A phase 2 trial of combination therapy with thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid (TADA) in patients with overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) or primary myelofibrosis (PMF)

Authors

  • Nelli Bejanyan MD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Ramon V. Tiu MD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    2. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Azra Raza MD,

    1. Columbia University, New York, New York
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  • Ania Jankowska PhD,

    1. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Matt Kalaycio MD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Anjali Advani MD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    2. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Josephine Chan PhD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Yogen Saunthararajah MD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    2. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Lindsey Mooney BS,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Jaroslaw P. Maciejewski MD, PhD,

    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    2. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
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  • Mikkael A. Sekeres MD, MS

    Corresponding author
    1. Leukemia Program, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    2. Department of Translational Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio
    • Director, Leukemia Program, Associate Professor of Medicine, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Desk R35, 9500 Euclid Avenue, Cleveland, OH 44195
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    • Fax: (216) 636-0636


  • Presented in part at the 49th Annual Meeting of the American Society of Hematology; December 8-11, 2007; Atlanta, Georgia.

Abstract

BACKGROUND.

Primary myelofibrosis (PMF) and overlap myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal hematopoietic disorders that share similar clinical features and molecular abnormalities, such as the Janus kinase 2 (JAK2) valine to phenylalanine mutation at codon 617 (V617F) and the tet methylcytosine dioxygenase 2 (TET2) mutation. There are limited therapeutic options available for these diseases, and single agents have only modest efficacy. In this phase 2 study, the authors combined multiple active agents (thalidomide, arsenic trioxide, dexamethasone, and ascorbic acid [TADA]) to treat patients with these disorders.

METHODS.

This multicenter trial was conducted from January 2005 to July 2007. The primary endpoint was to evaluate the efficacy of TADA therapy. Patients received the combination for one 12-week cycle followed by maintenance thalidomide for an additional 3 months. Response was assessed using International Working Group criteria.

RESULTS.

Among 28 enrolled patients, the median age was 66.5 years; 15 patients had MDS/MPN-unclassifiable, 8 patients had chronic myelomonocytic leukemia type 1, and 5 patients had PMF. Approximately 60% of the patients had normal cytogenetics. The JAK2V617F mutation was detected in 5 of 14 tested patients, and TET2 mutations were detected in 2 of 8 tested patients. Almost half of the patients had splenomegaly. With a median on-study follow-up of 5.7 months, 21 patients (75%) completed the entire 12-week course of therapy, and 6 patients (29%) responded to TADA. With a median extended follow-up of 24.1 months for 15 evaluable patients, the median progression-free survival was 14.4 months, and the median overall survival was 21.4 months.

CONCLUSIONS.

The TADA regimen yielded clinical responses in patients with PMF and MDS/MPN. To the authors' knowledge, this study represents the first trial targeting this patient population. The results indicated that it is reasonable to incorporate multiple novel agents in the treatment of these rare diseases. Cancer 2012. © 2011 American Cancer Society.

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