SOHO 2021 | The optimal treatment of lower risk MDS

In the midst of the proffered session, we are highlighting, obviously, all MDS, my task force talking about the lower risk MDS. We probably will discuss this further. First, I think really categorizing what’s lower risk MDS is very important. So obviously we use the revised IPSS coding system. We complement that with mutation testing. We look at the patient’s related factors. And at the end, if we label the patients as lower risk MDS, obviously the treatment is geared to alleviate cytopenia so far.

There are different patterns, obviously. So in the majority of the patients, we will be treating anemia. Rarely, maybe 10% of the patients, will present with isolated thrombocytopenia, and for those patients, options of treatment are relatively limited. In general, hypomethylating agents, immunosuppressive therapy with anti-thymocyte globulin and cyclosporine is an option, particularly for younger patients. Or sometimes we use a thrombopoetic stimulating agents like eltromobag that has data from our colleagues in Italy and lower risk MDS showing efficacy in those isolated thrombocytopenia.

But that’s around 10% of the cases. There is no magical platelet number, even where you pull the trigger on the treatment. In general I typically, when they drop below the 50 or 30 would think of starting the treatment, but obviously you have to factor a lot of other issues like the patient comorbidities, other bleeding tendencies, et cetera.

Isolated neutropenia is also rare in lower risk MDS. I typically don’t treat patients with isolated neutropenia unless they had recurrent infections. Studies in the past, showed that regular use of GCSF did not impact the outcome for those patients. And the choices are, again, probably limited even with the hypomethylating agents, 10 to 20% response is maybe a neutrophil response and the ATG cyclosporine can be an option for younger patients.

But the bulk we are treating is really anemia. So the first question, obviously we ask, is the anemia symptomatic? When do we pull the trigger and treatment of anemia and lower risk MDS? And in general, obviously patients that are transfusion dependent, definitely that’s an indication to treat patients that are symptomatic with anemia. And in some cases, probably earlier intervention is important. We get more responses. So those are the general guidelines.

Obviously, we go stepwise in managing anemia. The concomitant cytopenia because sometimes we’ll have patients that have anemia with thrombocytopenia and/or neutropenia. Those sometimes can dictate the choice of therapy, but not necessarily the indication to treat the patient. And I throw in stimulating agents, whether it’s erythropoietin or the longer acting darbopoetin, typically our first step. They work particularly well in patients that have low transfusion burden or not transfusion dependent. And in those patients that have a endogenous CRE level below 500.

In that setting the responses are high, if patients are getting transfusions on monthly basis or other endogenous serum level is high, those patients’ chances of response is very low, less than 10%. So we typically do somewhere around eight to 12 weeks of trying the erythro-stimulating agents. If they are working, we drive the benefit out of it. If not, then obviously we move to the next step.

So the next step, if patients are not responding to erythro-stimulating agents, we ask, are they del 5q isolated anemia? And for those patients obviously, particularly lenalidomide works very well in that subset of patients with prior studies showing almost 70% transfusion independent. What’s interesting or recent in del 5q, there was a study by the Spanish group looking at randomizing patients earlier on before they are transfusion independent. So they are looking at time to transfusion dependency, which is very interesting endpoint in lower risk MDS, particularly in the 5q given the unique activity of lenalidomide.

So in that study, they reported patients with anemia, but not transfusion dependent. So earlier on, randomized to five milligrams of lenalidomide, which is half of the typical dose that we use. And for two years only. And they showed that those patients that were treated with lenalidomide had almost 70 months time to become transfusion dependent compared to only a couple of years in the patients that were just observed.

So I think this study is challenging the paradigm of waiting until the patients are transfusion dependent or severely symptomatic and deletion 5q. And it makes me think of maybe introducing lenalidomide a little bit earlier in the 5q. Now, again, the del 5q is only a unique subset. It’s also important to note or say, if patients have concomitant thrombocytopenia, particularly platelets less than 50, severe neutropenia less than 500, even in the del 5q responses to lenalidomide unfortunately are not high.

If patients don’t have the 5q, then our next question, do they have ring sideroblasts or a splicing mutation SF3B1. Because now we have luspatercept, which was approved last year for that subset of patients. luspatercept is a monoclonal antibody that neutralizes TGF beta cytokines or ligands. And those tend to be important in regulating terminal erythroid maturation.

