Hagop M. Kantarjian, MD
The results of a phase II trial have shown high activity of guadecitabine, a next-generation hypomethylating drug, in treatment-naive older patients with acute myeloid leukemia. The findings were reported in The Lancet Oncology by Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, and colleagues. Guadecitabine has a longer half-life and exposure than its active metabolite decitabine.
In the phase II portion of the phase I/II trial, 107 patients aged ≥ 65 years from 14 U.S. sites who were not candidates for intensive chemotherapy were randomized between August 2012 and September 2014 to receive guadecitabine at 60 (n = 26) or 90 mg/m2 (n = 28) on days 1 to 5 of a 28-day cycle (total n = 54) or, after a protocol amendment, guadecitabine at 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle (n = 53). The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). The median age of patients was 77 years.
Outcomes and Toxicity
Composite complete response was achieved in 54% of patients receiving the lower dose on the 5-day schedule, 59% receiving the higher-dose on the 5-day schedule, and 50% receiving the 10-day schedule. The median response duration was 186 days in the 5-day cohort and 269 days in the 10-day cohort. Among responders, the median time to best response was 89 days in the 5-day cohort vs 69 days in the 10-day cohort.
At database lock in August 2016, 15 patients were still being followed for overall survival. Median follow-up was 1,107 days in the 5-day cohort and 705 days in the 10-day cohort. Median overall survival was 316 days vs 284 days, respectively. Median overall survival was 574 days among 37 patients achieving a complete response, 476 days among 18 patients achieving a complete response with incomplete platelet recovery or with incomplete neutrophil recovery regardless of platelets, and 93 days among 48 patients with no response.
The most common grade ≥ 3 adverse events were febrile neutropenia (61% in 5-day cohort vs 69% in 10-day cohort), thrombocytopenia (49% vs 42%), neutropenia (39% vs 35%), pneumonia (29% vs37%), anemia (29% vs 23%), and sepsis (16% vs 27%). The most common serious adverse events were febrile neutropenia (53% vs 48%), pneumonia (27% vs 31%), and sepsis (16% vs 27%). Death due to adverse events occurred in 23 patients (22%), with the most common causes being sepsis (8%) and pneumonia (5%). Four deaths in the 10-day cohort were considered possibly related to study treatment, with causes consisting of pneumonia in two patients, multiorgan failure in one patient, and sepsis in one patient.
The investigators concluded: “More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care.” ■