Sangmin Lee, MD
The OS was similar between the two arms, although the analysis was underpowered. Nausea, diarrhea, and vomiting were the most frequently occurring treatment-emergent adverse events for oral azacitidine vs placebo (76% vs 23%, 68% vs 23%, 63% vs 9%). While oral azacitidine is not approved for MDS and trial was stopped early, it can provide meaningful reduction in RBC transfusions in low grade MDS, and further evaluation is needed in MDS.
Paroxysmal nocturnal hemoglobinuria (PNH) clones have been observed in bone marrow failure syndromes including MDS and aplastic anemia (AA). Fattizzo et al analyzed PNH clone size with clinical outcomes in MDS and AA in a cohort of 3085 patients tested for PNH at King’s College Hospital in London. 20.3% of MDS patients had presence of PNH clone; PNH cases occurred more in hypoplastic MDS, and lower risk IPSS MDS patients. The presence of PNH clone was a predictor of response to immunosuppressive therapy and to allogeneic stem cell transplant (84% vs 45%, p=0.01, 71% vs 57%, p=0.09), but not to azacitidine. MDS patients with PNH clone had lower rate of progression by IPSS and AML transformation, and higher OS accounting for MDS with excess blasts. Each 10% increase in clone size resulted in a 1% decrease in cumulative incidence of death. PNH testing is often done especially in cases with hypoplastic MDS; the underlying mechanism and role for monitoring PNH clones in MDS needs further investigation.
Outcomes in MDS patients after azacitidine therapy are generally poor. Clavio et al analyzed outcomes of 402 MDS patients post-azacitidine in the Italian MDS Registry. At azacitidine discontinuation, 20% of patients still derived response to azacitidine, 35% had primary resistance, and 44% had adaptive resistance, which was defined as loss of response or progression after achievement of a response. As expected, OS was longer for patients who stopped treatment due to planned allogeneic stem cell transplant (median OS not reached), compared to patients with primary resistance (median OS 4 months), or adaptive resistance (median OS 5 months), or patients intolerant or noncompliant to azacitidine (median OS 4 months, p=0.004). The North American MDS Consortium scoring system was evaluated in the study cohort; patients with high risk had worse OS than low risk (3 and 7 months, p<0.001). This retrospective analysis confirms the poor outlook of MDS patients after treatment of azacitidine, and effective therapy in this patient population is an unmet need.