Comparison of Continuation of HMA Vs Allogeneic Stem Cell Transplant and Its Timing in Myelodysplastic Syndromes: Can It Wait? Results of a Retrospective Study

Background: Allogeneic stem cell transplant (ASCT) is a curative option for patients with higher risk myelodysplastic syndromes (MDS). Hypomethylating agents (HMA) have been shown to improve survival of patients with MDS and have an excellent toxicity profile. In eligible patients, HMA and ASCT are used as complementary strategies. The aim of this study is to compare outcome with HMA alone vs HMA+ASCT where ASCT is used as consolidation approach or as salvage therapy after HMA failure.

Methods: We performed a retrospective analysis of 216 patients with high-risk MDS who received HMA treatment at our institution from between April 2004 and October 2012; after HMA therapy, 61 (28%) patients underwent ASCT: 25 (41%) of them received as a consolidation treatment and 36 (59%) as a salvage therapy. The remaining 155 patients continued on HMA therapy until relapse or progression and did not receive a further ASCT. We used SPSS v.20 for all statistical analysis. Categorical and continuous variables were compared by chi-square and Student’s t test, respectively, and survival analysis was conducted using Kaplan-Meier analysis with the log-rank test and Cox regression for multivariate models. We also implemented a landmark survival analysis that considered median time to transplant.

Results: Median age was 65 (20-89), and patients were older in the group that did not receive ASCT (69 vs 58 years; p=0.000). WHO diagnoses were RA/RARS in 31 patients (15%), RCMD in 43 patients (19.9%), RAEB in 133 patients (62%), CMML in 23 patients (11%), and unclassifiable MDS in 18 patients (8.3%). IPSS risk was int-2 in 107 patients (50%) and high in 61 (28%), and the percentage of inttermediate-2/high-risk MDS was higher in the ASCT group (89% vs 73%; p=0.001). High-risk cytogenetics were found in 71% of patients (82% in ASCT vs 67% in HMA alone; p=0.02).

Patients received a median of 6 (1-58) courses of HMA. Overall response rate (ORR) to HMA was 45% (n=97), with 38% (n=82) having complete response (CR), 2% (n=5) partial response, and 5% (n=10) hematologic improvement. There were no significant differences between response to HMA in the ASCT group when compared to the group that did not receive ASCT (ORR: 46% vs 43%, p=0.3; CR: 38% vs 37%, p= 0.5).

When we further analyzed the 61 ASCT patients, 25 (41%) received it as a consolidation after achieving response and 36 (59%) as a salvage therapy after treatment failure. Response to ASCT was CR in 65% of patients, and 20% were not evaluable due to early mortality.

Median overall survival (OS) for the whole series was 14 months (12-16), with 1- and 2-year OS rates of 57% and 24%, respectively. To adjust for early mortality after ASCT and to eliminate any bias, we performed a landmark analysis after a median time of 7 months after ASCT. Patients who received ASCT had better survival. This advantage was more evident among patients who received ASCT as salvage therapy, although there were no differences between both strategies, with respective median survivals of 14 months for consolidation ASCT and 23 months for salvage ASCT (p=0.29)Furthermore, no significant differences in survival were observed between patients who received HMA alone and those who received ASCT as a consolidation therapy (median survival of 14 and 16 months; p=0.498), although there was a tendency for a better OS after 2 years of follow up: the OS for HMA treatment and HMA+ASCT consolidation were 68% and 56% at 1 year, 25% and 31% at 2 years, and 10% and 31% at 3 years. The 1-year survival rates for patients who received HMA alone, HMA followed by ASCT as consolidation, and HMA followed by ASCT as salvage were 68%, 56%, and 78%, respectively, and the 2-year survival rates were 25%, 31%, and 42%, respectively. In a Cox regression model to analyze effects on OS, receiving an ASCT (median OS of 13 (7-19) vs 10 months (8-12); HR 0.62 [0.42 – 0.92], p=0.018) and hemoglobin levels at diagnosis (HR 0.829 [0.73 – 0.93], p=0.002) had a significant impact.

Conclusions: ASCT is a feasible and curative strategy for patients with MDS, both as a consolidation or a salvage therapy, and thus it can be a good option after HMA failure. However, its benefits as a consolidation therapy after HMA treatment compared with continuation of HMA treatment are not clear owing to early mortality related to procedure, so ASCT should be carefully considered in patients responding to HMA.