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

Clin Cancer Res. 2020 May 15;26(10):2297-2307. doi: 10.1158/1078-0432.CCR-19-1251. Epub 2020 Jan 22.

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 hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 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 + CR without platelet recovery + 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Asparaginase / administration & dosage
  • Bortezomib / administration & dosage
  • Child
  • Child, Preschool
  • Decitabine / administration & dosage
  • Dexamethasone / administration & dosage
  • Doxorubicin / administration & dosage
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Male
  • Mitoxantrone / administration & dosage
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Pilot Projects
  • Polyethylene Glycols / administration & dosage
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Prognosis
  • Salvage Therapy / methods
  • Survival Rate
  • Vincristine / administration & dosage
  • Vorinostat / administration & dosage
  • Young Adult

Substances

  • Polyethylene Glycols
  • Vorinostat
  • Vincristine
  • Bortezomib
  • Decitabine
  • pegaspargase
  • Dexamethasone
  • Doxorubicin
  • Mitoxantrone
  • Asparaginase

Associated data

  • ClinicalTrials.gov/NCT01483690