    This study is to evaluate the effect of the addition of idelalisib (GS-1101) to ofatumumab on progression-free survival (PFS) in participants with previously treated chronic lymphocytic leukemia (CLL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Heidi Britton, 650-725-9167.

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  • Cytarabine and Daunorubicin Hydrochloride or Idarubicin and Cytarabine With or Without Vorinostat in Treating Younger Patients With Previously Untreated Acute Myeloid Leukemia Recruiting

    This randomized phase III trial studies cytarabine and daunorubicin hydrochloride or idarubicin and cytarabine with or without vorinostat to see how well they work in treating younger patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as cytarabine, daunorubicin hydrochloride, idarubicin, and vorinostat, work in different ways to stop the growth of cancer cells, either by killing the cells or stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving the drugs in different doses and in different combinations may kill more cancer cells. It is not yet known which combination chemotherapy is more effective in treating acute myeloid leukemia.

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  • An Extension Study for Subjects Who Are Deriving Benefit With Idelalisib (GS-1101; CAL-101) Following Completion of a Prior Idelalisib Study Recruiting

    This is a long-term safety extension study of idelalisib (GS-1101; CAL-101) in patients with hematologic malignancies who complete other idelalisib studies. It provides the opportunity for patients to continue treatment as long as the patient is deriving clinical benefit. Patients will be followed according to the standard of care as appropriate for their type of cancer. The dose of idelalisib will generally be the same as the dose that was administered at the end of the prior study, but may be titrated up to improve clinical response or down for toxicity. Patients will be withdrawn from the study if they develop progressive disease, unacceptable toxicity related to idelalisib, or if they no longer derive clinical benefit in the opinion of the investigator.

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  • Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Recruiting

    This phase I trial studies the side effects and best dose of lenalidomide when given together with ibrutinib in treating patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with ibrutinib may be an effective treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma.

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  • Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma Not Recruiting

    The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose dexamethasone to that of the combination of melphalan, prednisone and thalidomide.

    Stanford is currently not accepting patients for this trial. For more information, please contact Nini Estevez, (650) 725 - 4041.

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Teaching

2013-14 Courses


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Publications

Journal Articles


  • Targeting BTK with Ibrutinib in Relapsed Chronic Lymphocytic Leukemia NEW ENGLAND JOURNAL OF MEDICINE Byrd, J. C., Furman, R. R., Coutre, S. E., Flinn, I. W., Burger, J. A., Blum, K. A., Grant, B., Sharman, J. P., Coleman, M., Wierda, W. G., Jones, J. A., Zhao, W., Heerema, N. A., Johnson, A. J., Sukbuntherng, J., Chang, B. Y., Clow, F., Hedrick, E., Buggy, J. J., James, D. F., O'Brien, S. 2013; 369 (1): 32-42

    Abstract

    The treatment of relapsed chronic lymphocytic leukemia (CLL) has resulted in few durable remissions. Bruton's tyrosine kinase (BTK), an essential component of B-cell-receptor signaling, mediates interactions with the tumor microenvironment and promotes the survival and proliferation of CLL cells.We conducted a phase 1b-2 multicenter study to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of ibrutinib (PCI-32765), a first-in-class, oral covalent inhibitor of BTK designed for treatment of B-cell cancers, in patients with relapsed or refractory CLL or small lymphocytic lymphoma. A total of 85 patients, the majority of whom were considered to have high-risk disease, received ibrutinib orally once daily; 51 received 420 mg, and 34 received 840 mg.Toxic effects were predominantly grade 1 or 2 and included transient diarrhea, fatigue, and upper respiratory tract infection; thus, patients could receive extended treatment with minimal hematologic toxic effects. The overall response rate was the same in the group that received 420 mg and the group that received 840 mg (71%), and an additional 20% and 15% of patients in the respective groups had a partial response with lymphocytosis. The response was independent of clinical and genomic risk factors present before treatment, including advanced-stage disease, the number of previous therapies, and the 17p13.1 deletion. At 26 months, the estimated progression-free survival rate was 75% and the rate of overall survival was 83%.Ibrutinib was associated with a high frequency of durable remissions in patients with relapsed or refractory CLL and small lymphocytic lymphoma, including patients with high-risk genetic lesions. (Funded by Pharmacyclics and others; ClinicalTrials.gov number, NCT01105247.).

    View details for DOI 10.1056/NEJMoa1215637

    View details for Web of Science ID 000321263500008

    View details for PubMedID 23782158

  • Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study LANCET ONCOLOGY Kantarjian, H., Faderl, S., Garcia-Manero, G., Luger, S., Venugopal, P., Maness, L., Wetzler, M., Coutre, S., Stock, W., Claxton, D., Goldberg, S. L., Arellano, M., Strickland, S. A., Seiter, K., Schiller, G., Jabbour, E., Chiao, J., Plunkett, W. 2012; 13 (11): 1096-1104

    Abstract

    Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML.In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187.Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment.Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML.Cyclacel Limited.

    View details for DOI 10.1016/S1470-2045(12)70436-9

    View details for Web of Science ID 000310570900040

    View details for PubMedID 23075701

  • Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia JOURNAL OF CLINICAL ONCOLOGY Kreitman, R. J., Tallman, M. S., Robak, T., Coutre, S., Wilson, W. H., Stetler-Stevenson, M., FitzGerald, D. J., Lechleider, R., Pastan, I. 2012; 30 (15): 1822-1828

    Abstract

    To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL).Eligible patients had relapsed/refractory HCL after ? two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 ?g/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ? 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies.Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 ?g/kg, four patients at 40 ?g/kg, and 12 patients at 50 ?g/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/?L. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months.Moxetumomab pasudotox at doses up to 50 ?g/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.

    View details for DOI 10.1200/JCO.2011.38.1756

    View details for Web of Science ID 000304427600017

    View details for PubMedID 22355053

  • Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710 BLOOD Powell, B. L., Moser, B., Stock, W., Gallagher, R. E., Willman, C. L., Stone, R. M., Rowe, J. M., Coutre, S., Feusner, J. H., Gregory, J., Couban, S., Appelbaum, F. R., Tallman, M. S., Larson, R. A. 2010; 116 (19): 3751-3757

    Abstract

    Arsenic trioxide (As(2)O(3)) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ? 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As(2)O(3) consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As(2)O(3) consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As(2)O(3) arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As(2)O(3) arm, 90% compared with 70% at 3 years (P < .0001). The addition of As(2)O(3) consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

    View details for DOI 10.1182/blood-2010-02-269621

    View details for Web of Science ID 000284110400014

    View details for PubMedID 20705755

  • Optimizing therapy for acute myeloid leukemia. Journal of the National Comprehensive Cancer Network Kohrt, H. E., Coutre, S. E. 2008; 6 (10): 1003-1016

    Abstract

    The 10-year overall survival for younger patients with newly diagnosed acute myeloid leukemia has improved threefold in the past 2 decades. This improvement has occurred in large part because of advances in supportive care and efforts to optimize standard induction and consolidation therapies applied in a stratified approach based on predictors of individual patient risk. Innovations in diagnostic technologies have broadened the understanding of key prognostic factors, including cytogenetic and molecular status, which define the extensive interpatient heterogeneity of this clonal disease. Despite this progress, only approximately 25% of patients who experience a complete remission with cytotoxic chemotherapy (50%-70% of patients with newly diagnosed disease) remain disease-free. Efforts to develop novel agents are actively ongoing, particularly for older patients (age > or = 60), and targeted therapies, for specific subsets of patients are being based on a better understanding of the biology of the disease.

