Considering Lenalidomide in Non-Del 5q MDS

Transcript:Vinod Pullarkat, MD: Now we can talk a little bit about therapies for MDS. First, we’ll talk about the role of immunomodulatory agents. Thomas, can you comment about their efficacy in MDS? What’s your approach in the lower-risk patients using these agents, how we manage them?

Thomas Prebet, MD, PhD: I think those are 2 different situations, with basically a dichotomy between 5q MDS and the non-5q MDS. When we talk about immunomodulatory drugs, it is straightforward for deletion 5q MDS. We know that response rates are clearly in the 60% to 70% range with a potentially pretty prolonged duration of response. There’s still a matter of debate if we need to start from the get-go—lenalidomide for patients as a frontline therapy—or if you can wait after a failure of ESAs (erythropoietin-stimulating agents). Based on the guidelines, we don’t have the same answer. European guidelines still recommend to use ESAs first. Some experts recommend that by changing the natural evolution of the disease, natural history of the disease, we may have a more profound impact on the pathology using lenalidomide frontline. I think it’s definitely a situation where we don’t have a straight answer for the moment. We know that, probably, lenalidomide used in frontline will give, I would say, better results than ESA just in response rate, because patients with deletion 5q are not the best candidates for ESA. After that, I don’t think we have enough data, for the moment, saying that having lenalidomide frontline versus having lenalidomide after ESA really changes the overall survival of the patients. I don’t know, Rami, what do you think about it?

Rami S. Komrokji, MD: I think there a couple of important points you mentioned. I think deletion 5q is a more settled story. Some decisions models in the past looked at the threshold where starting a treatment before ESA would be more beneficial. If you had a 40% response rate with 1 agent or more, you could argue that we could go for that as a first-line therapy. I think what we know now with more data presented from the follow-up on the studies, that actually patients who become transfusion independent or have cytogenetic response are probably impacting the natural history of the disease. Those patients will have less leukemia transformation, and probably better overall survival. So, that’s to your point. I think it’s always important to remember that particularly with deletion 5q up front, we are going to see cytopenias. Those cytopenias predict response. You still start with the higher dose, because the aim is probably to get into that cytogenetic response, and then you dose modify, which is okay. Most of the patients actually will end up on a dose less than the 10 mg—especially when we are talking about deletion 5q—because in 2 to 3 weeks, you are going to be stopping the treatment because of cytopenia, and that’s okay. And, then, you go to the next dose and you maintain that dose. I think your point is well taken. I think the challenge is more of where to fit it in the non-deletion 5q, which you probably want to comment more on.

Vinod Pullarkat, MD: So, is it ESA failure followed by the lenalidomide or is it together?

Thomas Prebet, MD, PhD: In 5q, for the moment, we don’t have the combination of lenalidomide and ESA.

Rami S. Komrokji, MD: We are talking deletion 5q.

Thomas Prebet, MD, PhD: Yes. The question is more of which agents should come first. In the non-del 5q settings for the moment, we don’t have any approval of the drug, so that’s an important point. It’s not certain that we’ll have approval of the drug. At the end, we know that the response rates are more modest than what we see in deletion 5q. Probably for single-agent lenalidomide, based on different studies, response rates were in the 20% range. One of the big issues that we have for the analyses of these studies is that the endpoints that were used to define erythroid response may vary from one study to all of the others. Comparing the study may be a challenge, and we may have different rates of transfusion independence. Erythroid response may vary from one study to the other. And that sometimes is complicated.

After that, we know that we’re probably in the 20% range. To get to your point, it seems that a combination of lenalidomide plus ESA triggers more response. There are some nice recent biological data showing that you can stabilize the EPO (erythropoietin) receptor of the membrane, and that’s one of the reasons why you can increase the response rate by this combination. We also know that, basically, this response will be short lived and that after 1 to 2 years, most of the patients will progress. So, we need to have other options.

Rami S. Komrokji, MD: If I may add to what Thomas said, I think, basically, the response rates in non-deletion 5q are more modest compared to the deletion 5q. But, you could argue that 25% is in the range of what we get with other agents sometimes in non-deletion 5q. What we do typically in practice is you have to select patients a little bit. Those patients cannot be pancytopenic or bicytopenic. Patients who are purely anemic with lower risk, those could receive lenalidomide. Again, the challenge is it’s not approved by the FDA for that indication, but there are several studies that had looked at that. The NCCN guidelines actually list that as an option. So, to the point Thomas is bringing, there have been some preclinical data suggesting that the combination can improve. We conducted studies several years ago, that we published, that basically took out patients who were ESA failures, lenalidomide failures, and they do the combination, and we gain response back in the 20% range.

So, that led to 2 big studies. One was already published by the French group, and that showed that they increased the erythroid responses. One was from the US Intergroup study that randomized patients between lenalidomide up front versus lenalidomide plus ESA at high dose, and there was a crossover arm. If patients were on lenalidomide alone, and did not benefit, they could cross to the combination. What we learned that was interesting—and also to a very important that Thomas brought—is the response criteria between those studies are different. In the study, they used older criteria with major or minor erythroid responses, but a much more strict one that requires hemoglobin increase, not just reduction in transfusions. In the lenalidomide alone arm, the responses in all the population were in the range of 10%. They almost doubled in the combination. What was intriguing to me is, as the point mentioned, that in the non-deletion 5q, lenalidomide alone responses were in the range of 1 year or less. Now, when you look at the lenalidomide/ESA combination, some of those responses were in the average of 2 years. So, you may be increasing the durability.

But, it seems to be a function of starting both of them together at the beginning. The other study was a little bit more complicated for me. It was like almost an add-on strategy where patients started with lenalidomide, then they added EPO—step wise at the 30,000 dose—then increased the dose, then at the last step of G-CSF (granulocyte-colony stimulating factor), they tried to look at predictors of first response. And it was more difficult for me to interpret than the Intergroup study. My take-home message was the combination, probably by 2 studies, the French and the US, improves the responses and maybe the duration of response. So, again, the NCCN guidelines list it as an option. In the non-deletion 5q, I think it’s feasible to consider the combination as an option at this point with 2 studies.

Transcript Edited for Clarity