Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS

Abstract

Summary Reliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline has been associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analyzed a larger cohort of North American patients whose data was collected in a prospective clinical trial with a longer median follow-up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukemia (<30% bone marrow blasts, n=102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n=23, median OS, 21.0 months) compared to those who did not (n=79, median OS, 16.7 months, adjusted HR (no/yes)=1.88, 95% CI, 1.03-3.40, P=0.04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.

Genome sequencing in myelodysplastic syndromes: can molecular mutations predict benefit from hypomethylating agent therapy?

“…An important focus for current research in MDS revolves around predicting benefit (or lack thereof) to HMA therapy to avoid exposing patients with low probability of benefit to prolonged and potentially toxic ineffective treatment, increased costs, and to allow earlier consideration of clinical trials that can alter the natural history of the disease with potentially more time for benefit [11]. Unfortunately, all efforts to date have failed in discovering clinical and/or biomarkers that allow reliable prediction of clinical benefit from HMA therapy [4,11].…”

“…Unfortunately, all efforts to date have failed in discovering clinical and/or biomarkers that allow reliable prediction of clinical benefit from HMA therapy [4,11]. A French prediction tool was developed to separate higher risk MDS patients based on OS advantage achieved with azacitidine using readily available clinicopathologic parameters [12], but it was subsequently found to offer no prognostic utility beyond that of the more commonly used IPSS-R [13].…”

Molecular Testing in Myelodysplastic Syndromes for the Practicing Oncologist: Will the Progress Fulfill the Promise?

“…Similarly, although the prognostic impact of IDH mutations in MDS is less clear, testing for these mutations should be considered as evidence suggesting they are important in pathogenesis of IDH-mutant myeloid malignancies, and their inhibitors have also entered early clinical trials [83][84][85]. In addition to molecular mutations, other predictive biomarkers (e.g., methylation signatures, UCK1 enzyme expression) are also under investigation [86][87][88][89]. Nonetheless, logistical issues related to assay performance standardization, validation, interpretation, and development of guidelines for how to use the results to inform clinical decisions are yet to be resolved [88][89][90][91].…”

“…In addition to molecular mutations, other predictive biomarkers (e.g., methylation signatures, UCK1 enzyme expression) are also under investigation [86][87][88][89]. Nonetheless, logistical issues related to assay performance standardization, validation, interpretation, and development of guidelines for how to use the results to inform clinical decisions are yet to be resolved [88][89][90][91]. Success at these efforts will likely require the use of very large, international, ©AlphaMed Press 2015…”

The evolving field of prognostication and risk stratification in MDS: Recent developments and future directions

“…Another potential approach could be to assess short-term trackable variation in these factors, such as changes in blood counts or dynamic methylation changes, at 2 to 4 weeks of initiation of HMAs to predict the long-term clinical benefit of these agents. To illustrate this point, platelet count doubling after the first cycle of azacitidine has been shown to predict eventual responsiveness and survival benefit from azacitidine therapy [108,109].…”