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Investigational MDS Therapies
My Thoughts on Novel and Investigational Therapies in MDS

Released: November 22, 2021

Expiration: November 21, 2022

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A range of treatment options are available to healthcare professionals for their patients with myelodysplastic syndromes (MDS), yet most patients are not candidates for allogeneic hematopoietic stem cell transplantation, the only potentially curative intervention. Fortunately, the management of patients with MDS is being revolutionized at an unprecedented pace with a range of investigational therapies. Here are my thoughts on promising novel and investigational treatments in MDS.

In lower-risk (LR) MDS, the FDA-approved agent luspatercept has been added to a treatment armamentarium that includes erythropoiesis-stimulating agents (ESAs), lenalidomide, and immunosuppressive therapy. Luspatercept is a TGF-β pathway-targeting ligand trap that is indicated for patients with transfusion-dependent anemia due to LR MDS with ring sideroblasts in whom ESAs have failed or are unlikely to work, based on positive results from the randomized phase III MEDALIST trial. I have used luspatercept on the MEDALIST clinical trial and subsequently as a standard of care therapy based on the FDA-approved label, and my experience has been in line with the pivotal trial in terms of clinical efficacy and safety. Luspatercept now is being investigated in the randomized phase III COMMANDS trial in the frontline setting vs ESA therapy in patients with and without ring sideroblasts. Different luspatercept-based combinations also are being studied in an effort to increase response rates and durability of responses.

Two promising investigational drugs, imetelstat and roxadustat, also are in randomized phase III clinical trials of LR MDS after ESA failure. Imetelstat is a first-in-class oligonucleotide that specifically binds to the RNA template of telomerase, leading to its potent inhibition. It has been shown to result in high rates of durable transfusion independence among patients with anemic LR MDS, regardless of the presence of ring sideroblasts. In trials, imetelstat is given intravenously every 4 weeks, compared with luspatercept, which is given subcutaneously every 3 weeks. Roxadustat is an oral agent that inhibits hypoxia-inducible factor prolyl hydroxylase, leading to improvements in anemia in a phase II trial of patients with LR MDS.

The therapeutic landscape for higher-risk (HR) MDS is even busier. The hypomethylating agents (HMAs) azacitidine and decitabine, both used as monotherapies, have been the standard of care for patients with HR MDS since their approval in 2004 and 2006, respectively, either as definitive therapy or as a bridge to allogeneic hematopoietic stem cell transplantation. Both agents are injectables that require multiple consecutive days of clinic visits for administration each month.

The FDA approved the first oral HMA, a combination of decitabine and cedazuridine, for patients with HR MDS in 2020. I used this agent on the ASCERTAIN clinical trial, which led to its approval, and I have subsequently used it as a standard of care agent in clinical practice. I find it most useful to give to patients who already have achieved complete responses from IV decitabine therapy but want to minimize visits for the 5 daily infusions each month due to distance, transportation difficulties, or other reasons, especially during the COVID-19 pandemic. It is important to remember that, even with an oral agent, patients still should be monitored closely based on their blood counts, and cytopenias must be managed as needed with transfusions, prophylactic antibiotics, and regular and frequent follow-up.

Several other agents are in phase III clinical trials for HR MDS. I urge caution regarding expectations for investigational agents in MDS, as there have been setbacks for some promising agents at the randomized clinical stage. For example, 2 agents—eprenetapopt (APR-246) and pevonedistat—initially reported promising results in single-arm phase II trials, and both received FDA breakthrough therapy designation. Recently, however, press releases have been issued for the phase III trials of both agents in HR MDS. In August 2021, the FDA placed a partial clinical hold on trials with eprenetapopt and azacitidine after concerns regarding the risk‒benefit profile of the combination in the phase III MDS trial. In the phase III pevonedistat plus azacitidine PANTHER trial, a September 2021 press release reported failure to achieve the primary endpoint of event-free survival in MDS, acute myeloid leukemia (AML), and chronic myelomonocytic leukemia for this registration-intent trial. While we await the release of the full results of these phase III trials, doubts remain regarding the future of these agents in MDS.

Immune checkpoint inhibition has led to a therapeutic revolution in the management of solid tumors, particularly with the anti‒PD-1 antibodies pembrolizumab and nivolumab. In MDS, 2 novel antibodies—magrolimab, which targets CD47, and sabatolimab, which targets TIM3—have shown encouraging early clinical trial efficacy for management of HR MDS, and both are currently in randomized phase III clinical trials. Venetoclax, a selective oral BCL-2 inhibitor already approved for management of older unfit patients with AML, also is being evaluated in a randomized phase III trial of HR MDS and has shown encouraging activity combined with azacitidine in phase I/II clinical trials both as frontline therapy and as salvage therapy for patients with HR MDS. Lastly, SY-1425, also known as tamibarotene, is a first-in-class selective RARα agonist that also is being studied in a randomized phase III trial for patients with RARA-positive HR MDS in combination with azacitidine.

In addition, many other agents are in earlier stages of clinical development, with oral HMAs expected to become the partner HMA for numerous novel agents over time. (Oral azacitidine is approved for AML but remains investigational for MDS.) The current clinical drug development for MDS appears very promising, and it reminds me of the pre-2017 era for AML, which was followed by 9 drug approvals in the span of 5 years. I look forward to being able to offer our patients a broader range of options in managing their MDS.

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