    View details for PubMedID 19176198

  • Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study BLOOD Ottmann, O., Dombret, H., Martinelli, G., Simonsson, B., Guilhot, F., Larson, R. A., Rege-Cambrin, G., Radich, J., Hochhaus, A., Apanovitch, A. M., Gollerkeri, A., Coutre, S. 2007; 110 (7): 2309-2315

    Abstract

    Patients with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) have a rapid disease course and a poor prognosis. Dasatinib, a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, has previously induced responses in patients with imatinib-resistant or -intolerant Ph-positive ALL. We present the interim results of a phase 2 study designed to further assess the efficacy, safety, and tolerability of dasatinib 140 mg in this patient population (n = 36). With a minimum follow-up of 8 months, treatment with dasatinib resulted in substantial hematologic and cytogenetic response rates. Major hematologic responses were achieved in 42% (15/36) of patients, 67% of whom remained progression-free. Complete cytogenetic responses were attained by 58% (21/36) of patients. The presence of BCR-ABL mutations conferring imatinib resistance did not preclude a response to dasatinib. Dasatinib was also tolerable, with 6% (2/36) of patients discontinuing therapy as a result of study-drug toxicity. Most adverse events (AEs) were grade 1 or 2; febrile neutropenia was the most frequent severe AE, but this and other cytopenias were manageable with dose reduction. Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015.

    View details for DOI 10.1182/blood-2007-02-073528

    View details for Web of Science ID 000249800900025

    View details for PubMedID 17496201

  • Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801 BLOOD DeAngelo, D. J., Yu, D., Johnson, J. L., Coutre, S. E., Stone, R. M., Stopeck, A. T., Gockerman, J. P., Mitchell, B. S., Appelbaum, F. R., Larson, R. A. 2007; 109 (12): 5136-5142

    Abstract

    Nelarabine (506U78) is a soluble pro-drug of 9-beta-D-arabinofuranosylguanine (ara-G), a deoxyguanosine derivative. We treated 26 patients with T-cell acute lymphoblastic leukemia (T-ALL) and 13 with T-cell lymphoblastic lymphoma (T-LBL) with nelarabine. All patients were refractory to at least one multiagent regimen or had relapsed after achieving a complete remission. Nelarabine was administered on an alternate day schedule (days 1, 3, and 5) at 1.5 g/m(2)/day. Cycles were repeated every 22 days. The median age was 34 years (range, 16-66 years); 32 (82%) patients were male. The rate of complete remission was 31% (95% confidence interval [CI], 17%, 48%) and the overall response rate was 41% (95% CI, 26%, 58%). The principal toxicity was grade 3 or 4 neutropenia and thrombocytopenia, occurring in 37% and 26% of patients, respectively. There was only one grade 4 adverse event of the nervous system, which was a reversible depressed level of consciousness. The median disease-free survival (DFS) was 20 weeks (95% CI, 11, 56), and the median overall survival was 20 weeks (95% CI, 13, 36). The 1-year overall survival was 28% (95% CI, 15%, 43%). Nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL and T-LBL.

    View details for DOI 10.1182/blood-2006-11-056754

    View details for Web of Science ID 000247360200020

    View details for PubMedID 17344466

  • Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis BLOOD Cortes, J., Rousselot, P., Kim, D., Ritchie, E., Hamerschlak, N., Coutre, S., Hochhaus, A., Guilhot, F., Saglio, G., Apperley, J., Ottmann, O., Shah, N., Erben, P., Branford, S., Agarwal, P., Gollerkeri, A., Baccarani, M. 2007; 109 (8): 3207-3213

    Abstract

    The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.

    View details for DOI 10.1182/blood-2006-09-046888

    View details for Web of Science ID 000245658500022

    View details for PubMedID 17185463

  • Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation BLOOD Gotlib, J., Berube, C., Growney, J. D., Chen, C. C., George, T. I., Williams, C., Kajiguchi, T., Ruan, J., Lilleberg, S. L., Durocher, J. A., Lichy, J. H., Wang, Y. F., Cohen, P. S., Arber, D. A., Heinrich, M. C., Neckers, L., GALLI, S. J., Gilliland, D. G., Coutre, S. E. 2005; 106 (8): 2865-2870

    Abstract

    The majority of patients with systemic mast cell disease express the imatinib-resistant Asp816Val (D816V) mutation in the KIT receptor tyrosine kinase. Limited treatment options exist for aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL). We evaluated whether PKC412, a small-molecule inhibitor of KIT with a different chemical structure from imatinib, may have therapeutic use in advanced SM with the D816V KIT mutation. We treated a patient with MCL (with an associated myelodysplastic syndrome (MDS)/myeloproliferative disorder [MPD]) based on in vitro studies demonstrating that PKC412 could inhibit D816V KIT-transformed Ba/F3 cell growth with a 50% inhibitory concentration (IC50) of 30 nM to 40 nM. The patient exhibited a partial response with significant resolution of liver function abnormalities. In addition, PKC412 treatment resulted in a significant decline in the percentage of peripheral blood mast cells and serum histamine level and was associated with a decrease in KIT phosphorylation and D816V KIT mutation frequency. The patient died after 3 months of therapy due to progression of her MDS/MPD to acute myeloid leukemia (AML). This case indicates that KIT tyrosine kinase inhibition is a feasible approach in SM, but single-agent clinical efficacy may be limited by clonal evolution in the advanced leukemic phase of this disease.

    View details for DOI 10.1182/blood-2005-04-1568

    View details for Web of Science ID 000232466000047

    View details for PubMedID 15972446

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Seminars in cancer biology Coutré, S., Gotlib, J. 2004; 14 (4): 307-315

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for PubMedID 15305431

  • The HP1L1-PDIGFR alpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management BLOOD Gotlib, J., Cools, J., Malone, J. M., Schrier, S. L., Gilliland, D. G., Coutre, S. E. 2004; 103 (8): 2879-2891

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) comprise a spectrum of indolent to aggressive diseases characterized by unexplained, persistent hypereosinophilia. These disorders have eluded a unique molecular explanation, and therapy has primarily been oriented toward palliation of symptoms related to organ involvement. Recent reports indicate that HES and CEL are imatinib-responsive malignancies, with rapid and complete hematologic remissions observed at lower doses than used in chronic myelogenous leukemia (CML). These BCR-ABL-negative cases lack activating mutations or abnormal fusions involving other known target genes of imatinib, implicating a novel tyrosine kinase in their pathogenesis. A bedside-to-benchtop translational research effort led to the identification of a constitutively activated fusion tyrosine kinase on chromosome 4q12, derived from an interstitial deletion, that fuses the platelet-derived growth factor receptor-alpha gene (PDGFRA) to an uncharacterized human gene FIP1-like-1 (FIP1L1). However, not all HES and CEL patients respond to imatinib, suggesting disease heterogeneity. Furthermore, approximately 40% of responding patients lack the FIP1L1-PDGFRA fusion, suggesting genetic heterogeneity. This review examines the current state of knowledge of HES and CEL and the implications of the FIP1L1-PDGFRA discovery on their diagnosis, classification, and management.

