Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study

Michael J. Burke, Rumen Kostadinov, Richard Sposto, Lia Gore, Shannon M. Kelley, Cara Rabik, Jane B. Trepel, Min Jung Lee, Akira Yuno, Sunmin Lee, Deepa Bhojwani, Sima Jeha, Bill H. Chang, Maria Luisa Sulis, Michelle L. Hermiston, Paul Gaynon, Van Huynh, Anupam Verma, Rebecca Gardner, Kenneth M. HeymRobyn M. Dennis, David S. Ziegler, Theodore W. Laetsch, Javier E. Oesterheld, Steven G. Dubois, Jessica A. Pollard, Julia Glade-Bender, Todd M. Cooper, Joel A. Kaplan, Midhat S. Farooqi, Byunggil Yoo, Erin Guest, Alan S. Wayne, Patrick A. Brown

Research output: Contribution to journalArticle

Abstract

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1–21) were treated in this trial. Results: The most common grade 3–4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypo-calcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n ¼ 1); seizure, somnolence, and delirium (n ¼ 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n ¼ 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR þ CR without platelet recovery þ CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www. clinicaltrials.gov as NCT01483690.

Original languageEnglish (US)
Pages (from-to)2297-2307
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number10
DOIs
StatePublished - May 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burke, M. J., Kostadinov, R., Sposto, R., Gore, L., Kelley, S. M., Rabik, C., Trepel, J. B., Lee, M. J., Yuno, A., Lee, S., Bhojwani, D., Jeha, S., Chang, B. H., Sulis, M. L., Hermiston, M. L., Gaynon, P., Huynh, V., Verma, A., Gardner, R., ... Brown, P. A. (2020). Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study. Clinical Cancer Research, 26(10), 2297-2307. https://doi.org/10.1158/1078-0432.CCR-19-1251