San Diego, CA—Approximately 33% of patients with newly diagnosed, higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) attained complete responses with the novel hypomethylating agent guadecitabine, according to results of a phase 2 study reported by Guillermo Montalban-Bravo, MD, M.D. Anderson Cancer Center, Houston, at the 2016 American Society of Hematology meeting.
Treatment with guadecitabine led to objective responses in 71% of the 50 patients who were included in the efficacy analysis. Guadecitabine therapy was associated with a high incidence of febrile neutropenia and infections, which were manageable with dose adjustment.
“Guadecitabine was active in the presence of high-risk features, and we identified mutations that were both prognostic and predictive. A phase 3 study of guadecitabine in patients with hypomethylating agent failure is ongoing,” said Dr Montalban-Bravo.
Another phase 2 clinical trial of patients who previously received treatment for MDS, including patients with azacitidine (Vidaza)-refractory disease, showed that guadecitabine also had activity in this patient population.
Guadecitabine Active in Patients with MDS or CMML
Dr Montalban-Bravo reported findings from a clinical trial involving patients with intermediate- or high-risk MDS or CMML, a patient population for which therapeutic options are limited. First-line therapy with standard hypomethylating agents (azacitidine, decitabine) led to overall response rates of 30% to 40%, including complete responses in 10% to 15% of patients.
Guadecitabine is a dinucleotide compound that is derived from decitabine and deoxyguanosine. Phase 1 clinical trials demonstrated safety and efficacy in patients with MDS or CMML and determined the optimal dosing schedule to be 60 mg/m2 daily for 5 days. Guadecitabine is administered subcutaneously, which distinguishes it from the current intravenous drugs.
Eligible patients had newly diagnosed MDS or CMML that met the International Prognostic Scoring System (IPSS) criteria for intermediate-2 or high-risk disease status or ≥10% marrow blast count. Patients received guadecitabine at the standard dose in 28-day cycles. The protocol required evaluation of all patients by means of a 28-gene next-generation sequencing panel.
The primary end point was complete response. Patients were enrolled in cohorts of 10. The clinical trial would end if the complete response rate did not reach at least 25%.
The study population comprised 43 patients with MDS and 7 patients with CMML. By standard IPSS criteria, all but 4 patients had intermediate-2 disease. By revised IPSS criteria, all but 7 patients had high- or very high-risk disease status.
Grade ≥3 febrile neutropenia was reported in 32% of patients, and grade ≥3 infections in 26% of patients. Dose reductions because of cytopenias and related complications was required in 34% of patients. The most frequently reported grade 1 or 2 adverse events were fatigue (66%), nausea (38%), dyspnea (26%), and fever (24%).
Overall, 71% of patients achieved objective response with guadecitabine, including 68% of patients with MDS and 83% of patients with CMML. Complete responses were documented in 32% of patients, 12 patients with MDS and 2 patients with CMML. An additional 32% of patients had complete responses in the bone marrow. Overall, 7 patients achieved complete cytogenetic responses.
Patients received a median of 6 cycles of guadecitabine. The median time to response was 3 treatment cycles, and the median duration of response was 4 treatment cycles (range, 0-14).
The study median overall survival was 14.1 months and the median event-free survival was 8.4 months.
By univariate analysis, ASXL1 mutation–positive disease was significantly associated with improved survival (hazard ratio, 2.99; P = .047). The RUNX1 mutation was predictive of response to guadecitabine therapy.
Another Study in Patients with Myelodysplastic Syndromes
A multicenter French study that evaluated guadecitabine in patients with MDS who received previous therapy with azacitidine included 56 patients—15 with primary resistance to azacitidine (after at least 6 cycles of therapy) and 41 patients with progressive disease after treatment with azacitidine, reported Marie Sebert, MD, Hôpital St-Louis, Université Paris 7, France.
Treatment with guadecitabine led to 9 objective responses (16% overall response rate), including 3 patients who had complete responses. Complete responses in the bone marrow were achieved in 5 patients and hematologic improvement in 1 patient.
“Four patients had responses exceeding 11 months, and 2 patients maintained responses for more than 17 months,” said Dr Sebert. “Long responders had no particular baseline features that distinguished them from other responders.”
Responding patients had a median overall survival of 19.7 months compared with 6.7 months for the entire study population.