    View details for DOI 10.1182/blood-2003-06-1824

    View details for Web of Science ID 000222163500012

    View details for PubMedID 15070659

  • A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome NEW ENGLAND JOURNAL OF MEDICINE Cools, J., DeAngelo, D. J., Gotlib, J., Stover, E. H., Legare, R. D., Cortes, J., Kutok, J., Clark, J., Galinsky, I., GRIFFIN, J. D., Cross, N. C., Tefferi, A., MALONE, J., Alam, R., Schrier, S. L., Schmid, J., Rose, M., Vandenberghe, P., Verhoef, G., Boogaerts, M., Wlodarska, I., Kantarjian, H., Marynen, P., Coutre, S. E., Stone, R., Gilliland, D. G. 2003; 348 (13): 1201-1214

    Abstract

    Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause.We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response.Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib.The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

    View details for Web of Science ID 000181790800002

    View details for PubMedID 12660384

  • Acute Myeloid Leukemia, Version 2.2013 Featured Updates to the NCCN Guidelines JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Tallman, M. S., Abboud, C. N., Altman, J. K., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Lancet, J., Maness, L. J., Marcucci, G., Martin, M. G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Wang, E. S., Gregory, K. M., Naganuma, M. 2013; 11 (9): 1047-1055
  • Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia. Haematologica Pollyea, D. A., Zehnder, J., Coutre, S., Gotlib, J. R., Gallegos, L., Abdel-Wahab, O., Greenberg, P., Zhang, B., Liedtke, M., Berube, C., Levine, R., Mitchell, B. S., Medeiros, B. C. 2013; 98 (4): 591-596

    Abstract

    There are limited treatment options for older patients with acute myeloid leukemia and prognosis of these patients remains poor, thereby warranting development of novel therapies. We evaluated the efficacy and safety of azacitidine in combination with lenalidomide as front-line therapy for older patients with acute myeloid leukemia. Patients ? 60 years of age with untreated acute myeloid leukemia received azacitidine 75 mg/m2 for 7 days followed by escalating doses of lenalidomide daily for 21 days starting on day 8 of each cycle every 6 weeks. Patients received continued therapy until disease progression, unacceptable toxicity, or completion of 12 cycles. Forty-two patients (median age, 74 years) were enrolled with equal distribution according to European LeukemiaNet risk. The overall response rate was 40% (rate of complete remission with or without complete recovery of blood counts = 28%). The median time to complete remission with or without complete recovery of blood counts was 12 weeks, and duration of this status was 28 weeks (range, 4 - >104 weeks). Therapy-related acute myeloid leukemia and a high score on the Hematopoietic Cell Transplantation Comorbidity Index were negative predictors of response. Early death was noted in 17% of patients. Grades ? 3 toxicities were uncommon and most adverse events were gastrointestinal, fatigue and myelosuppression. In conclusion, a sequential combination of azacitidine plus lenalidomide has clinical activity in older patients with acute myeloid leukemia, and further studies of this combination are underway.

    View details for DOI 10.3324/haematol.2012.076414

    View details for PubMedID 23242596

  • Treatment of adults with acute lymphoblastic leukemia: Do the specifics of the regimen matter? Results From a Prospective Randomized Trial CANCER Lamanna, N., Heffner, L. T., Kalaycio, M., Schiller, G., Coutre, S., Moore, J., Seiter, K., Maslak, P., Panageas, K., Golde, D., Weiss, M. A. 2013; 119 (6): 1186-1194

    Abstract

    Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m(2) daily for 5 days with mitoxantrone 80 mg/m(2) (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL.The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004.The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20.Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.

    View details for DOI 10.1002/cncr.27901

    View details for Web of Science ID 000315696600012

    View details for PubMedID 23280086

  • High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia JOURNAL OF CLINICAL ONCOLOGY O'Brien, S., Schiller, G., Lister, J., Damon, L., Goldberg, S., Aulitzky, W., Ben-Yehuda, D., Stock, W., Coutre, S., Douer, D., Heffner, L. T., Larson, M., Seiter, K., Smith, S., Assouline, S., Kuriakose, P., Maness, L., Nagler, A., Rowe, J., Schaich, M., Shpilberg, O., Yee, K., Schmieder, G., Silverman, J. A., Thomas, D., Deitcher, S. R., Kantarjian, H. 2013; 31 (6): 676-683

    Abstract

    Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery. We evaluated high-dose VSLI monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT).Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi).The CR/CRi rate was 20% and overall response rate was 35%. VSLI monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%).High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

    View details for DOI 10.1200/JCO.2012.46.2309

    View details for Web of Science ID 000315086400015

    View details for PubMedID 23169518

  • Absolute lymphocyte count at day 28 independently predicts event-free and overall survival in adults with newly diagnosed acute lymphoblastic leukemia AMERICAN JOURNAL OF HEMATOLOGY Sun, D., Elson, P., Liedtke, M., Medeiros, B. C., Earl, M., Alizadeh, A., Bates, J., Sekeres, M. A., Coutre, S., Kalaycio, M., Sobecks, R., Copelan, E., Advani, A. S. 2012; 87 (10): 957-960

    Abstract

    We investigated the prognostic impact of absolute lymphocyte count (ALC) following induction chemotherapy in newly diagnosed adult acute lymphoblastic leukemia (ALL). Patients with ALC ?350 cells/?L at day 28 had a median overall survival (OS) of 47.4 months when compared with 17.6 months for those with an ALC <350 cells/?L (HR = 1.98, P = 0.007). Among patients who achieved a complete remission, median event-free survival (EFS) for those with ALC ?350 cells/?L on day 28 was 42.1 months when compared with 13.9 months in those with ALC <350 cells/?L (HR = 2.08, P = 0.006). In multivariable analysis, the ALC on day 28 (<350 cells/?L vs. ?350 cells/?L, P ? .0004 for OS and EFS) along with WBC at diagnosis (?6.0 or >30.0 K/?L vs. >6.0-30.0 K/?L, P ? 0.002 for OS and EFS) and cytogenetics (abnormal vs. normal, P = 0.002 for OS and P = 0.02 for EFS) were independent prognostic factors of both OS and EFS. Combining these three factors segregates patients in three well-defined risk groups. These data suggest that ALC can be used in combination with other prognostic features to better predict outcome and that targeting the immune system to improve ALC may be a worthwhile strategy in ALL.

    View details for DOI 10.1002/ajh.23279

    View details for Web of Science ID 000309065700081

    View details for PubMedID 22729847

  • Acute Myeloid Leukemia Clinical Practice Guidelines in Oncology JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Arber, D. A., Attar, E., Borate, U., Coutre, S. E., Damon, L. E., Goorha, S., Lancet, J., Maness, L. J., Marcucci, G., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S., Naganuma, M., Gregory, K. M. 2012; 10 (8): 984-1021

    Abstract

    Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML provide recommendations on the diagnostic evaluation and workup for AML, risk assessment based on cytogenetic and molecular features, treatment options for induction and consolidation therapies for younger and older (age ≥ 65 years) adult patients, and key supportive care considerations.

    View details for Web of Science ID 000307494000010

  • Acute Lymphoblastic Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Alvarnas, J. C., Brown, P. A., Aoun, P., Ballen, K. K., Bellam, N., Blum, W., Boyer, M. W., Carraway, H. E., Coccia, P. F., Coutre, S. E., Cultrera, J., Damon, L. E., DeAngelo, D. J., Douer, D., Frangoul, H., Frankfurt, O., Goorha, S., Millenson, M. M., O'Brien, S., Petersdorf, S. H., Rao, A. V., Terezakis, S., Uy, G., Wetzler, M., Zelenetz, A. D., Naganuma, M., Gregory, K. M. 2012; 10 (7): 858-913

    Abstract

    The inaugural NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) were developed as a result of meetings convened by a multi-disciplinary panel of experts in 2011. These NCCN Guidelines provide recommendations on the diagnostic evaluation and workup for ALL, risk assessment, risk-stratified treatment approaches based on the Philadelphia chromosome status and age (adults vs. adolescents/young adults), assessment of minimal residual disease, and supportive care considerations. It is recommended that patients be treated at specialized centers with expertise in the management of ALL.

