Oral Sapacitabine for Treating Elderly Patients with AML

Abstract & Commentary

By Mamatha Prabhakar, MD, Hematology/Oncology Division, IASIA-Falls Church, VA. Dr. Prabhakar reports no financial relationships relevant to this field of study.

Synopsis: In this Phase 2 trial, 105 older patients with acute myeloid leukemia who were either treatment-naïve or at first relapse were treated with one of three schedules of oral sapacitabine: 200 mg twice daily for 7 days (group A), 300 mg twice daily for 7 days (group B), or 400 mg twice daily for 3 days each week for 2 weeks (group C). The treatment was well tolerated with 1-year overall survival of 35%, 10%, and 30% in groups A, B, and C, respectively. The 400 mg dose schedule had the best efficacy profile. A platelet count of ≤ 50 × 109/L and an unfavorable cytogentic risk profile were adverse prognostic factors for 1-year overall survival.

Source: Kantarjian H, et al. Oral sapacitabine for the treatment of acute myeloid leukemia in elderly patients: A randomized phase 2 study. Lancet Oncol 2012;13:1096-1104.

Available treatments are inadequate for many elderly patients with acute myeloid leukemia (AML) who are considered to be medically unfit for intensive chemotherapy. At least 80% of patients die within 1 year of diagnosis. The treatment of elderly AML patients is challenging, with poor response rates and high mortality rates following intensive chemotherapy.1 Findings from cancer registry studies suggest that up to 70% of patients are not offered any treatment other than best supportive care. Recent research trends have emphasized investigational low-intensity and targeted therapies in older patients with AML, hoping to reduce the early mortality and to improve the benefit/risk ratio for long-term survival. Investigational therapies included low-dose cytarabine, arsenic trioxide, gemtuzumab ozogamycin, clofarabine, hypomethylating agents, and others. In this Phase 2 study testing oral sapacitabine, Kantarjian and colleagues recruited 105 elderly AML patients who were previously untreated or at the point of their first relapse. Sapacitabine, 1-(2-C-cyano-2-deoxy-ß-D-arabinopentafuranosyl)-N4-palmitoylcytosine also known as CYC682, CS-682 is a rationally designed oral prodrug of cytarabine that acts through a dual mechanism. The compound interferes with DNA synthesis causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase.2 Using computer-generated randomization, the researchers assigned the patients to receive one of three schedules of oral sapacitabine: 200 mg twice a day for 1 week (group A), 300 mg twice a day for 1 week (group B), or 400 mg twice a day for 3 days each week over a 2-week period (group C). All schedules were administered in 28-day cycles. After 20 patients were treated in a group, an expanded cohort of 20-25 patients were enrolled to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery and if the 30-day mortality was 20% or less. The primary endpoint was 1-year overall survival (OS), analyzed by intent-to-treat in those patients who were assigned to treatment. In all, 60 patients were randomized to treatment. For those patients, 1-year OS was 35% (95% confidence interval [CI], 16-59) in group A, 10% (CI, 2-33) in group B, and 30% (CI, 13-54) in group C. In the expanded cohort of 200 mg, the 1-yr OS was low (10% [CI, 2-33]) when compared to the 400 mg expanded cohort (24% [CI, 10-46]). Within 30 days, 14 (13%) of the 105 patients enrolled died; 27 (26%) died within 60 days. Seven deaths were potentially linked to sapacitabine treatment. The most common grade 3-4 adverse events were anemia, neutropenia, febrile neutropenia, thrombocytopenia, and pneumonia. The most common grade 5 adverse events were pneumonia and sepsis. The most common non-hematological adverse events were gastrointestinal (90% were grade 1-2) which was easily manageable. Fifteen percent in group A, 45% in group B, and 40% in group C required dose reductions because of myelosuppression. A platelet count of ≤ 50 × 109/L and an unfavorable cytogentic risk profile were adverse prognostic factors for 1-year OS.

Commentary

The current study has shown that oral sapacitabine has encouraging activity in elderly patients with AML. The 200 mg and 400 mg dose schedules had better 1-year OS than did the 300 mg group. The results indicated that the 400 mg dose schedule had the superior efficacy profile in terms of 1-year OS and the number of patients who achieved a complete response. However, all patients who achieved a complete remission in group C had their dose reduced, suggesting that a lower dose of sapacitabine has to be used in future clinical trials, especially if combining with other myelosuppressive agents.

Effective treatment for elderly AML patients has been elusive until the recent trials with targeted therapies, which have shown remarkable activity but their use is restricted to patients with the appropriate target. Hypomethylating agents have also shown encouraging results with low treatment-associated mortality and improved survival despite low rates of complete remissions.3,4 The literature on randomized trials in AML suggests that improvement of survival in elderly patients might be possible by controlling the disease with low-intensity therapy that has a favorable safety profile rather than by achieving higher complete remission rates with intensive, toxic therapy. Sapacitabine is added to the basket of low-intensity therapies and is shown from the current study to be safe and efficacious. Compared to intensive therapy and to low-dose cytarabine, 30- and 60-day mortality rates were significantly reduced with sapacitabine.1,5 Another advantage is oral administration of sapacitabine, a feature of importance for the elderly in whom the treatment goal is both improved survival and good quality-of-life. This also allows for combining other low-intensity therapies that might improve outcomes in this poor-prognosis group. Considering that most of the patients in the better tolerated group required dose reductions, a slightly reduced dose of sapacitabine should be considered. We eagerly await the results of one such combination regimen (SEAMLESS STUDY), which is testing sapacitabine (300 mg twice daily for 3 days for 2 weeks) with decitabine.

References

1. Kantarjian H, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 2010;116:4422-4429.

2. Matsuda A, et al. Nucleosides and nucleotides. 100. 2’-C-cyano-2’-deoxy-1-beta-D-arabinofuranosylcytosine (CNDAC): Design of a potential mechanism-based DNA-strand-breaking antineoplastic nucleoside. J Med Chem 1991;34:2917-2919.

3. Fenaux P, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-569.

4. Thomas XG, et al. Results from a randomized phase III trial of decitabine versus supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed AML. Proc Am Soc Clinic Oncol 2011;29(suppl):abstract 6504.

5. Burnett AK, et al. A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 2007;109:1114-1124.