Advances in the Treatment of Myelodysplastic Syndrome: Targeting CD47 - Episode 6

The Future of Myelodysplastic Syndrome

An oncologist discusses the future of myelodysplastic syndrome, including upcoming studies and potential treatments.

Naval Daver, MD: There are several exciting new therapies that are in phase 1/2 and phase 3 studies now in MDS [myelodysplastic syndrome]. I would say in the last 4 to 5 years, we have now more exciting drugs than we have had in the prior 2 decades for MDS. I think part of this is because we are seeing a lot of the drugs that have been recently approved in the acute myeloid leukemia [AML] space, now moving to the myelodysplastic syndrome space. These include a drug called venetoclax, which in combination with hypomethylating agents [HMAs] like azacitidine and decitabine, showed dramatic improvement in response rates in older, unfit patients with AML, with a response rate of 70% CR [complete response]/CRi [complete response with incomplete hematologic recovery] compared to 30% with azacitidine alone. It has been approved in the combination of azacitidine/venetoclax in frontline older, unfit AML.

We know that the biology, especially in patients with MDS with high blasts, can be quite similar to AML in the older, unfit population. This has now led to studies of azacitidine/venetoclax in MDS with high blasts, which have shown very encouraging response rates, close to 80% overall response, and 40% to 45% true CR rates. This has led to a randomized phase 3 study looking at azacitidine/venetoclax versus azacitidine therapy in frontline, higher-risk, high-blast MDS. Given the success and the efficacy of this combination in older, unfit AML, we are hoping it will also have a similar efficacy and have a good shot of being approved for MDS.

Another new drug that is also very exciting is pevonedistat. This drug has been evaluated in combination with azacitidine, both in a single arm and randomized phase 2 study. The data show that the response rate of [azacitidine]/pevonedistat is very encouraging, especially the true CR rate of close to 50%. In a randomized study, especially in higher-risk MDS, there seemed to be a very strong trend toward improvement both in event-free and overall survival. This has led to another large phase 3 study called PANTHER, it just completed enrollment, of [azacitadine]/pevonedistat versus [azacitadine], about 6 months ago. We’re hoping by the end of this year we may see the results of that study, which again could then lead to the approval of azacitidine/pevonedistat in the older, higher-risk MDS population.

Then there’s a fourth drug called sabatolimab, which is also an immune drug. Unlike magrolimab, which works on the innate immune system and the macrophage system, the sabatolimab seems to work more on the T cells, blocking TIM-3 and activating T cells. This is also now in a randomized phase 2 study and has shown some very promising responses and activity in the prior phase 1/2 study. This especially seems to be good at improving the duration of responses and was very well tolerated compared to many other immune checkpoint antibodies we have tried in MDS and AML.

I think the big question is, let’s say, if all 4 of these drugs get approval in the next 1.5 years, how will we optimally use them? There are now some hints of how this will happen coming from the molecular and cytogenetic analyses of these ongoing phase 2 studies, where we’re seeing, for example, magrolimab/azacitidine seems to work really even in TP53 and adverse cytogenetics. It works well across the board, but it seems to work well in this high-risk group, where almost nothing else works. If I have a patient with TP53-mutated AML or adverse cytogenetics, I really am trying to get them on azacitidine with the CD47 SIRP-alpha, such as magrolimab, because we know venetoclax and others may not work as well. On the other hand, if I have a patient with MDS with an IDH mutation, a splice mutation, or RUNX1, based on the knowledge we have from AML, we know [azacitadine]/venetoclax could have a very high response in that population, and we may consider it.

I think as we do more molecular analysis and cytogenetics, we will find that there will be different populations that could benefit specifically from one of these combos. Then the next step is how can we optimally combine or sequence these drugs? For example, if [azacitadine]/magrolimab and [azacitadine]/venetoclax are both approved, could we consider doing [azacitadine]/venetoclax/magrolimab to really improve the depth of remission, the molecular and MRD [minimal residual disease] clearance, and the survival? A lot of these are already starting as phase 1 trials while we’re waiting for the readouts from the doublet phase 3.

I think if all goes well, just like in AML in the last 4 years, the complete landscape and treatment approach could change very dramatically and in the benefit of the patients and the clinical research for MDS. We’re looking forward to that.

My main advice would be to recognize that there is a lot happening in both MDS and its related disease, acute myeloid leukemia, compared to 10 years ago when we really had not had any major drug approvals and major changes in molecular and immune therapies. Today there has been a huge shift in the treatment, and a lot of these treatments are significantly improving response rates, survival, and are often as tolerable or even better tolerated than the previous therapies.

In addition, I would strongly consider thinking about clinical trial options for the patients, especially because today all the 4 or 5 most exciting drugs in frontline higher-risk MDS are all available mainly through clinical trial. If you have a patient who has higher-risk MDS and is willing to travel, they may really benefit quite significantly by going onto one of these frontline trials. Often, we get a huge number of patients for trial referrals, and we will keep them here for the first cycle, which is usually the first month. Then for the subsequent cycles, we usually work closely with the community or local oncologist. The patient comes back here for 1 or 2 days for clearance to start the next cycle, and then the rest of the blood work, monitoring, and even treatment is done locally. If you have local academic centers that are willing to work with you, this could be a great option for your patients to get access to these novel combinations that may not yet be fully approved for a little while, but they are showing very exciting responses and data.

Lastly, even in patients who have failed traditional and standard HMA therapies, there are now other new immune therapies and oral therapies that are emerging that could be of high interest. You should consider these options, and maybe again have a discussion with your colleagues in the large academic centers close to you, or any time feeling free to reach out to us; there are now many trials developed in post-HMA with NK [natural killer] cells, CAR T [chimeric antigen receptor T-cell therapy], bispecific antibodies, others, that could be an option if your patient is willing to travel. All in all, I think the future is looking bright. We will hopefully continue to make rapid strides and progress in improving the outcomes for patients with high-risk MDS. Thank you for listening.

Transcript edited for clarity.