Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia

Abstract

BACKGROUNDOutcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next‐generation hypomethylating agent, could be useful in treating such patients.METHODSIn this multicenter, open‐label, phase 2 dose‐expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28‐day cycle (5‐day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10‐day regimen).RESULTSBetween June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2/d, respectively [5‐day regimen] and 53 patients who were assigned to 60 mg/m2/d [10‐day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10‐day regimen versus the 5‐day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10‐day regimen. Early all‐cause mortality was low and similar between regimens. Twenty patients (8 on the 5‐day regimen and 12 on the 10‐day regimen) were bridged to hematopoietic cell transplantation.CONCLUSIONSGuadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325‐34. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

“Epigenetic” modification as therapy for acute myeloid leukemia

“…1 When patients who achieved a complete response with an incomplete count recovery were added, the response rate increased, but the median duration of the complete response was short, and this is consistent with the historically refractory nature of AML in this patient population. Earlier studies with guadecitabine produced generally similar results, 6,7 with higher response rates in previously untreated patients.…”

“…The results reported by Roboz et al 1 are of interest but are not decidedly better than what might have been achieved with other chemotherapy approaches. In phase 2 studies and even randomized studies in this group of higher risk MDS/AML patients, selection factors are a major impediment when one is trying to compare results from different trials.…”

“…In this issue of Cancer, Roboz et al 1 report on the use of guadecitabine, a new formulation of decitabine, in patients with AML that has relapsed or is refractory to standard treatment.…”

“…Using the long interspersed nuclear element 1 (LINE-1) assay as a surrogate for global DNA methylation, 5 Roboz et al 1 noted a maximum of 25% to 30% hypomethylation; it was highest with the 10-day schedule and decreased after the guadecitabine was stopped. This was felt to be a greater hypomethylation effect than that seen with decitabine or 5-azacytidine.…”

New Food and Drug Administration–Approved and Emerging Novel Treatment Options for Acute Myeloid Leukemia

“…Therefore, compared to decitabine, guadecitabine is able to resist cytidine deaminase‐mediated degradation of decitabine, which prolongs its half‐life. In a phase II study, 103 patients with relapsed/refractory AML received either a 5‐ or 10‐day guadecitabine regimen . Fifty patients received 60 or 90 mg/m 2 /day in the 5‐day regimen, and 53 patients received 60 mg/m 2 /day in the 10‐day regimen.…”