The Future of MDS Management

Rami Komrokji, MD: I’ll ask you to briefly comment on what’s exciting you of the compounds out there. There are several phase 3 trials, very exciting compounds both in lower and higher risk. I’ll ask you to give us a few minutes of what’s exciting you.

Amy DeZern, MD, MHS: Well, I think we should be clear, we still only have 5 drugs in our MDS [myelodysplastic syndromes] space. We mentioned the oral hypomethylating agent, azacitidine, decitabine, luspatercept, and lenalidomide, which we haven’t spent a lot of time on because it’s for patients with del(5q) [deletion 5q], but I think we are entering a really exciting time in the myeloid space. By my count, we’re going to have 4 phase 3 trials open in a year or 9 months from now. One in lower-risk disease, which is looking at a novel mechanism to augment hemoglobin in patients. And then one for higher-risk disease, looking at 3 novel mechanisms, all seemingly compared to azacitidine backbone alone, which is analogous to the acute myeloid leukemia space. We’re looking to target BCL2 inhibition with venetoclax, which is a compound many people are familiar with. Then there are a couple of other pathways, like magrolimab, or other ways to target different aspects of myeloid maturation pathways that are deranged in patients who have excess blasts. I think we’re really going to start to see changes to the landscape and that these patients have more options. Once they’re approved, something else that excites me is that we really need to understand how to sequence these drugs. I’m not sure your thoughts on those topics.

Rami Komrokji, MD: Yes, I totally agree. I think it’s very exciting that, as you mentioned, we have several trials, but we also have huge unmet needs for our patients that we still have to work hard on. Obviously, in the lower risk, for example, even with the drugs approved like luspatercept, we are trying to see if there’s benefit outside the approval. The COMMANDS study is ongoing looking at up-front ESA [erythropoiesis-stimulating agent] failure. We have some interesting data with a compound called entinostat. In higher risk, as you mentioned, we have 3 drugs that look interesting: magrolimab, APR-246, venetoclax. In the lower risk, I do think we’ll have to sequence those therapies. You mentioned briefly now about lenalidomide for del(5q). We use it sometimes outside, non-del(5q), for patients who are just anemic. But when we look at the sequence, we see higher responses if they were used before hypomethylating agents, for example. I think the sequence in the lower risk matters. I will be sequencing those treatments.

I think the exciting thing in the higher-risk disease is that now we probably, at least in the phase 2 or early phase 3 data, we are doubling the responses to hypomethylating agents. That will be an opportunity for us to maybe take more patients to transplant. I’m starting to try to introduce this concept of what I call total therapy for patients; we have to factor all those things in: the up-front treatment, the transplant, the maintenance of transplant, and maybe it’s also a time for us to introduce the minimal residual disease MRD status in MDS. It’s something we never used to think of because we could not achieve it. Now with the new treatments, I think we’ll start to think of a continuum for the patients, about how we are going to sequence those treatments, or whether we’re going to try to achieve MRD, take patients to transplant, or do maintenance after transplant. It’s really an exciting time for me. Now we can think of things we could not think of because we have better compounds, and hopefully, by next year, we’ll have a couple of those approved for our patients.

Amy DeZern, MD, MHS: I think that’s tremendous. You did mention a drug that I should have highlighted about clinical trials, and it gets back to tying together everything we’ve talked about. It is a heterogeneous disease, we both do molecular sequencing, and TP53 is a very, unfortunately, unfavorable mutation for these patients. You mentioned APR-246, which was a phase 3 study that’s already completed accrual, but we don’t have the readout yet. As I see the future to improved outcomes for patients with MDS, it’s a path like this: We define them very clearly, we have a sense of the biology of whatever mutation they have, and then we rationally develop drugs and trials that are able to target what we think is driving the disease biology to improve outcomes for patients.

In that schema, do you have any advice for community oncologists for how to handle a patient who is newly diagnosed with MDS in their clinics?

Rami Komrokji, MD: I think we tried to cover most of this now, and we went through the steps, diagnosis, risk stratification, trying to set the goals of management, thinking of it, as you mentioned, as a long-term treatment for those patients, and thinking of a transplant. All those things factor in. I would say also at time of failure of therapy, if somebody was on an ESA or on an HMA [hypomethylating agent] in higher risk, I think it’s always a good idea to pause, reevaluate the disease, sometimes get some molecular data. For example, we know that HMA failure in higher-risk MDS is associated with worse outcome, 4 to 6 months survival. Traditional intensive chemotherapy doesn’t work, and if we can take those patients to transplant, it’s helpful. Every now and then, we repeat the molecular testing and we see a new molecular mutation or a mutation that we didn’t know about, like IDH1 or IDH2 mutations. There are now drugs available for that if patients are transforming to AML [acute monocytic leukemia].

I would say it’s really going through the sequence of things, like establishing diagnosis, risk stratification and ongoing, and in a fashion of setting the goals and selecting the treatments accordingly. It’s really an exciting time. For the patients with TP53, as you mentioned, I think those patients don’t do well with intensive chemotherapy; they do better with HMAs. Both APR-246, which is the p53 regulator, and magrolimab, the anti-CD47, have shown some promising activity there. When possible, those patients should be referred for a clinical trial, but if not, I always prefer treating those patients with HMAs rather than intensive chemotherapy.

Amy DeZern, MD, MHS: Good. I think doctors like Dr Komrokji and I are always more than happy to help and see these patients. There are many other large MDS referral centers around if that is of use for even a one-time consultation, just to map out a little bit of a plan and then return to the community to receive their HMA or transfusional support. I really enjoyed talking to you today, Rami. It’s been fun thinking about our patients together, and thanks everybody for your time.

Transcript edited for clarity.