And the drug had been tested in phase one phase two trials. And then a phase three that particularly focused in patients with ring sideroblasts that were transfusion dependent. It’s an injection subcutaneous every three weeks. And it showed superiority obviously to a placebo and the drug is approved. So I said, injection every three weeks, that those can be escalated as the package says from one to 1.3 to 1.75, every two doses. Responses are roughly around 40% and there are some patients that will have more than, duration of transfusion and dependency. Well-tolerated, it does have fatigue the first couple of cycles, rarely arthralgias, myalgias. But in general, very well tolerated treatment with no signs of increasing disease progression.

Again, the magnitude of benefit of luspatercept is higher if those treatments were introduced in patients that are not heavily transfusion dependent, and those patients that were requiring more than six units of blood, there were transfusion reductions, but rarely we encountered in the study becoming transfusion independent. So again, after ESA failure in patients with ring sideroblasts we should be thinking of luspatercept early after the ESA failure before patients become heavily transfusion dependent. And luspatercept also has been looked at other subtypes because the activity is not just limited to ring sideroblast patients.

So there’s ongoing study for the command study, looking at patients upfront that are needing some blood transfusion, randomizing them between erythropoietin and luspatercept. There are other studies looking at combinations, whether it’s lenalidomide or with erytho-stimulating agents. So we have to explore more the activity of luspatercept, but now it’s available for patients with ring sideroblasts.

If the patients don’t have ring sideroblasts or not deletion 5q in our practice, if they are younger early in their course of disease, we do consider immunosuppressive therapy with ATG cyclosporine. This is one course of the antithymocyte globulin. The hospital followed by cyclosporine somewhere six to 12 months. If you select patients that are younger, not having transfusion dependent again, earlier in the disease, the response rate can exceed 50% and they are durable responses.

So that’s an option again, for a limited number of patients. For the rest of the patients that are non ring sideroblasts, not candidate for immunosuppressive therapy, I think our choices are either standard lenalidomide, which can be used at least in the United States for non del 5q or hypomethylating agents. Those are obviously unique treatments in the USA compared to Europe or Canada, where they are not approved for lower risk MDS, but we use lenalidomide with or without erythropoietin in patients or in patients starter failure in those patients that have isolated anemia.

So they have to have adequate platelets and good neutrophils. If there’s concomitant cytopenias that even don’t need treatment, then chances lenalidomide of working are not high. And the default option becomes the hypomethylating agents. But in those patients that have isolated anemia lenalidomide with erythropoietin could be a valid option for those patients with roughly around 30% responses.

And in the past, we’ve published our experience on the sequence. If we use lenalidomide in the non 5q before hypomethylating agents that you did higher responses while the response to hypomethylating agents were the same. So in our practice again, we prefer using them before. Then obviously, if patients have gone through all those options or they have concomitant cytopenia non del 5q, non ring sideroblast, then the default is hypomethylating agents. And then I had stayed typically azacitidine is just as five days and decitabine, we’ve done studies through the MDS consortium, looking at three days regimen, which seems promising. We’re waiting for the randomization to confirm that.

And always the oral hypomethylating agents are making their way. There is oral decitabine that’s approved for higher risk MDS, not for lower risk MDS. And there’s oral azacitidine that was tested in lower risk MDS, but the dosing is not yet figured. And it’s important to point out that oral azacitidine is not equivalent to IV or subcutaneous azacitidine. While the oral decitabine is almost 99% bioequivalent.

Obviously, clinical trials are always important. I feel very comfortable enrolling patients on clinical trials at any time point in the lower risk MDS. We are looking at anti-inflammatory agents earlier in the disease. There are a couple of randomized clinical trials one with entinostat, that’s a telomere inhibitor that in the phase two short, a very robust 40% response, transient independency, and durable with some suggestion, maybe even altering the natural history of the disease. So now it’s finishing a phase three trial. And there is a drug called roxadustat that’s a HIF pathway inhibitor. That’s also in phase three and shown some promising activity in the phase one phase two.

So that’s in general, my approach for the lower risk. I think the first step assuring that the patients lower risk and then identifying the cytopenia. Some patients are okay to observe if they don’t have significant profound cytopenia, then if it’s isolated thrombocytopenia or isolated neutropenia. And then as we discussed for the isolated anemia.