    View details for Web of Science ID 000306303900009

    View details for PubMedID 22773801

  • Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia LEUKEMIA Pollyea, D. A., Kohrt, H. E., Gallegos, L., Figueroa, M. E., Abdel-Wahab, O., Zhang, B., Bhattacharya, S., Zehnder, J., Liedtke, M., Gotlib, J. R., Coutre, S., Berube, C., Melnick, A., Levine, R., Mitchell, B. S., Medeiros, B. C. 2012; 26 (5): 893-901

    Abstract

    Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

    View details for DOI 10.1038/leu.2011.294

    View details for Web of Science ID 000303883500005

    View details for PubMedID 22033493

  • Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia LEUKEMIA & LYMPHOMA Wendtner, C., Hillmen, P., Mahadevan, D., Buehler, A., Uharek, L., Coutre, S., Frankfurt, O., Bloor, A., Bosch, F., Furman, R. R., Kimby, E., Gribben, J. G., Gobbi, M., Dreisbach, L., Hurd, D. D., Sekeres, M. A., Ferrajoli, A., Shah, S., Zhang, J., Moutouh-de Parseval, L., Hallek, M., Heerema, N. A., Stilgenbauer, S., Chanan-Khan, A. A. 2012; 53 (3): 417-423

    Abstract

    Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.

    View details for DOI 10.3109/10428194.2011.618232

    View details for Web of Science ID 000300451100012

    View details for PubMedID 21879809

  • Treatment advances have not improved the early death rate in acute promyelocytic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL McClellan, J. S., Kohrt, H. E., Coutre, S., Gotlib, J. R., Majeti, R., Alizadeh, A. A., Medeiros, B. C. 2012; 97 (1): 133-136

    Abstract

    Early mortality in acute promyelocytic leukemia has been reported to occur in less than 10% of patients treated in clinical trials. This study reports the incidence and clinical features of acute promyelocytic leukemia patients treated at Stanford Hospital, CA, USA since March 1997, focusing on early mortality. We show that the risk of early death in acute promyelocytic leukemia patients is higher than previously reported. In a cohort of 70 patients who received induction therapy at Stanford Hospital, 19% and 26% died within seven and 30 days of admission, respectively. High early mortality was not limited to our institution as evaluation of the Surveillance, Epidemiology and End Results Database demonstrated that 30-day mortality for acute promyelocytic leukemia averaged 20% from 1977-2007 and did not improve significantly over this interval. Our findings show that early death is now the greatest contributor to treatment failure in this otherwise highly curable form of leukemia.

    View details for DOI 10.3324/haematol.2011.046490

    View details for Web of Science ID 000299870500022

    View details for PubMedID 21993679

  • Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia HAEMATOLOGICA-THE HEMATOLOGY JOURNAL Liedtke, M., Twist, C. J., Medeiros, B. C., Gotlib, J. R., Berube, C., Bieber, M. M., Bhat, N. M., Teng, N. N., Coutre, S. E. 2012; 97 (1): 30-37

    Abstract

    This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6-65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.

    View details for DOI 10.3324/haematol.2011.045997

    View details for Web of Science ID 000299870500009

    View details for PubMedID 21993685

  • Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia AMERICAN JOURNAL OF HEMATOLOGY Medeiros, B. C., Kohrt, H. E., Gotlib, J., Coutre, S. E., Zhang, B., Arber, D. A., Zehnder, J. L. 2012; 87 (1): 45-50

    Abstract

    Temozolomide sensitivity is determined by methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can "prime" blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m(2) orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m(2) orally for 14 days followed by 200 mg/m(2) orally for 7 days every 6weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247.

    View details for DOI 10.1002/ajh.22191

    View details for Web of Science ID 000298257700010

    View details for PubMedID 22052619

  • Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse BLOOD Levis, M., Ravandi, F., Wang, E. S., Baer, M. R., Perl, A., Coutre, S., Erba, H., Stuart, R. K., Baccarani, M., Cripe, L. D., Tallman, M. S., Meloni, G., Godley, L. A., Langston, A. A., Amadori, S., Lewis, I. D., Nagler, A., Stone, R., Yee, K., Advani, A., Douer, D., Wiktor-Jedrzejczak, W., Juliusson, G., Litzow, M. R., Petersdorf, S., Sanz, M., Kantarjian, H. M., Sato, T., Tremmel, L., Bensen-Kennedy, D. M., Small, D., Smith, B. D. 2011; 117 (12): 3294-3301

    Abstract

    In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 ?M. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

    View details for DOI 10.1182/blood-2010-08-301796

    View details for Web of Science ID 000288848500012

    View details for PubMedID 21270442

  • Acute Myeloid Leukemia JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK O'Donnell, M. R., Abboud, C. N., Altman, J., Appelbaum, F. R., Coutre, S. E., Damon, L. E., Foran, J. M., Goorha, S., Maness, L. J., Marcucci, G., Maslak, P., Millenson, M. M., Moore, J. O., Ravandi, F., Shami, P. J., Smith, B. D., Stone, R. M., Strickland, S. A., Tallman, M. S., Wang, E. S. 2011; 9 (3): 280-317

    View details for Web of Science ID 000287991200005

    View details for PubMedID 21393440

  • CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies BLOOD Kohrt, H. E., Houot, R., Goldstein, M. J., Weiskopf, K., Alizadeh, A. A., Brody, J., Mueller, A., Pachynski, R., Czerwinski, D., Coutre, S., Chao, M. P., Chen, L., Tedder, T. F., Levy, R. 2011; 117 (8): 2423-2432

    Abstract

    Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.

    View details for DOI 10.1182/blood-2010-08-301945

    View details for Web of Science ID 000287698800023

    View details for PubMedID 21193697

  • Yield of diagnostic procedures for invasive fungal infections in neutropenic febrile patients with chest computed tomography abnormalities MYCOSES Ho, D. Y., Lin, M., Schaenman, J., Rosso, F., Leung, A. N., Coutre, S. E., Sista, R. R., Montoya, J. G. 2011; 54 (1): 59-70

    Abstract

    Haematological patients with neutropenic fever are frequently evaluated with chest computed tomography (CT) to rule out invasive fungal infections (IFI). We retrospectively analysed data from 100 consecutive patients with neutropenic fever and abnormal chest CT from 1998 to 2005 to evaluate their chest CT findings and the yield of diagnostic approaches employed. For their initial CTs, 79% had nodular opacities, with 24.1% associated with the halo sign. Other common CT abnormalities included pleural effusions (48%), ground glass opacities (37%) and consolidation (31%). The CT findings led to a change in antifungal therapy in 54% of the patients. Fifty-six patients received diagnostic procedures, including 46 bronchoscopies, 25 lung biopsies and seven sinus biopsies, with a diagnostic yield for IFI of 12.8%, 35.0% and 83.3%, respectively. In conclusion, chest CT plays an important role in the evaluation of haematological patients with febrile neutropenia and often leads to a change in antimicrobial therapy. Pulmonary nodules are the most common radiological abnormality. Sinus or lung biopsies have a high-diagnostic yield for IFI as compared to bronchoscopy. Patients with IFI may not have sinus/chest symptoms, and thus, clinicians should have a low threshold for performing sinus/chest imaging, and if indicated and safe, a biopsy of the abnormal areas.

