Stephanie Halene, M.D.
Section of Hematology/Department of Internal Medicine and Yale Cancer Center
Edo Kapetanovic, Visiting Medical Student, University of Rijeka, Croatia
Yale University School of Medicine
In this article, Roberts and Steensma explore the critical question of what to do for those patients with myelodysplasia (MDS) who fail hypomethylating agents (HMAs) either upfront or after a period of response. HMAs, azacytidine and decitabine, were approved for International Prognostic Scoring System (IPSS) intermediate-2 and high-risk MDS in 2004 and 2006, respectively. However, HMAs do not cure the disease and once HMAs fail the only curative option is stem cell transplantation (SCT). It is thus critical to identify those patients who are likely to respond to HMA to identify mechanisms of HMA failure and novel alternative treatments.
Gene mutations occur in over 90% of patients with MDS. Mutations cluster in genes belonging to key pathways that regulate DNA methylation; that effect processing (splicing) of the messengers (mRNA) that carry the information from the DNA in the cell nucleus to the protein machinery in the cell cytoplasm; that determine how DNA is packaged in the nucleus (epigenetic regulators), and others.
Several studies have sought to identify which mutations may either predict response to HMA or be responsible for their failure. While a few gene mutations carry some predictive response, a definite correlation remains elusive. Treatment options when HMAs fail and SCT is not available are being studied extensively, including: low dose cytarabine; aggressive chemotherapy; switching to the other of the two HMAs – preferably lenalidomide in the presence of deletion of the long arm of chromosome 5, or del(5q); or combination strategies with approved agents. The effectiveness of these options is encouraging but still under investigation.
New treatments are desperately needed. Several interesting medications are currently in clinical trials, amongst them AG-221, an inhibitor of one of the mutant proteins, IDH2; and SGI-110, a combination between decitabine and and deoxyguanine, with promising responses. For now, however, stem cell transplantation for those who are eligible and enrollment in clinical trials for those who are not have to be the current recommendations to MDS patients for whom HMAs are no longer effective.