Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium

Lauren Pommert, Eric S. Schafer, Jemily Malvar, Nathan Gossai, Ellynore Florendo, Kirthi Pulakanti, Katelyn Heimbruch, Cary Stelloh, Yueh Yun Chi, Richard Sposto, Sridhar Rao, Van Thu Huynh, Patrick Brown, Bill H. Chang, Susan I. Colace, Michelle L. Hermiston, Kenneth Heym, Raymond J. Hutchinson, Joel A. Kaplan, Rajen ModyTracey A. O'Brien, Andrew E. Place, Peter H. Shaw, David S. Ziegler, Alan Wayne, Deepa Bhojwani, Michael J. Burke

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Survival outcomes for relapsed/refractory pediatric acute myeloid leukemia (R/R AML) remain dismal. Epigenetic changes can result in gene expression alterations which are thought to contribute to both leukemogenesis and chemotherapy resistance. We report results from a phase I trial with a dose expansion cohort investigating decitabine and vorinostat in combination with fludarabine, cytarabine, and G-CSF (FLAG) in pediatric patients with R/R AML [NCT02412475]. Thirty-seven patients enrolled with a median age at enrollment of 8.4 (range, 1–20) years. There were no dose limiting toxicities among the enrolled patients, including two patients with Down syndrome. The recommended phase 2 dose of decitabine in combination with vorinostat and FLAG was 10 mg/m2. The expanded cohort design allowed for an efficacy evaluation and the overall response rate among 35 evaluable patients was 54% (16 complete response (CR) and 3 complete response with incomplete hematologic recovery (CRi)). Ninety percent of responders achieved minimal residual disease (MRD) negativity (<0.1%) by centralized flow cytometry and 84% (n = 16) successfully proceeded to hematopoietic stem cell transplant. Two-year overall survival was 75.6% [95%CI: 47.3%, 90.1%] for MRD-negative patients vs. 17.9% [95%CI: 4.4%, 38.8%] for those with residual disease (p <.001). Twelve subjects (34%) had known epigenetic alterations with 8 (67%) achieving a CR, 7 (88%) of whom were MRD negative. Correlative pharmacodynamics demonstrated the biologic activity of decitabine and vorinostat and identified specific gene enrichment signatures in nonresponding patients. Overall, this therapy was well-tolerated, biologically active, and effective in pediatric patients with R/R AML, particularly those with epigenetic alterations.

Original languageEnglish (US)
Pages (from-to)613-622
Number of pages10
JournalAmerican Journal of Hematology
Volume97
Issue number5
DOIs
StatePublished - May 2022

ASJC Scopus subject areas

  • Hematology

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