    View details for DOI 10.1111/j.1439-0507.2009.01760.x

    View details for Web of Science ID 000284900600009

    View details for PubMedID 19793207

  • Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia BRITISH JOURNAL OF HAEMATOLOGY Advani, A. S., Gundacker, H. M., Sala-Torra, O., Radich, J. P., Lai, R., Slovak, M. L., Lancet, J. E., Coutre, S. E., Stuart, R. K., Mims, M. P., Stiff, P. J., Appelbaum, F. R. 2010; 151 (5): 430-434

    Abstract

    Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ?2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.

    View details for DOI 10.1111/j.1365-2141.2010.08387.x

    View details for Web of Science ID 000284169700003

    View details for PubMedID 21113977

  • Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: A single-center experience AMERICAN JOURNAL OF HEMATOLOGY Kohrt, H. E., Patel, S., Ho, M., Owen, T., Pollyea, D. A., Majeti, R., Gotlib, J., Coutre, S., Liedtke, M., Berube, C., Alizadeh, A. A., Medeiros, B. C. 2010; 85 (11): 877-881

    Abstract

    The majority of patients with acute myeloid leukemia (AML) will require second-line chemotherapy for either relapsed or refractory disease. Currently, only allogeneic hematopoietic cell transplantation (HCT) offers a curative option in this setting and no preferred regimen has been established. The reported efficacy of second-line regimens is widely disparate, thus limiting informed clinical decision making. A retrospective review of 77 patients receiving therapy between 2001 and 2008 with relapsed, 42, and refractory, 35, AML was performed to determine overall response rate and survival following mitoxantrone (8 mg/m(2)/day), etoposide (100 mg/m(2)/day), and cytarabine (1,000 mg/m(2)/day) chemotherapy administered over 5 days. Among 77 patients (median age of 54 years and 64% intermediate risk karyotype) with median follow-up of 153 days, 18% achieved a complete response and 8% a morphologic leukemia-free state. Fifty-seven (74%) experienced treatment failure, 10 of whom achieved a remission after additional therapy. Median overall survival (OS) was 6.8 months. Among patients achieving a response, 50% received consolidation with allogeneic HCT, autologous HCT (5%), or consolidation chemotherapy alone (45%). A nonsignificant trend in overall response (50%, 27%, and 23.8%) and median OS (8.3, 6.8, and 4.7 months) was observed by cytogenetic stratification into favorable, intermediate, and unfavorable risk. Patients with refractory versus relapsed disease had similar overall responses (20% and 31%, P = 0.41) and median OS (5.3 and 7.6 months, P = 0.36). Despite risk stratification by the European Prognostic Index, our series demonstrates inferior rates of response and survival, illustrating the limited activity of this regimen in our cohort.

    View details for DOI 10.1002/ajh.21857

    View details for Web of Science ID 000283568200010

    View details for PubMedID 20872554

  • Classification and Risk Stratification for Acute Promyelocytic Leukemia CLINICAL LYMPHOMA MYELOMA & LEUKEMIA Coutre, S. 2010; 10: S127-S129

    Abstract

    Acute promyelocytic leukemia (APL) as a distinct clinical entity was first described only 50 years ago. The last twenty years are notable for rapid advances in understanding the molecular basis of the disease as well as dramatic improvements in treating APL. A new classification system that stratifies patients by risk has also lead to dramatic improvement in managing the disease. Molecular monitoring for minimal residual disease holds great promise for continued improvement in decreasing relapse risk. We are now able to tailor our therapy based on risk of relapse, and ongoing clinical trials use this risk-adapted framework in an attempt to further improve outcomes.

    View details for DOI 10.3816/CLML.2010.s.024

    View details for Web of Science ID 000284236600002

    View details for PubMedID 21115430

  • Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma JOURNAL OF CLINICAL ONCOLOGY Tong, W., Chen, R., Plunkett, W., Siegel, D., Sinha, R., Harvey, R. D., Badros, A. Z., Popplewell, L., Coutre, S., Fox, J. A., Mahadocon, K., Chen, T., Kegley, P., Hoch, U., Wierda, W. G. 2010; 28 (18): 3015-3022

    Abstract

    SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy.Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course.There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m(2), and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m(2), owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis.SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

    View details for DOI 10.1200/JCO.2009.26.1347

    View details for Web of Science ID 000278883200015

    View details for PubMedID 20479412

  • Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma BRITISH JOURNAL OF HAEMATOLOGY Chen, C., Reece, D. E., Siegel, D., Niesvizky, R., Boccia, R. V., Stadtmauer, E. A., Abonour, R., Richardson, P., Matous, J., Kumar, S., Bahlis, N. J., Alsina, M., Vescio, R., Coutre, S. E., Pietronigro, D., Knight, R. D., Zeldis, J. B., Rajkumar, V. 2009; 146 (2): 164-170

    Abstract

    Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1-21) and dexamethasone 40 mg/d (days 1-4, 9-12, and 17-20 of cycles 1-4; days 1-4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, approximately 60% were male, median age was 64 years, and 61.7% had Durie-Salmon stage III disease. Median time on study was 15.4 weeks (range: 0.1-49.1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade > or =3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.

    View details for DOI 10.1111/j.1365-2141.2009.07728.x

    View details for Web of Science ID 000267657300005

    View details for PubMedID 19545290

  • Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase LEUKEMIA Cortes, J., Kim, D., Raffoux, E., Martinelli, G., Ritchie, E., Roy, L., Coutre, S., Corm, S., Hamerschlak, N., Tang, J., Hochhaus, A., Khoury, H. J., Bruemmendorf, T. H., Michallet, M., Rege-Cambrin, G., Gambacorti-Passerini, C., Radich, J. P., Ernst, T., Zhu, C., Van Tornout, J. M., Talpaz, M. 2008; 22 (12): 2176-2183

    Abstract

    Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in

    View details for DOI 10.1038/leu.2008.221

    View details for Web of Science ID 000261862200006

    View details for PubMedID 18754032

  • Acute myeloid leukemia. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Appelbaum, F. R., Coutre, S. E., Damon, L. E., Erba, H. P., Foran, J., Lancet, J., Maness, L. J., Marcucci, G., Maslak, P. G., Millenson, M., Moore, J. O., Ravandi, F., Schuening, F., Shami, P., Smith, B. D., Stone, R. M., Tallman, M. S., Wang, E., White, F. L. 2008; 6 (10): 962-993

    View details for PubMedID 19176196

  • Acute postoperative thrombotic thrombocytopenic purpura following hysterectomy and lymphadenectomy for endometrial cancer GYNECOLOGIC ONCOLOGY Hamilton, C. A., Kao, J. M., Coutre, S. E., Teng, N. N. 2007; 106 (2): 423-426

    Abstract

    Thrombotic thrombocytopenic purpura (TTP) in the acute postoperative setting is a recently recognized syndrome that, similar to classic or idiopathic TTP, presents variably with microangiopathic hemolytic anemia, thrombocytopenia, fever, renal failure, and mental status changes. Though most reports of postoperative TTP are in conjunction with cardiac or vascular surgery, it has also been reported following orthopedic and abdominal surgeries.We present a case of a 53 year-old female diagnosed with metastatic poorly differentiated endometrial cancer who developed TTP the day following her cytoreductive cancer surgery.To our knowledge, this represents the first reported case of postoperative TTP following gynecologic cancer surgery. Because the presentation can be confused with other early postoperative complications, awareness of this syndrome is essential as initiation of plasmapheresis can be life-saving.

