Bio

Clinical Focus


  • Pregnancy-related hematologic conditions
  • Anemia
  • Hemostasis Thrombosis
  • Idiopathic thrombocytopenic purpura
  • Anticoagulation
  • Hematology
  • Cancer > Hematology
  • Leukemia - Hematology

Academic Appointments


Administrative Appointments


  • Medical Director, Oral Anticoagulation Clinic, Stanford Hospital and Clinics (2004 - Present)

Professional Education


  • Board Certification: Medical Oncology, Royal College of Physicians and Surgeons of Canada (1990)
  • Board Certification: Hematology, Royal College of Physicians and Surgeons (1989)
  • Board Certification: Internal Medicine, Royal College of Physicians and Surgeons of Canada (1988)
  • Residency:Laval University (1987) Canada
  • Internship:Laval University (1984) Canada
  • Fellowship:McMaster University (1991) Canada
  • Fellowship:The University of British Columbia (1990) Canada
  • Oncology, University of BC, Canada, Medical Oncology (1990)
  • Board certification, Hematology, Canadian Hematology Board (1989)
  • Fellowship:University of Montreal (1989) Canada
  • Hematology, University of Montreal, Canada, Hematology (1989)
  • Medical Education:Laval University (1983) Canada
  • F.R.C.P.(C), Internal Medicine, Canadian Board (1987)
  • M.D., Laval University, Canada, Medicine (1984)

Research & Scholarship

Clinical Trials


  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-Directed Thrombolysis Recruiting

    The purpose of this study is to determine if the use of adjunctive Pharmacomechanical Catheter Directed Thrombolysis, which includes the intrathrombus administration of rt-PA--Activase (Alteplase),can prevent the post-thrombotic syndrome(PTS)in patients with symptomatic proximal deep vein thrombosis(DVT)as compared with optimal standard DVT therapy alone.

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Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • 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

  • Accessory splenules in autoimmune hemolytic anemia AMERICAN JOURNAL OF HEMATOLOGY Logan, A., Berube, C., Gotlib, J. 2013; 88 (2): 156-156

    View details for DOI 10.1002/ajh.23335

    View details for Web of Science ID 000314149700015

    View details for PubMedID 23027373

  • 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

  • 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

  • Moxifloxacin-acetaminophen-warfarin interaction during bacille Calmette-Guerin treatment for bladder cancer AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY Lee, R., Wen, A., Berube, C. 2011; 68 (9): 814-817

    Abstract

    The case of a patient receiving long-term anticoagulation with warfarin who had supratherapeutic International Normalized Ratios (INRs) after receiving concomitant acetaminophen and moxifloxacin as prophylaxis with bacille Calmette-Guérin (BCG) therapy for bladder cancer is reported.An 89-year-old man receiving long-term anticoagulation with warfarin sodium (total weekly dosage of 19 mg) arrived at the anticoagulation clinic for his monthly visit. On the day before this visit, he had received the third of six serial weekly BCG bladder instillations for the treatment of bladder cancer. He did not report that acetaminophen 1000 mg four times daily and one dose of moxifloxacin 400 mg had been prescribed before these instillations. An INR check revealed a value of 6.7. He was instructed to take 2.5 mg of oral phytonadione and to withhold his warfarin dose that night. On the next day, his INR was 3.2. Each time he arrived at the anticoagulation clinic after his BCG therapy, his INR was supratherapeutic, except after his fourth treatment (INR of 2.5), which can be explained by residual effects from the phytonadione he received a week earlier. After completion of his BCG therapy, he was instructed to resume his usual warfarin sodium dosage of 19 mg weekly, and his INR remained in the desired therapeutic range. According to the Drug Interaction Probability Scale, the development of supratherapeutic INRs was probably associated with concomitant acetaminophen and moxifloxacin use.An 89-year-old man receiving long-term anticoagulation with warfarin had supratherapeutic INRs after receiving acetaminophen and moxifloxacin as prophylaxis during BCG therapy for bladder cancer.

    View details for DOI 10.2146/ajhp100159

    View details for Web of Science ID 000297773000011

    View details for PubMedID 21515865

  • 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

  • Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9 PHARMACOGENETICS AND GENOMICS Sagrieya, H., Berube, C., Wen, A., Ramakrishnan, R., Mir, A., Hamilton, A., Altman, R. B. 2010; 20 (7): 407-413

    Abstract

    Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC).we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm.When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R) explained by the IWPC pharmacogenetic algorithm (P<0.05). Importantly, we show that pooling rare variants substantially increases the R for CYP2C9 (rare variants: P=0.0065, R=6%; common variants: P=0.0034, R=7%; rare and common variants: P=0.00018; R=12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R=50%; Gage: R=49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R=22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments.CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.

    View details for DOI 10.1097/FPC.0b013e328338bac2

    View details for Web of Science ID 000278879400001

    View details for PubMedID 20442691

  • 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

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