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

Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia. Improving outcomes by targeting mechanisms of drug resistance is a potential solution. Experimental Design: 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 on 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 (DLT) which included cholestasis, steatosis, hyperbilirubinemia (n=1); seizure, somnolence, delirium (n=1); and pneumonitis, hypoxia, hyperbilirubinemia (n=1). Infectious complications were common with 17/23 (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 5 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 anti-leukemic effects. Conclusion/Discussion: 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.