Much-Needed Progress in Therapies for Myelodysplastic Syndromes

This time last year, we reviewed the remarkable news of several new U.S. Food and Drug Administration (FDA) –approved therapies for acute myeloid leukemia (AML).¹  After decades without new treatments, in 2017 four new drugs were approved for patients with AML; these include midostaurin, vyxeos, enasidenib, and gemtuzumab ozogamicin. At the beginning of 2018, ivosidenib was approved for relapsed/refractory AML with IDH1 mutations followed by the exciting approvals of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as initial therapy for newly diagnosed AML in adults older than 75 years. Now it seems that the therapeutic landscape may also be improving for myelodysplastic syndromes (MDS). Several advances in novel and targeted therapies for MDS were highlighted at the 2018 ASH Annual Meeting.

The last FDA approval of a drug for MDS occurred in 2006 with the approval of lenalidomide for low- or intermediate-risk MDS with 5q deletion. Before that, azacitidine and decitabine were approved in 2004 and 2005, respectively. While these drugs were surely breakthroughs and have helped extend and improve the lives of numerous MDS patients, they are not curative for most and relapsed disease is almost certain. The only known cure for MDS is an allogeneic hematopoietic stem cell transplant, the use of which can be limited by the older age and attendant comorbidities of typical MDS patients. Therefore, the need for new therapies is great for newly diagnosed and relapsed/refractory patients, as well as patients that relapse after transplant.

For many years our understanding of MDS was derived from research in AML due to the lack of cell lines and preclinical in vivo models of MDS. That has changed somewhat over the last decade as studies of the genetics of MDS, bone marrow microenvironment, genetically engineered mouse models, and humanized mouse xenografts have shed light on the genetics and biology of MDS. One important finding from this effort was the discovery that TGF-β signaling contributes to the erythroid maturation defect in MDS and that decreased TGF-β signaling achieved through a TGF-β receptor decoy (ACE-536; luspatercept) can restore normal erythroid maturation.²  The therapeutic relevance of this finding was reported in the Plenary Session at the 2018 ASH Annual Meeting in the form of a phase 3, randomized, double-blind, placebo-controlled study. In this study, luspatercept resulted in a significantly reduced transfusion burden in patients with anemia due to very low-, low-, or intermediate-risk MDS with ring sideroblasts (MDS-RS). 

MDS-RS has a unique association with mutations in the splicing factor, SF3B1³ ; however, this only accounts for a subset of MDS bearing mutations in spliceosomal proteins including SF3B1, SRSF2, U2AF1, and ZRSR2. Altogether, more than 50 percent of patients with MDS have mutations in one of these splicing factor genes.⁴  While the exact pathogenic role these mutations play in MDS biology is still being worked out, it’s clear that cell lines and patient-derived xenografts bearing splicing factor mutations are more sensitive to spliceosomal disruption than wild-type cells in preclinical assays.⁵  This hypothesis is being further tested clinically in a phase 1 trial of a novel spliceosomal modulator named H3B-8800⁶  (NCT02841540) in relapsed/refractory myeloid malignancies with splicing factor mutations including MDS and chronic myelomonocytic leukemia.

Other MDS clinical advances highlighted at the 2018 ASH Annual Meeting are the novel hypomethylating agent guadecitabine, eltrombopag, and the nuclear export inhibitor selinexor. The investigator-initiated phase II trial of selinexor (NCT02228525) found an overall response rate of 32 percent in high-risk patients refractory to hypomethylating agents, a very tough group to treat. Selinexor inhibits the function of the main nuclear protein exporter, XPO1, and thus interferes with many important cellular processes. Discovering why only a subset of patients respond is therefore of extreme interest and may help us learn which of the downstream effects of selinexor is the most important for response. This information might lead to a biomarker that would allow for targeted application of selinexor to a group enriched for responses.

There are other exciting therapies on the horizon for MDS including IDH1/2 inhibitors, pevonedistat (a NEDD8-activated enzyme inhibitor), and glasdegib (a smoothened inhibitor that targets the Hedgehog pathway and was just approved by the FDA for AML). While a new specific approval for MDS was just out of reach in 2018, luspatercept, and hopefully others, seem to be on their way to approval in 2019.