    View details for DOI 10.1016/j.ygyno.2007.04.005

    View details for Web of Science ID 000248585700023

    View details for PubMedID 17499845

  • International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia LEUKEMIA Rawstron, A. C., Villamor, N., Ritgen, M., Boettcher, S., Ghia, P., Zehnder, J. L., Lozanski, G., Colomer, D., Moreno, C., Geuna, M., Evans, P. A., Natkunam, Y., Coutre, S. E., Avery, E. D., Rassenti, L. Z., Kipps, T. J., Caligaris-Cappio, F., Kneba, M., Byrd, J. C., Hallek, M. J., Montserrat, E., Hillmen, P. 2007; 21 (5): 956-964

    Abstract

    The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it to real-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR). Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.

    View details for DOI 10.1038/sj.leu.2404584

    View details for Web of Science ID 000245999900014

    View details for PubMedID 17361231

  • Von Willebrand disease presenting as recurrent hemorrhage after transvaginal oocyte retrieval AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY Moayeri, S. E., Coutre, S. E., Ramirez, E. J., Westphal, L. M. 2007; 196 (4)

    Abstract

    A 34-year-old nulligravid woman experienced hemorrhage after each of 2 oocyte retrievals. Initial coagulopathy screening was negative. Treatments used during in vitro fertilization likely interfered with assay performance. Reevaluation remote from medications confirmed the diagnosis of von Willebrand disease. Treatments used during in vitro fertilization may increase bleeding risk and confound coagulopathy evaluation.

    View details for DOI 10.1016/j.ajog.2007.01.025

    View details for Web of Science ID 000245747600063

    View details for PubMedID 17403383

  • Minimal residual disease in chronic lymphocytic leukaemia: is it ready for primetime? BRITISH JOURNAL OF HAEMATOLOGY Nabhan, C., Coutre, S., Hillmen, P. 2007; 136 (3): 379-392

    Abstract

    New therapeutic modalities have substantially improved response rates and outcomes in chronic lymphocytic leukaemia (CLL), yet the mindset remains that palliation is the only goal of therapy because the disease is considered incurable. Ultimately, all patients relapse despite achieving an initial response, as minimal residual disease (MRD) persisting after therapy eventually evolves into morphological and clinical recurrence. The emergence of immune-based combination therapies capable of inducing molecular remissions, the availability of highly sensitive assays that detect MRD, and emerging data showing a longer duration of response or longer survival in patients with no detectable disease, suggest that eradicating MRD may be a reasonable option for some patients. Moreover, novel biological prognostic markers have divided CLL into favourable and unfavourable subtypes, arguing in favour of defining different goals of therapy for different patients. Clinicians are increasingly challenged with the task of how best to incorporate MRD assessment into clinical practice, especially in an era when these novel prognostic factors exist. This review summarises the current understanding of MRD from a clinical standpoint, suggests that MRD eradication maybe a reasonable option for some patients, and argues in favour of designing large randomised studies to determine whether MRD-negative remission improves outcome.

    View details for DOI 10.1111/j.1365-2141.2006.06428.x

    View details for Web of Science ID 000244038800003

    View details for PubMedID 17129223

  • Refractory hematuria from amyloidosis successfully treated by splenectomy UROLOGY Ma, J. F., Coutre, S. E., Curet, M. J., Brooks, J. D. 2006; 67 (5)

    Abstract

    Systemic amyloidosis can result in a coagulopathy that is associated with low levels of factor X. We present a case of intractable, life-threatening hematuria that was successfully managed with activated recombinant human factor VII and splenectomy.

    View details for DOI 10.1016/j.urology.2005.11.048

    View details for Web of Science ID 000238390800059

    View details for PubMedID 16698382

  • Acute myeloid leukemia clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network O'Donnell, M. R., Appelbaum, F. R., Baer, M. R., Byrd, J. C., Coutre, S. E., Damon, L. E., Erba, H. P., Estey, E., Foran, J., Lancet, J., Maness, L. J., Maslak, P. G., Millenson, M., Moore, J. O., Przepiorka, D., Shami, P., Smith, B. D., Stone, R. M., Tallman, M. S. 2006; 4 (1): 16-36

    View details for PubMedID 16403402

  • The evolving role of alemtuzumab in management of patients with CLL LEUKEMIA Faderl, S., Coutre, S., Byrd, J. C., Dearden, C., Denes, A., Dyer, M. J., Gregory, S. A., Gribben, J. G., Hillmen, P., Keating, M., Rosen, S., Venugopal, P., Rai, K. 2005; 19 (12): 2147-2152

    Abstract

    New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.

    View details for DOI 10.1038/sj.leu.2403984

    View details for Web of Science ID 000233462300015

    View details for PubMedID 16239912

  • Therapeutic efficacy and safety of platelets treated with a photochemical process for pathogen inactivation: the SPRINT Trial BLOOD McCullough, J., Vesole, D. H., Benjamin, R. J., Slichter, S. J., Pineda, A., Snyder, E., Stadtmauer, E. A., Lopez-Plaza, I., Coutre, S., Strauss, R. G., GOODNOUGH, L. T., Fridey, J. L., Raife, T., Cable, R., Murphy, S., Howard, F., Davis, K., Lin, J. S., Metzel, P., Corash, L., Koutsoukos, A., Lin, L., Buchholz, D. H., Conlan, M. G. 2004; 104 (5): 1534-1541

    Abstract

    We report a transfusion trial of platelets photochemically treated for pathogen inactivation using the synthetic psoralen amotosalen HCl. Patients with thrombocytopenia were randomly assigned to receive either photochemically treated (PCT) or conventional (control) platelets for up to 28 days. The primary end point was the proportion of patients with World Health Organization (WHO) grade 2 bleeding during the period of platelet support. A total of 645 patients (318 PCT and 327 control) were evaluated. The primary end point, the incidence of grade 2 bleeding (58.5% PCT versus 57.5% control), and the secondary end point, the incidence of grade 3 or 4 bleeding (4.1% PCT versus 6.1% control), were equivalent between the 2 groups (P =.001 by noninferiority). The mean 1-hour posttransfusion platelet corrected count increment (CCI) (11.1 x 10(3) PCT versus 16.0 x 10(3) control), average number of days to next platelet transfusion (1.9 PCT versus 2.4 control), and number of platelet transfusions (8.4 PCT versus 6.2 control) were different (P <.001). Transfusion reactions were fewer following PCT platelets (3.0% PCT versus 4.4% control; P =.02). The incidence of grade 2 bleeding was equivalent for PCT and conventional platelets, although posttransfusion platelet count increments and days to next transfusion were decreased for PCT compared with conventional platelets.

