Clinical cancer research, 2020-05-15, Vol.26 (10), p.2297-2307
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.
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.
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 (
= 1); seizure, somnolence, and delirium (
= 1); and pneumonitis, hypoxia, and hyperbilirubinemia (
= 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
modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.
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.
Decitabine - administration & dosage ; Prognosis ; Follow-Up Studies ; Mitoxantrone - administration & dosage ; Humans ; Child, Preschool ; Neoplasm Recurrence, Local - drug therapy ; Infant ; Male ; Neoplasm Recurrence, Local - pathology ; Young Adult ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy ; Vincristine - administration & dosage ; Adult ; Female ; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Child ; Doxorubicin - administration & dosage ; Dexamethasone - administration & dosage ; Survival Rate ; Polyethylene Glycols - administration & dosage ; Asparaginase - administration & dosage ; Pilot Projects ; Bortezomib - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Adolescent ; Vorinostat - administration & dosage ; Salvage Therapy - methods ; Index Medicus ; decitabine ; vorinostat ; relapse ; acute lymphoblastic leukemia ; epigenetic
HighWire Press (Free Journals)
Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
© ProQuest LLC All rights reserved〈img src="https://exlibris-pub.s3.amazonaws.com/PQ_Logo.jpg" style="vertical-align:middle;margin-left:7px"〉
Permalink to record