Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure

Abstract

Purpose: Azacitidine (AZA) is the current standard of care for high-risk (ie, International Prognostic Scoring System high or intermediate 2) myelodysplastic syndrome (MDS), but most patients will experience primary or secondary treatment failure. The outcome of these patients has not yet been described.

Patients and methods: Overall, 435 patients with high-risk MDS and former refractory anemia with excess blasts in transformation (RAEB-T) were evaluated for outcome after AZA failure. The cohort of patients included four data sets (ie, AZA001, J9950, and J0443 trials and the French compassionate use program).

Results: The median follow-up after AZA failure was 15 months. The median overall survival was 5.6 months, and the 2-year survival probability was 15%. Increasing age, male sex, high-risk cytogenetics, higher bone marrow blast count, and the absence of prior hematologic response to AZA were associated with significantly worse survival in multivariate analysis. Data on treatment administered after AZA failure were available for 270 patients. Allogeneic stem-cell transplantation and investigational agents were associated with a better outcome when compared with conventional clinical care.

Conclusion: Outcome after AZA failure is poor. Our results should serve as a basis for designing second-line clinical trials in this population.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Kaplan-Meier estimates of the overall survival (OS) after azacitidine (AZA) failure. (A) Survival estimates for the different data sets. (B) Survival estimates for the myelodysplastic syndrome (MDS) population. The curves represent the survival estimates for the MDS and AML cohorts of patients and of the three independent data sets. Each tick mark represent a censored patient. There were no significant differences of survival among the Johns Hopkins University (JHU) study, the AZA001 study, and the French AZA compassionate use program (ie, French ATU); median OS times were 6.9 months, 7.1 months, and 5.6 months, respectively (P = .34 by log-rank test).

Fig 2.

Survival analysis according to the salvage treatment regimens. Overall response rate for each treatment group is presented with the number of patients evaluable for response in each cohort. (*) Univariate analysis (log-rank test) showed significant differences between palliative care and intensive chemotherapy (CT; P = .04), investigational therapy (IT; P < .001), or allogeneic stem-cell transplantation (ASCT; P < .001). (†)There was also a significant difference between intensive CT and IT (P = .05) and intensive CT and ASCT (P = .008). The difference between IT and ASCT reached borderline significance (P = .09). AZA, azacitidine; NA, not applicable; ORR, overall response rate; OS, overall survival.