    View details for Web of Science ID 000223544000052

    View details for PubMedID 15138160

  • Management guidelines for use of alemtuzumab in B-Cell chronic lymphocytic leukemia CLINICAL LYMPHOMA Keating, M., Coutre, S., Rai, K., Osterborg, A., Faderl, S., Kennedy, B., Kipps, T., Bodey, G., Byrd, J. C., Rosen, S., Dearden, C., Dyer, M. J., Hillmen, P. 2004; 4 (4): 220-227

    Abstract

    An expert opinion roundtable held August 8-9, 2002, brought together clinicians with the most extensive experience with the use of alemtuzumab to pool knowledge and develop treatment goals and guidelines for optimal therapy. By sharing our collective experience, we have been able to formulate recommendations for current clinical practice, which are included in this report, and have emphasized results that have implications for future practice. Guidelines for the management of acute "first-dose" events, prophylaxis for infection, detection and treatment of cytomegalovirus reactivation, and hematologic support are presented, with emphasis on allowing patients to proceed smoothly through therapy while maximizing therapeutic benefit. Management of adverse events is facilitated by the predictable timing of their appearance. In general, hematologic adverse events are transient, manageable, and reversible. Clinicians should be cautious of prematurely terminating treatment at 4-6 weeks in patients whose disease responds to treatment. Although resolution of peripheral blood lymphocytosis occurs early in most patients, bone marrow is unlikely to be clear of disease. In particular, grade 4 neutropenia at this time is common and, because it is manageable, it is not an indication to discontinue treatment. The eradication of minimal residual disease from blood and bone marrow observed with alemtuzumab therapy is a major step forward in the treatment of B-cell chronic lymphocytic leukemia. Combination therapies such as alemtuzumab/fludarabine with the potential to maximize eradication at all disease sites should be systematically investigated. Because high response rates and few complications are observed in previously untreated patients, the use of alemtuzumab earlier in therapy may provide optimum benefit to patients.

    View details for Web of Science ID 000220780700005

    View details for PubMedID 15072613

  • Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate SEMINARS IN CANCER BIOLOGY Coutre, S., Gotlib, J. 2004; 14 (1): 23-31

    Abstract

    Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilia leukemia (CEL) represent the most recent additions to the list of molecularly defined chronic myeloproliferative disorders. Beginning with the observation that imatinib mesylate (Gleevec) could elicit rapid and complete hematologic remissions in a proportion of patients with HES, a reverse bedside-to-bench translational research effort led to the discovery of FIP1L1-PDGFRA, a novel fusion gene on chromosome 4q12 whose product is an imatinib-sensitive protein tyrosine kinase. FIP1L1-PDGFRA is the first description of a gain-of-function fusion gene derived from an interstitial chromosomal deletion rather than a reciprocal translocation. Empiric use of imatinib in HES and CEL provides a dramatic example of how the development of targeted therapeutics can provide tremendous insight into the molecular etiology of what appear to be a diverse and otherwise indecipherable collection of diseases. In this review, we discuss the role of imatinib in HES/CEL and other malignancies characterized by constitutively activated tyrosine kinases, and examine molecular features of the FIP1L1-PDGFRA fusion.

    View details for DOI 10.1016/j.semcancer.2003.11.004

    View details for Web of Science ID 000189081200004

    View details for PubMedID 14757533

  • PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFR alpha-induced myeloproliferative disease CANCER CELL Cools, J., Stover, E. H., Boulton, C. L., Gotlib, J., Legare, R. D., Amaral, S. M., Curley, D. P., Duclos, N., Rowan, R., Kutok, J. L., Lee, B. H., Williams, I. R., Coutre, S. E., Stone, R. M., DeAngelo, D. J., Marynen, P., Manley, P. W., Meyer, T., Fabbro, D., Neuberg, D., Weisberg, E., GRIFFIN, J. D., Gilliland, D. G. 2003; 3 (5): 459-469

    Abstract

    FIP1L1-PDGFRalpha causes hypereosinophilic syndrome (HES) and is inhibited by the tyrosine kinase inhibitor imatinib (Gleevec). Imatinib is a potent inhibitor of ABL, ARG, PDGFRalpha, PDGFRbeta, and KIT and induces durable hematologic responses in HES patients. However, we observed relapse with resistance to imatinib as consequence of a T674I mutation in FIP1L1-PDGFRalpha, analogous to the imatinib-resistant T315I mutation in BCR-ABL. We developed a murine bone marrow transplant model of FIP1L1-PDGFRalpha-induced myeloproliferative disease to evaluate the efficacy of PKC412, an alternative inhibitor of PDGFRalpha, for the treatment of HES. PKC412 is effective for treatment of FIP1L1-PDGFRalpha-induced disease and of imatinib-induced resistance due to the T674I mutation. Our data establish PKC412 as molecularly targeted therapy for HES and other diseases expressing activated PDGFRalpha and demonstrate the potential of alternative kinase inhibitors to overcome resistance in target tyrosine kinases.

    View details for Web of Science ID 000183104800009

    View details for PubMedID 12781364

  • T-cell prolymphocytic leukemia: update and focus on alemtuzumab (Campath-1H). Hematology Cao, T. M., Coutre, S. E. 2003; 8 (1): 1-6

    Abstract

    T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell lymphoproliferative disorder. While the etiology of T-PLL is unknown, recent progress in unraveling the molecular basis of leukemogenesis has been substantial and may yield novel therapeutic targets. T-PLL is a distinct disease entity and the diagnosis can be readily made based on characteristic clinical features and laboratory findings. Prior to the appearance of pentostatin and alemtuzumab in clinical protocols, outcome for T-PLL patients was exceedingly poor with median survival measured in months. While the use of alemtuzumab in particular has improved remissions, the disease remains incurable. Future collaborative efforts investigating novel treatment approaches will be crucial to improving survival for patients with this disease.

    View details for PubMedID 12623420

  • Management of advanced chronic lymphocytic leukemia. Current hematology reports Cao, T. M., Coutre, S. E. 2003; 2 (1): 65-72

    Abstract

    Chronic lymphocytic leukemia (CLL) is generally considered to be incurable. It is the most common of the adult leukemias, and many patients are asymptomatic when diagnosed. Most patients survive for several years, and some never require treatment for their disease, leading to the belief that it is an indolent disease. However, this view is changing with the introduction of more effective therapies. Purine nucleoside analogs have become standard in the therapy of most patients. Monoclonal antibodies including alemtuzumab (Campath-IH; Berlex Laboratories, Richmond, CA) and rituximab are playing an increasingly important role in the treatment of patients with advanced disease. Clinical trials will be crucial in defining how and when to treat patients with CLL and will help establish the role of newer prognostic markers and more sensitive methodologies to detect minimal residual disease.

    View details for PubMedID 12901156

  • Cytomegalovirus viremia during Campath-1H therapy for relapsed and refractory chronic lymphocytic leukemia and prolymphocytic leukemia CLINICAL LYMPHOMA Nguyen, D. D., Cao, T. M., Dugan, K., Starcher, S. A., Fechter, R. L., Coutre, S. E. 2002; 3 (2): 105-110

    Abstract

    Campath-1H is effective therapy for patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL), but it is associated with profound lymphopenia and deficiencies in cell-mediated immunity. We report the incidence of cytomegalovirus (CMV) viremia in 34 patients treated with Campath-1H for relapsed or refractory CLL and PLL. All patients received infection prophylaxis during therapy and continuing for at least 2 months following Campath-1H. Five patients (15%) developed CMV viremia at a median of 28 days (range, 20-30 days) after the first dose of Campath-1H. The median CMV viral load was 860/mL (range, 420-2100/mL), as determined by quantitative plasma polymerase chain reaction (PCR). All 5 patients had a temperature > 38.5 degrees C, normal chest radiographs, normal liver function tests, and negative bacterial blood cultures with no clinical evidence of CMV disease at the time of presentation with CMV viremia. The median absolute neutrophil count (ANC) was 740/ microL (range, 340-1600/ microL), and the median absolute lymphocyte count (ALC) was 16/microL (range, 11-169/ microL) for the 5 patients at the time of CMV viremia. All 5 patients received ganciclovir therapy followed by prompt fever resolution and clearance of CMV viremia by plasma PCR. By univariate regression analysis, the following were not risk factors for CMV viremia: age, number of prior regimens, prior rituximab therapy, prior splenectomy, modified Rai stage at Campath-1H therapy (low/intermediate vs. high), ANC, and ALC; although, there was a trend towards significance for prior rituximab therapy (P = 0.07). Cytomegalovirus viremia may be a significant infectious complication during Campath-1H therapy and should be investigated further in future studies.

