More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) encompass a diverse group of hematologic disorders characterized by ineffective and malignant hematopoiesis, peripheral cytopenias and significantly increased risk of progression to acute myeloid leukemia (AML). The hypomethylating agents (HMA) azacitidine and decitabine induce meaningful clinical responses in a significant subset of patients with MDS. Though never compared directly with decitabine, only azacitidine has improved overall survival (OS) compared to conventional care in a randomized trial in patients with higher-risk MDS. The azacitidine regimen used in this pivotal trial AZA-001 included administration at 75 mg/m2/day for 7 consecutive days in 28-day cycles (7–0 regimen). Given the logistical difficulties of weekend administration in the 7–0 regimen, as well as in efforts to improve response rates, alternative dosing schedules have been used. In a typical 28-day cycle, administration schedules of 3, 5, 10, and (with the oral version of azacitidine) 14 and 21 days have been used in clinical trials. Most trials that evaluated alternative administration schedules of azacitidine did so in lower-risk MDS and did not directly compare to the 7–0 schedule. Given the lack of randomized prospective studies comparing the 7–0 schedule to the other regimens of azacitidine in MDS, Shapiro et al. conducted a systematic review in an attempt to answer this question. Here we place the findings of this important work in clinical context and review the current knowledge and unresolved issues regarding the impact of administration schedules of azacitidine on outcomes of patients with both lower-risk and higher-risk MDS.

Direct Medical Costs Associated With Treatment Nonpersistence in Patients With Higher-Risk Myelodysplastic Syndromes Receiving Hypomethylating Agents: A Large Retrospective Cohort Analysis

“…Specifically the 7-day treatment schedule of HMA, which requires weekend administration, has been noted to be challenging for both patients and treatment centers. 7 In order to elicit clinical response, HMA treatment is recommended to be provided to patients for least 4, or even 6, treatment cycles. 8 Premature treatment discontinuation or suboptimal treatment is likely to affect clinical and economic outcomes.…”

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

“…Given logistic difficulties with on-label administration schedules of AZA, various alternatives have been explored [77]. For instance, a 5-2-2 type of regimen (Monday-Friday with weekend off and then Monday-Tuesday) is widely used by many centers (85% of 105 US centers according to a registry study [78]) to avoid the issue of weekend infusions, but no clinical randomized trial supports its equivalence with the 7-0 approved schedule [79].…”

Society of Hematologic Oncology (SOHO) State of the Art Updates and Next Questions: Myelodysplastic Syndromes

“…Novel schedules, doses, 57 and combinations with numerous other agents have been investigated to increase the efficacy of these drugs and have been previously reported. [58][59][60] New HMAs are under evaluation in the hopes of obtaining increased clinical efficacy. These include guadecitabine, previously known as SGI-110, a dinucleotide of decitabine and deoxyguanosine, that prolongs the in vivo exposure of decitabine by protecting it from deamination.…”