Pooled Analysis of Elderly Patients with Newly Diagnosed AML Treated with Sapacitabine and Decitabine Administered in Alternating Cycles.

Sapacitabine is a novel nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double strand DNA breaks and/or G2 cell cycle arrest. In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents with the synergy being more apparent if cells are treated with hypomethylating agents first. In addition to single-agent activity, sapacitabine has recently shown sufficient activity when administered in alternating cycles with decitabine to be further evaluated in a large randomized phase III study. Here we report the pooled analysis of 46 patients who were treated in a phase I/II study (n=25) and the lead-in phase of the phase III study (n=21). Methods: Decitabine 20 mg/m² was administered intravenously daily × 5 days of a 4-week cycle (odd cycles) alternating with sapacitabine 300 mg po b.i.d. × 3 days/week × 2 weeks of a 4-week cycle (even cycles). After these doses were shown to be safe and active in the phase I/II study, this treatment was further evaluated in the lead-in phase of the phase III study to confirm the findings from the phase I/II study. Eligible patients must have been ≥70 years with untreated AML unsuitable for or unwilling to receive standard induction chemotherapy; patients who received hypomethylating agents for prior MDS or MPD were excluded. Results: As of August 2012, 46 patients were treated with the above regimen. Median age is 77 years (range, 72–90). Thirty-three patients are 75 years or older (71.7%). Two DLTs were observed (lung infection/sepsis, typhlitis). Seventeen patients responded (37%) with 10 CRs, 2 PRs and 5 major HIs. Median time to response is 2 cycles, i.e., one cycle of decitabine and one cycle of sapacitabine (range 1– 10). Twenty-five patients have received ≥ 5 cycles of treatment (54.3%). Six patients died within 60-days (13%) with one death from typhlitis considered to be possibly related to decitabine by investigator assessment. Median overall survival is 238 days and 13 patients are still alive (28.3%). Sixteen patients survived 1 year or longer (34.8%). Common adverse events (regardless of causality) included asthenia, fatigue, decreased appetite, nausea, vomiting, constipation, diarrhea, dyspnea, peripheral edema, back pain, cellulitis, febrile neutropenia, neutropenia, and thrombocytopenia, mostly moderate in intensity. Conclusion: The sequential combination of decitabine and sapacitabine appears to be safe and active. A large randomized, phase III trial is currently underway comparing this treatment regimen against single agent decitabine in the treatment of elderly AML.

Ravandi:Eisai: Honoraria, Research Funding. Off Label Use: Use of decitaboine in AML. Goldberg:Cyclacel: Research Funding. Wetzler:Cyclacel: Membership on an entity's Board of Directors or advisory committees, Research Funding. Seiter:Eisai: Speakers Bureau; Cyclacel: Honoraria. Chiao:Cyclacel: Employment, Equity Ownership, Patents & Royalties. Kantarjian:Cyclacel: Research Funding; Eisai: Research Funding.