Updates in Myelodysplastic Syndrome - Episode 11
Mikkael Sekeres, MD, MS: What about lenalidomide for deletion 5q? What kind of response rates can we expect?
Jamile M. Shammo, MD: For patients who were enrolled in the study, they mostly had lower-risk disease. There were a handful of patients who had higher risk. But for the most part low-risk disease, deletion 5q, with 1 or 2 cytogenetic abnormalities, and platelet count above 50,000. Those patients you could expect a hematological improvement rate of about 67% with a complete transfusion independent state. If you added to that those who had reduction in transfusions, it would go up to about 75%. If you assume, again, reasonable kidney function because lenalidomide is renally excreted, you have to really familiarize yourself with the dosing for every level of creatinine. I think that essentially is the drug of choice in this patient population.
Mikkael Sekeres, MD, MS: I would agree. How long can they expect a response to last?
Jamile M. Shammo, MD: Well, I had such a variable duration, but I think it’s been stated as 2.2 years.
Mikkael Sekeres, MD, MS: 2.2 years. That’s a high rate of response for lower-risk MDS [myelodysplastic syndrome] and a long duration of response.
Ellen K. Ritchie, MD: A long duration.
Mikkael Sekeres, MD, MS: What about non-deletion 5q?
Ellen K. Ritchie, MD: It can be used, but the response rate is much lower, in a 40% range, for those patients. The duration is not as long. So, it can be used but with less efficacy certainly than in the 5q-minus population.
Mikkael Sekeres, MD, MS: Yes, I think with strict criteria, transfusion independence, it is about….
Ellen K. Ritchie, MD: It has to be transfusion independence.
Mikkael Sekeres, MD, MS: Twenty-seven percent rate for non-deletion 5q.
Jamile M. Shammo, MD: I’ll use the drug if I have a reason to believe that this patient has isolated anemia and relatively preserved neutrophils and platelet counts such that you can actually deliver an adequate dose.
Mikkael Sekeres, MD, MS: Yes, good point.
Jamile M. Shammo, MD: Then I think you have a chance of trying to assess the response. One out of 4 patients becoming totally transfusion independent, that’s actually very reasonable, and actually add to that the PR [partial remission] rate, we’re talking about 43%. Again, before committing my patient to the next agent, which would be committing them to chemotherapy indefinitely, I think it would be very reasonable to give it a 3-month or 4-month trial of all tablets.
Ellen K. Ritchie, MD: But you have to be careful when you are dosing lenalidomide I think because you have to look at the renal function of your patient. The adverse effect profile is real. There are patients who developed blood clots even on lenalidomide for MDS. You have to be mindful when you’re dosing these patients of where their creatinine clearance is, and you have to remember that there are serious adverse effects to using the medication.
Mikkael Sekeres, MD, MS: In truth, the blood clots, at least the literature I’ve reviewed, has shown that there’s a higher risk if they’re used with steroids, like in multiple myeloma. But in MDS, it’s probably not as common except for the fact that these are older folks who have comorbidities.
Ellen K. Ritchie, MD: Right. I have been surprised. I have had patients on lenalidomide who have taken a plane trip or have taken a long car trip who have developed serious blood clots. Even though they’re not on steroids, you have to remember that they’re still older individuals with old vasculature and other problems at higher risk.
Rami Komrokji, MD: We actually did the combination LEN [lenalidomide]-prednisone and non-deletion 5q, hoping for better responses. We didn’t see much of an increased rate of clotting. Going back, just to bring a point, I think something you’ve published before on is also when you use lenalidomide, in deletion 5q particularly, cytopenia on therapy upfront is going to predict response. I often see many patients were stopped from treatment and never tried again because their platelets or ANC [absolute neutrophil count] in 2 or 3 weeks were low. That’s expected. We tell patients 80% will have it in 3 weeks. We’re going to stop the treatment for 2 or 3 weeks and restart. So cytopenia on treatment is predictable for response and del 5q. That’s not the case in non-deletion 5q, and you could probably elaborate more because that was your work.
Mikkael Sekeres, MD, MS: Well, thank you for citing that work. I think that makes you and my mother who’ve read it. That’s probably from when I still actually had 25-year-old muscles.
In deletion 5q, cytopenias, particularly thrombocytopenia, is predictive of response. This does not hold true though in non-deletion 5q. It’s just simply an adverse effect of the drug.
Rami Komrokji, MD: Sorry to interrupt, but I don’t know how many of you, based on the French data and the Intergroup study combining LEN with erythropoiesis-stimulating agents, have done this combination in the setting of non-deletion 5q. I think we’re going to hear some updates at this ASH [American Society of Hematology 2019 annual meeting] on the Intergroup study. I don’t know how much you use it or not. I do use it a little bit, and in those patients, I think the duration of response is higher. I’m not sure if the responses are higher, but we do see longer duration of the combination. I know that there are believers and nonbelievers.
Mikkael Sekeres, MD, MS: I think I’m agnostic. I haven’t used it yet because I’m waiting for more mature data, but I wouldn’t say I’m a believer or nonbeliever. They are interesting data. It’s come from both the United States in 1 form and Europe in another—they’re not directly comparable. The US data seemed to be positive whereas the European data seemed to be negative. But it was a totally different study design and populations.
What about patients who have multiple cytopenias and the use of hypomethylating agents? If they have lower-risk disease, do you adjust the dosing schedule, or do you keep at it? You’ve done a lot of work in this, Rami.
Rami Komrokji, MD: Right. I think what had become common practice is using the 5-day azacitidine regimen or still using 5 days of decitabine, so lower doses are accepted. This is based on studies published by Roger Lyons, MD, FACP, in a community setting where they did 5 days versus AZA [azacitidine] 5-2-2 [75 mg/m2/day for 5 days, followed by 2 days no treatment, then 75 mg/m2/day for 2 days], versus azacitidine 5-2-5 [50 mg/m2/day for 5 days, followed by 2 days no treatment, then 50 mg/m2/day for 5 days].
I’m sure the responses were the same. Maybe there was a little more toxicity with more prolonged regimens. Five days had emerged the best. There had been no randomization data looking at bone marrows and stuff like that. But I think it’s reasonable to do 5 days. As we mentioned, we usually try to use hypomethylating agents as the last option for patients with lower risk. But obviously other cytopenias can dictate that, and we end using them. That’s only in the United States because in Europe they’re not approved for lower risk.
Where things have been moving is, also, maybe even 5 days is too much for those patients. Perhaps a lower dose is reasonable. There have been some efforts, within the MDS Clinical Research Consortium, looking at 3 days of decitabine, 3 days of azacitidine. The data from The University of Texas MD Anderson Cancer Center is published on 3 days of decitabine versus 3 days of azacitidine, showing reasonable responses compared to historical numbers. We just finished a bigger study with the MDS consortium that randomized patients between the 5-day standard, 3 days decitabine, or 3 days azacitidine, and another randomization looking at when to start treatment, whether to start treatment immediately or if patients were cytopenic. I think the results of that study will be very informative. I do think that we probably could get by with 3 days in lower risk, but we still have to see the data.
Mikkael Sekeres, MD, MS: I’ve become more of a believer in 3 days of azacitidine or decitabine for lower-risk patients. The initial study and then updates, which was through the US MDS consortium, showed response rates that appeared to about 15% higher than what we’ve traditionally seen for hypomethylating agents. Traditionally we see about a 35% response rate. This was up to 50%, and it seemed to be durable and approaching a year and a half, which is a long time. So, we’ll see what happens with the randomized study.
Transcript Edited for Clarity