Decitabine and vorinostat with chemotherapy in relapsed pediatric acute lymphoblastic leukemia: A TACL pilot study Journal Article

   


Authors: 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.; Heym, K. M.; Dennis, R. M.; Ziegler, D. S.; Laetsch, T. W.; Oesterheld, J. E.; Dubois, S. G.; Pollard, J. A.; Glade-Bender, J.; Cooper, T. M.; Kaplan, J. A.; Farooqi, M. S.; Yoo, B.; Guest, E.; Wayne, A. S.; Brown, P. A.
Article Title: Decitabine and vorinostat with chemotherapy in relapsed pediatric acute lymphoblastic leukemia: A TACL pilot study
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. ©2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 26
Issue: 10
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2020-05-15
Start Page: 2297
End Page: 2307
Language: English
DOI: 10.1158/1078-0432.Ccr-19-1251
PUBMED: 31969338
PROVIDER: scopus
PMCID: PMC7477726
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85084921034&doi=10.1158%2f1078-0432.CCR-19-1251&partnerID=40&md5=61c817709ba9f9d5f1770a6b9bc162e3
Notes: Article -- Source: Scopus
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MSK Authors
  1. Julia L Glade Bender
    85 Glade Bender
  2. Maria Luisa Sulis
    43 Sulis
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