1. Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study
- Author
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Burke, Michael J, Kostadinov, Rumen, Sposto, Richard, Gore, Lia, Kelley, Shannon M, Rabik, Cara, Trepel, Jane B, Lee, Min-Jung, Yuno, Akira, Lee, Sunmin, Bhojwani, Deepa, Jeha, Sima, Chang, Bill H, Sulis, Maria Luisa, Hermiston, Michelle L, Gaynon, Paul, Huynh, Van, Verma, Anupam, Gardner, Rebecca, Heym, Kenneth M, Dennis, Robyn M, Ziegler, David S, Laetsch, Theodore W, Oesterheld, Javier E, Dubois, Steven G, Pollard, Jessica A, Glade-Bender, Julia, Cooper, Todd M, Kaplan, Joel A, Farooqi, Midhat S, Yoo, Byunggil, Guest, Erin, Wayne, Alan S, and Brown, Patrick A
- Subjects
Hematology ,Pediatric Cancer ,Genetics ,Cancer ,Rare Diseases ,Childhood Leukemia ,Pediatric ,Clinical Research ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Adolescent ,Adult ,Antineoplastic Combined Chemotherapy Protocols ,Asparaginase ,Bortezomib ,Child ,Child ,Preschool ,Decitabine ,Dexamethasone ,Doxorubicin ,Female ,Follow-Up Studies ,Humans ,Infant ,Male ,Mitoxantrone ,Neoplasm Recurrence ,Local ,Pilot Projects ,Polyethylene Glycols ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Salvage Therapy ,Survival Rate ,Vincristine ,Vorinostat ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeTreatment 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 methodsWe 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.ResultsThe 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.ConclusionsDespite 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.
- Published
- 2020