Sangmin Lee, MD
Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.
For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.
Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026). There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.