Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium
Pommert, Lauren; Schafer, Eric S.; Malvar, Jemily; Gossai, Nathan; Florendo, Ellynore; Pulakanti, Kirthi; Heimbruch, Katelyn; Stelloh, Cary; Chi, Yueh-Yun; Sposto, Richard; Rao, Sridhar; Huynh, Van Thu; Brown, Patrick; Chang, Bill H.; Colace, Susan I.; Hermiston, Michelle L.; Heym, Kenneth; Hutchinson, Raymond J.; Kaplan, Joel A.; Mody, Rajen; O’Brien, Tracey A.; Place, Andrew E.; Shaw, Peter H.; Ziegler, David S.; Wayne, Alan; Bhojwani, Deepa; Burke, Michael J.
2022-05
Citation
Pommert, Lauren; Schafer, Eric S.; Malvar, Jemily; Gossai, Nathan; Florendo, Ellynore; Pulakanti, Kirthi; Heimbruch, Katelyn; Stelloh, Cary; Chi, Yueh-Yun ; Sposto, Richard; Rao, Sridhar; Huynh, Van Thu; Brown, Patrick; Chang, Bill H.; Colace, Susan I.; Hermiston, Michelle L.; Heym, Kenneth; Hutchinson, Raymond J.; Kaplan, Joel A.; Mody, Rajen; O’Brien, Tracey A.; Place, Andrew E.; Shaw, Peter H.; Ziegler, David S.; Wayne, Alan; Bhojwani, Deepa; Burke, Michael J. (2022). "Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium." American Journal of Hematology 97(5): 613-622.
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.Publisher
John Wiley & Sons, Inc.
ISSN
0361-8609 1096-8652
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