MDS Armamentarium Expands With Luspatercept Approval, Novel Compounds

Partner | Cancer Centers | <b>Dana Farber</b>

David P. Steensma, MD, discusses some new data in myelodysplastic syndromes and ongoing research in the space.

David P. Steensma, MD

The armamentarium in myelodysplastic syndromes (MDS) is slated to grow with agents such as luspatercept-aamt (Reblozyl), venetoclax (Venclexta), APR-246, and magrolimab, despite some of the challenges with drug development in the space, explained David P. Steensma, MD.

For example, in April 2020, the FDA approved luspatercept for the treatment of anemia failing an erythropoiesis stimulating agent (ESA) and requiring ≥2 red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts or with MDS/myeloproliferative neoplasm (MPN) with ring sideroblasts and thrombocytosis.

Data from the phase III MEDIALIST trial served as the basis for the approval. The results, which were updated at the 2019 ASH Annual Meeting, showed that 47.7% of patients achieved RBC-transfusion independence ≥8 weeks with luspatercept versus 15.8% with placebo (odds ratio, 5.978; 95% CI, 2.840-12.581; P <.0001).1

Venetoclax has also shown promising data in combination with azacitidine in the up-front and relapsed/refractory settings. Data from a phase Ib trial (NCT02942290) showed that, among 57 evaluable patients with high-risk disease, 31.57% experienced an objective response with complete response and 19.29% experienced stable disease to frontline venetoclax.2

In the relapsed/refractory setting, data from a phase Ib trial (NCT02966782) showed that 50% of patients experienced an objective response with the combination and 31% experienced stable disease.3

In addition, APR-246 and magrolimab are both agents under investigation for use in combination with azacitidine.

In January 2020, the FDA granted a breakthrough therapy designation to the combination of APR-246 and azacitidine for the treatment of patients with MDS who harbor susceptible TP53 mutations. In a phase Ib/II study, the combination led to an objective response rate, by International Working Group criteria, of 87% in patients with TP53-mutant MDS and oligoblastic acute myeloid leukemia (AML).4

In September 2019, the FDA granted a fast track designation to magrolimab for the treatment of patients with AML and MDS. The designation is based on findings from the phase Ib 5F9005 study (NCT03248479), in which the combination of magrolimab and azacitidine showed an objective response rate of 100% in the MDS cohort in the upfront setting.5

In an interview with OncLive, Steensma, associate professor of medicine, Harvard Medical School, clinic director, Center for Prevention of Progression, Edward P. Evans Chair in Myelodysplastic Syndromes Research, and institute physician, Dana-Farber Cancer Institute, discussed some of these data in MDS and ongoing research in the space.

OncLive: Could you discuss recent advances in the treatment of patients with MDS?

Steensma: By and large, MDS is still treated in 2020 like it was in 2007. There hasn’t been a drug approval since decitabine in 2006, but that will change with the approval of luspatercept for patients with MDS who have ring sideroblasts. There are a number of other interesting compounds that are in development.

Could you highlight some of the findings in MDS that were presented at the 2019 ASH Annual Meeting?

We have emerging data with the combination of venetoclax and azacitidine. Venetoclax is approved in AML and many lymphoid malignancies. It’s used off label in MDS, but there has been interest in combining it with hypomethylating agents (HMAs) in the hope of leading to deeper and more durable responses, particularly in high-risk patients with p53 mutations where responses to HMAs alone are not very durable.

We saw data with the combination of venetoclax and azacitidine as initial therapy, as well as venetoclax alone or in combination in patients [who progressed] on an HMA. The responses were much better in the up-front setting, with a complete response (CR) rate of almost 40% and a marrow response rate of 40%. Altogether, almost 80% of patients had cytoreduction with the combination.

Cytopenias were a real problem though. The initial therapy with 28-day dosing led to some patient deaths from infection. The dosing was revised 14-day dosing and prophylactic antibiotics were mandated. Patients seemed to tolerate [the combination] a bit better [after these amendments were made].

Could you highlight some of the data we’ve seen with luspatercept?

Pierre Fenaux, MD, PhD, of Hôpital Saint Louis in Paris, [presented] the updated data from the MEDALIST trial. The data showed that almost half of patient had an 8-week period of transfusion independence. For some patients, that's a very durable period, and that 8 weeks extends to 24 or more weeks. Other patients may become transfusion dependent at week 9, so it's a transient response. Fifteen percent of patients with placebo also experienced 8 weeks of transfusion independence. That being said, the safety profile is really quite benign, and it's not an inconvenient drug to give. It’s subcutaneous, and it’s given once every 3 weeks. That subset of patients in the MEDALIST trial will likely be reflected in the label. We'll see rapid uptake of luspatercept.