    View details for Web of Science ID 000178917700006

    View details for PubMedID 12435283

  • Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed JOURNAL OF CLINICAL ONCOLOGY Keating, M. J., Cazin, B., Coutre, S., Birhiray, R., Kovacsovics, T., Langer, W., Leber, B., Maughan, T., Rai, K., Tjonnfjord, G., Bekradda, M., Itzhaki, M., Herait, P. 2002; 20 (1): 205-213

    Abstract

    We conducted a retrospective analysis to evaluate the safety and efficacy of Campath-1H, an anti-CD52 humanized monoclonal antibody, in previously treated T-prolymphocytic leukemia (T-PLL) patients in a compassionate-use program.Seventy-six patients with T-PLL (including four chemotherapy-naive patients) received 3, 10, and 30 mg of Campath-1H on sequential days, followed by 30 mg three times weekly, as 2-hour intravenous infusions, for 4 to 12 weeks.Median patient age was 60 years (range, 35 to 84). Spleen liver, lymph node, and skin involvement were present in 64%, 40%, 54%, and 18% of patients, respectively. All tested patients had CD2, CD7, CD4, and/or CD8 positivity, whereas CD5 and CD3 were positive in 98% and 96% of tested patients, respectively. The objective response rate was 51% (95% confidence interval [CI], 40% to 63%), with a 39.5% complete response (CR) rate (95% CI, 28% to 51%). The median duration of CR was 8.7 months (range, 0.13+ to 44.4), and median time to progression was 4.5 months (range, 0.1 to 45.4) compared with 2.3 months (range, 0.2 to 28.1) after first-line chemotherapy. The median overall survival was 7.5 months (14.8 months for CR patients). The most common Campath-1H-related adverse events were acute reactions during or immediately after infusions. Fifteen infectious episodes occurred during treatment in 10 patients (13%), leading to treatment discontinuation in three. Eight patients experienced possibly related, late-onset infections. Severe thrombocytopenia and/or neutropenia occurred in six patients (8%), leading to treatment discontinuation in four. Two treatment-related deaths occurred.Campath-1H is an active drug in T-PLL patients for whom first-line therapy has failed. It has a favorable risk/benefit ratio and should be prospectively investigated in chemotherapy-naive patients.

    View details for Web of Science ID 000173231900027

    View details for PubMedID 11773171

  • NCCN Practice Guidelines for acute myelogenous leukemia ONCOLOGY-NEW YORK O'Donnell, M. R., Appelbaum, F. R., Baer, M. R., Carabasi, M. H., Coutre, S. E., Erba, H. P., Estey, E., Glenn, M. J., Kraut, E. H., Maslak, P., Millenson, M., Miller, C. B., Saba, H. I., Stone, R., Tallman, M. S. 2000; 14 (11A): 53-61

    View details for Web of Science ID 000166713700004

    View details for PubMedID 11195419

  • CONVERSION OF THROMBIN INTO AN ANTICOAGULANT BY PROTEIN ENGINEERING NATURE Gibbs, C. S., Coutre, S. E., Tsiang, M., Li, W. X., Jain, A. K., Dunn, K. E., Law, V. S., Mao, C. T., MATSUMURA, S. Y., MEJZA, S. J., Paborsky, L. R., Leung, L. L. 1995; 378 (6555): 413-416

    Abstract

    At sites of vascular injury, thrombin interacts with multiple procoagulant substrates, to mediate both fibrin clotting and platelet aggregation. But upon binding to thrombomodulin on the vascular endothelium, thrombin instead activates protein C, thereby functioning as an anticoagulant and attenuating clot formation. Upon infusion in vivo, both the procoagulant and anticoagulant effects of thrombin were observed. Preliminary studies indicating that thrombin's protein C activating and fibrinogen clotting activities could be dissociated by mutagenesis suggested to us that a thrombin variant that lacked procoagulant activity while retaining anticoagulant function might be an attractive antithrombotic agent. Using protein engineering, we introduced a single substitution, E229A, that substantially shifted thrombin's specificity in favour of the anticoagulant substrate, protein C. In monkeys, this modified thrombin functioned as an endogenous protein C activator demonstrating dose-dependent, reversible anticoagulation without any indication of procoagulant activity. Notably, template bleeding times were not prolonged, suggesting a reduced potential for bleeding complications.

    View details for Web of Science ID A1995TF89300066

    View details for PubMedID 7477382

Conference Proceedings


  • Final Results of the Phase I Study of Lenalidomide In Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL-001 Study) Wendtner, C., Hillmen, P., Mahadevan, D., Stilgenbauer, S., Uharek, L., Coutre, S., Frankfurt, O., Bloor, A., Bosch, F., Furman, R. R., Kimby, E., Gribben, J. G., Gobbi, M., Dreisbach, L., Hurd, D. D., Sekeres, M. A., Ferrajoli, A., Shah, S., Zhang, J., de Parseval, L. M., Chanan-Khan, A. A. AMER SOC HEMATOLOGY. 2010: 591-592
  • Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study Sawyers, C. L., Hochhaus, A., Feldman, E., Goldman, J. M., Miller, C. B., Ottmann, O. G., Schiffer, C. A., Talpaz, M., Guilhot, F., Deininger, M. W., Fischer, T., O'Brien, S. G., Stone, R. M., Gambacorti-Passerini, C. B., Russell, N. H., Reiffers, J. J., Shea, T. C., Chapuis, B., Coutre, S., TURA, S., Morra, E., Larson, R. A., Saven, A., Peschel, C., Gratwohl, A., MANDELLI, F., Ben-Am, M., Gathmann, I., Capdeville, R., Paquette, R. L., Druker, B. J. AMER SOC HEMATOLOGY. 2002: 3530-3539

    Abstract

    Blast crisis is the most advanced stage of chronic myelogenous leukemia (CML) and is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase II trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs.

    View details for Web of Science ID 000175496300010

    View details for PubMedID 11986204

  • United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia Soignet, S. L., Frankel, S. R., Douer, D., Tallman, M. S., Kantarjian, H., Calleja, E., Stone, R. M., Kalaycio, M., Scheinberg, D. A., Steinherz, P., Sievers, E. L., Coutre, S., DAHLBERG, S., Ellison, R., Warrell, R. P. AMER SOC CLINICAL ONCOLOGY. 2001: 3852-3860

    Abstract

    To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL).Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study.Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes.This study establishes ATO as a highly effective therapy for patients with relapsed APL.

    View details for Web of Science ID 000171043400009

    View details for PubMedID 11559723

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