Multivariable Time-Dependent Analysis Of The Impact Of 5 Azacitidine In Patients With Lower-Risk Myelodysplastic Syndrome and Unfavorable Specific Lower-Risk Score

Specific scoring systems developed for patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) (Garc'a-Manero G et al. Leukemia 2008; Falantes J et al. Clin Lymphoma Myeloma Leuk 2013) are able to identify a significant fraction of pts with a poorer (median OS, 13 months) than expected outcome (Greenberg P et al. Blood 1997). Retrospective data of azacitidine (AZA) in LR-MDS showed hematological improvement and survival when compared to non-responder pts (Lyons R et al. J Clin Oncol 2009; Musto P et al. Cancer 2010). However, the impact of AZA treatment in the group of LR-MDS with poor prognosis by a LR-specific score (LR-S) is uncertain.

To evaluate the impact of AZA treatment in LR-MDS pts with more adverse LR-S by multivariable time-dependent analysis.

Eighty-eight LR-MDS pts (IPSS Low/Int-1 or <10% bone marrow blast with no unfavorable karyotype according to Schanz J et al. J Clin Oncol 2012) with the most adverse specific LR-S were retrospectively analyzed. Patients were separated in two cohorts: Non-AZA cohort (n=61), that included pts who received only best supportive care (BSC; n=46) or BSC plus erythroid stimulating agents (ESA; n=15) at Hospital Universitario Virgen del Roc'o (Seville, Spain) from 2000-2010 who were the core for the development of the LR specific model, versus AZA-cohort (n=27), that included pts treated with AZA (75 mg/m²/day for 5 or 7 days every 4 weeks subcutaneously) in a compassionate use program in Spain

Median age was 71 years (range, 48-86). Patients in the AZA cohort were older and included more RAEB-1, transfusion dependent and elevated LR-S pts. Baseline characteristics and differences between cohorts are shown in Table 1. Median time from diagnosis to AZA therapy was 4 months (range, 0.5-21). At last follow-up, 72 pts (81%) had died (Non-AZA cohort: 55/61; 90% and 17/27; 63% in the AZA group). Median OS for the overall series was 18 months. The actuarial probabilities of OS at 1 and 2 years were 62.4% and 45% for AZA and 25.4% and 11% for Non-AZA cohort (P=10^-4). In a multivariable analysis including blast % (<4% vs 4-9%), neutropenia (<0.5 vs >0.5x10e⁹/L), thrombocytopenia (<50 vs >50x10e⁹/L) and AZA treatment as time-dependent covariate, the later did not significantly influenced OS (HR, 1.502; 95% CI, 0.258-3; P=0.258) and only severe thrombocytopenia (<50x10⁹/L) showed an independent association with OS (HR, 1.690; 95% CI, 1.036-2.756; P=0.03. Table 2). However, a 3-month landmark analysis showed a survival advantage for pts treated with AZA as compared to non-AZA cohort (median OS, 10m [Non-AZA] vs 23 months [AZA]; P=0.019) and estimated OS rate at 12 and 24 months were 31.5% and 5.7% for Non-AZA vs 50.2% and 41.1% for AZA cohort respectively. Progression to acute myeloid leukemia (AML) occurred in 24.6% (Non-AZA) vs 14.8% (AZA)(P=0.19).

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Azacitidine appeared to increase survival in LR-MDS pts within the most adverse LR-S although differences in OS were not statistically significant in a multivariable time-dependent analysis. Larger number of pts and prospective randomized trials are needed to better address this issue. Thrombocytopenia (<50x10e⁹/L) is confirmed as the most significant clinical parameter with impact on outcome in LR-MDS.

Off Label Use: 5 azacitidine. Treatment for lower-risk MDS in Europe.