LAUSR

Myelodysplastic syndromes (MDS) are genetically, biologically, and clinically very heterogeneous. Although allogeneic stem cell transplantation (alloSCT) remains the only intervention with a potential for cure, less than 5% of patients undergo transplantation because of age and comorbidities. Before the approval of hypomethylating agents (HMAs), patients with higher-risk (HR)-MDS had a median overall survival (OS) of< year. The approval of the 2 HMAs azacitidine and decitabine in the United States in 2004 and 2006, respectively, represented a major milestone in the management of MDS. Those 2 drugs result in objective hematologic responses in 40% to 50% of patients, including a 10% to 15% complete remission (CR) rate and an improved quality of life. Furthermore, in the case of azacitidine, OS improved by a median of 9.5 months (24.5 vs 15 months) over conventional care regimens (CCR) in the landmark randomized phase 3 clinical trial AZA-001. Indeed, a Surveillance, Epidemiology, and End Results-based analysis indicates that the OS of patients with HR-MDS in the United States has improved over the last 15 years. The use of HMAs as the frontline therapy for patients with HR-MDS nonetheless leaves a lot to be desired. HMAs require 4 to 6 months of therapy before the lack of a response can be determined, and approximately one-half of patients never respond. The majority of those who do respond would progress in less than 18 months, and patients with primary or secondary resistance to HMAs have a dismal OS, with a median of 4 to 6 months. Furthermore, population-based studies not only observed a substantially worse median OS with azacitidine than reported in the AZA-001 trial (median OS, 13-17 and 24.5 months, respectively), but some analyses have even questioned the OS advantage of azacitidine in HR-MDS. Despite extensive clinical research, and compared with the many new agents approved in other hematologic malignancies, such as multiple myeloma and chronic lymphocytic leukemia, 10 years have passed since decitabine was approved without any new drug approvals in the MDS world. With no drugs to outperform HMAs in the upfront setting and no drugs to improve OS in the post-HMA failure setting to date, a big focus in the MDS research community has been on identifying HMA-based combination regimens that could improve the clinical outcomes of patients compared with HMA monotherapy. The goals of combinationbased strategies are to increase the response rate, deepen and/or accelerate responses, and eventually improve clinical survival over HMA monotherapy without significantly increasing toxicity. One of the commonly used combinationbased approaches revolves around targeting the epigenetic dysregulation that has been recognized as a central mechanism in the pathogenesis of MDS and its progression to acute myeloid leukemia (AML), and has been associated with worse survival. Both DNA promoter hypermethylation as well as post-translational modification of histone tails (eg, deacetylation) lead to transcriptional silencing of tumor-suppressor genes and genes involved in differentiation and apoptosis. Preclinical evidence supported synergy between HMAs and histone deacetylase (HDAC) inhibitors. Compared with HMAs, monotherapy with HDAC inhibitors has had only limited efficacy in phase 1 and 2 clinical studies in both HR-MDS and AML. Therefore, extensive trials of combined HMAs and HDAC inhibitors have been taking place. Although early phase trials of these combinations had promising results, phase 2, randomized clinical trials to date have failed to demonstrate a significant improvement in response rates or survival when azacitidine was combined with the HDAC