I don't know where we'll see it used in MDS more broadly. There is an ongoing trial comparing luspatercept with ESAs as upfront therapy in lower-risk patients, regardless of ring sideroblasts or SF3B1 status. That’s something we’re eagerly awaiting.

Are there any other agents under investigation?

One [agent under investigation] is APR-246, which is being evaluated in patients with p53-mutant MDS. The agent helps refold the mutant TP53 and restore chemosensitivity in preclinical models. The phase Ib/II trial led by David Sallman, MD, from Moffitt Cancer Center, looked quite good in terms of CR rate. There’s an ongoing randomized trial of APR-246 plus azacitidine versus azacitidine alone. We eagerly await those data.

In addition, Dr. Sallman presented a trial of magrolimab which is a CD47-directed antibody and macrophage checkpoint inhibitor in combination with azacitadine. In a small trial, in which less than 50 patients were treated, the response rate was intriguing.

A number of other studies are ongoing. Checkpoint inhibitors haven't been very effective in MDS or in myeloid diseases overall. Magrolimab provides a new way of approaching an immune checkpoint, in this case a macrophage immune checkpoint. The one problem with this drug and other CD47-targeted agents in the past has been red cell hemolysis, because CD47 is expressed on senescent red cells. The investigators took a very clever approach where they used a small loading dose to saturate binding sites, which reduce hemolysis, allowing it to be given in a much safer way. Hopefully, that approach will mitigate some of the problems with red cell hemolysis.

What are the biggest challenges that remain in this space?

The biggest challenge has been that drug development has lagged behind other diseases. There are many reasons for that. One is that [MDS tends to occur] in an elderly frail patient population. The median age of diagnosis is in the 70s. Fifteen to 20% of patients have been treated or are being treated for other malignancies. Patients who have therapy-related MDS are tough to deal with. That’s a group in which we're seeing an uptick in [therapy-related] MDS as patients survive longer from other diseases, such as multiple myeloma, lymphoma, and solid tumors. PARP inhibitors may increase the risk of therapy-related MDS. That's part of the reason why drug development has been challenging.

It's a very heterogeneous group. There are a lot of different molecular entities. Unlike myeloproliferative neoplasms, in which 3 mutations dominate the whole picture, there are dozens in MDS.

It's also easier to decrease an excess growth than it is to increase an absent growth—in this case, hematopoiesis and normal growth of blood cells.

Luspatercept’s [indication would be for] a subset of patients with lower-risk disease. We need new options for higher-risk patients.

There are new drugs that are showing reasonable activity in MDS. Clinical trial enrollment remains very important. Venetoclax is interesting, but you need to be very careful if you're going to use it off-label in your practice. [You should use] short schedules, not 28-day continuous dosing and use prophylactic antibiotics like they did in the trial. It’s important to be aware that cytopenias are real risk.

*Editor’s note: This interview took place prior to the FDA approval of luspatercept in MDS.


  1. Fenaux P, Mufti GJ, Buckstein R, et al. Assessment of longer-term efficacy and safety in the phase 3, randomized, double-blind, placebo-controlled medalist trial of luspatercept to treat anemia in patients (pts) with revised International Prognostic Scoring System (IPSS-R) very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusions. Blood. 2019;134(suppl 1):841. doi: 10.1182/blood-2019-123064
  2. Wei AH, Garcia JS, Borate U, et al. A phase Ib study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(suppl 1):568. doi: 10.1182/blood-2019-124437
  3. Zeidan AM, Pollyea DA, Garcia JS, et al. A phase Ib study evaluating the safety and efficacy of venetoclax as monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome. Blood. 2019;134(suppl 1): 565. doi: 10.1182/blood-2019-124994
  4. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of apr-246 and azacitidine (aza) in patients with tp53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134 (suppl 1):676. doi: 10.1182/blood-2019-131055
  5. Forty Seven, Inc. Granted Fast Track Designation for Magrolimab (5F9) for the Treatment of Myelodysplastic Syndrome and Acute Myeloid Leukemia [press release]. Menlo Park, CA: Forty Seven, Inc.; September 3, 2019. Accessed April 4, 2020.