Decitabine (DAC) Can Be Safely Reduced After Achievement of Best Response In Patients (pts) with Myelodysplastic Syndrome (MDS)
Authors: Cornelison A. Megan , Manero Guillermo Garcia , Kantarjian Hagop , Ravandi Farhad , Kadia Tapan , Cortes Jorge , O'Brien Susan , Borthakur Gautam , Brandt Mark , Jabbour Elias J 
Published: October 2019

Abstract
Abstract 1858
DAC is standard therapy in pts with MDS. Current recommendations suggest a dose of 20 mg/m2 IV daily for 5 days every 4 weeks for as many cycles as possible to secure the best outcome. However, this therapy is associated with frequent grade 3–4 hematologic toxicity, requiring dose reduction (DR) and frequent dose delay (DD). We investigated the outcome of pts who had DD/DR and whether the timing of this dose modification relative to the time of response is relevant. Pts enrolled in phase II trials using DAC for frontline therapy for MDS were analyzed: 124 pts were treated at the dose of 10 mg/m2 IV daily × 10 days (n=17), 20 mg/m2 subcutaneously daily × 5 days (n=14), and 20 mg/m2 IV daily × 5 days (n=93). Median age was 65 years (range 37–90). Median follow up was 48 months. Seventy six pts responded, with 54 (44%) achieving a complete response (CR), 5 (4%) marrow CR, and 17 (14%) clinical benefit. The median transformation free survival (TFS) and overall survival (OS) was 13 and 20 months, respectively. Responders had better performance status (p=0.015), better baseline hemoglobin (p=0.006) and lower baseline blast percentage (p=0.05) than non responders. Sixty five pts (53%) had DR by at least 25% or DD (defined by a delay beyond 5 weeks between cycles) for a median of 7 days (range, 1 to 97), 25 had both. The main reasons for DR/DD were myelosuppression in 48 pts (74%) and infection in 10 pts (15%). Pts with DD/DR were more likely to have diploid cytogenetics (p=0.001) and received more DAC cycles (4 versus 11; p=0.001). There were no other statistically significant differences in characteristics between pts who had DD/DR versus those who did not. DD occurred after a median of 2 courses, with a median of 4 delays per pt (range, 1 to 22). DR occurred after a median of 7 courses (range, 2 to 24) with a median reduction of 25%. The median number of courses with DR was 6 (range, 1 to 18). Thirty five pts (54%) underwent DD/DR after achieving an objective response including 27 (42%) after CR. There was a trend for more durable responses in favor of pts requiring DD/DR after the achievement of an objective response (median not reached) compared to those who required DD/DR before (median of 18 months) (p=0.5). The 2-year OS rate trended higher for pts who had DD/DR after obtaining best response compared to those who had DD/DR prior to best response. The median OS was 30 and 22 months, respectively (p=0.15). There was no worsening in outcome when comparing pts who had no DD/DR to those who had DD/DR after the achievement of an objective best response. Transformation free survival (TFS) rates also trended higher for those with DD/DR after response compared to those who required DD/DR before. The median TFS was 27 and 18 months, respectively (p=0.12).
In conclusion, DAC is effective in treating pts with MDS; DD/DR can be safely accomplished once the pt has achieved the best objective response (preferably CR) without impacting outcome. Prospective evaluation of an approach conceiving a loading dose for induction of a best objective response followed by a maintenance schedule is to be considered.

Disclosures:
Ravandi: Eisai: Honoraria, Research Funding. Cortes:Eisai: Research Funding.