One plus one does not always equal two, especially with regard to hypomethylating agents: the question of synergy of azacitidine and lenalidomide for treatment of relapsed acute myeloid leukemia and myelodysplastic syndromes post allogeneic hematopoietic stem cell transplant.

Key paper evaluation: Craddock C, et al. Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia. J Clin Oncol. 2019; 37: 580-8. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only potentially curative treatment for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, most patients relapse after allo-HSCT and treatment options are limited. Craddock et al. reported recently in the Journal of Clinical Oncology results from a small phase Ib study combining azacitidine (AZA) and lenalidomide (LEN) for treatment of 29 patients (24 AML and 5 MDS patients) who relapsed after allo-HSCT. Overall response rate was 24%. Patients who received ≥3 cycles of treatment had a higher response rate and responders had a better survival compared to non-responders (27 months vs. 10 months; p = 0.004). Combination treatment was well tolerated with three cases of graft-versus-host disease. While this study suggests a potential synergistic effect of LEN + AZA combination therapy, many questions remain. Efficacy and safety should be confirmed in larger, ideally randomized, studies. Further research on mechanism of action of this combination, comparison with other treatment combinations (e.g. AZA + venetoclax) and use during other disease stages are needed.