Treatment Goals for Higher Risk MDS

Transcript:Mikkael A. Sekeres, MD, MS: Jamile, what are your goals of therapy for patients with higher risk MDS, and how does that differ from your goals for lower risk MDS?

Jamile Shammo, MD: If I have a patient who is high risk, I think the very first thought that comes to my mind is control. I want to control this disease and hopefully get a response and delay leukemia evolution, hopefully prevent transfusions, infections, etc. So, in that sense—as opposed to me evaluating this low-risk patient—how long can I monitor them without therapy? And in this case, it’s probably the other way around. And also the second thing that comes to my mind is, is this patient a transplant candidate? Because, clearly, even with the best agent you have, when you have something with a median overall survival of about 50% at 24 months, this is no cure. And hence, you have to have an alternate for your patient. Though, again the percentage of patients who can undergo transplantation is relatively small. Having said that, with the advent of reduced intensity transplant, it’s probably a worthwhile discussion to have with the patient, potentially having then seen a transplanted patient, and determine whether or not they had a sibling or a match with an unrelated donor. But, again, it’s somewhat problematic, because let’s say, in the best case scenario, you have a younger patient in their 60s perhaps with a perfect donor. Then the gray areas happen such that, would you actually treat them? Would you induce them into a CR (complete remission), would you send them to transplant immediately? All these things tend to be issues that we have to think about. But this is pretty much the standard of what I would do.

Mikkael A. Sekeres, MD, MS: What doses do you use of hypomethylating agents, and what schedule?

Jamile Shammo, MD: So, usually for high-risk, it’s 75 mg/m2 for 7 days now. We don’t have clinic hours.

Mikkael A. Sekeres, MD, MS: For azacitidine.

Jamile Shammo, MD: Yes, for azacitidine. And then for Dacogen, 20 mg/m2 for 5 days for high-risk patients. We usually do the 5, 2, and 2 for azacitidine and then the 5 days for Dacogen. I must confess that sometimes for people who have high, multiple comorbidities, transfusion dependent, etc, and cannot receive outpatient treatment, I end up hospitalizing them for 3 days of Dacogen. Sometimes that’s easier logistically.

Mikkael A. Sekeres, MD, MS: Yes, sometimes it is. People travel long distance, we’re not all in New York City where people can sometimes hop on a subway or get caught in midtown traffic on their way to the treatment center. So, sometimes you’d have to do that when particularly we’ll have some patients who travel hundreds of miles to come to our treatment center and need to work out those logistics. Rami, Jamile brought up allogeneic transplant, which of course is the only curative therapy for MDS. What criteria do you use for recommending that a patient go for transplant?

Rami S. Komrokji, MD: Obviously, when I look at this, it’s a very complex thing. And I learned over time that this is a discussion with the patients, and that patients have to weigh in on the decision to go to transplant. I look at two things, obviously the disease risk itself and those decision models published by Dr. Cutler and other groups looking at the timing of transplant, lower risk versus higher risk. In lower risk, the maximum gain of survival taking advantage of transplant is holding on the transplant. In higher risk, the maximum gain of survival is to proceed to transplant. So, one factor I look at is the disease risk. If they are higher risk disease, those are patients that, as mentioned, have a median survival of less than 2 years.

I think the whole thing is really weighing the benefit and the risk of the procedure. No matter what we talk about with transplant, we are always talking about around 20% transplant-related mortality. The cure rates vary. Yes, in lower risk disease, we may have a 60%, 70% cure rate, but there is a zero chance of mortality in the coming 2 years in lower risk, so we don’t take that action. In higher risk, there is 40%, 50% mortality in 2 years so you can justify the transplant. The cure rates are a little bit less. In general, I think those are the patients we discuss with them directly the transplant. The lower risk disease, if they are younger patients and they’ve gone through all the standard treatments and clinical trials, I think it’s reasonable also sometimes to discuss the transplant with them. If you have somebody in their 50s, had ATG (anti-thymocyte globulin), hypomethylating agents, enrolled in a couple of trials, and there is no other option, I think those patients are definitely worth discussing it with.

Then the other thing is basically the patient factors, age per se. I’m not sure that nowadays there is cutoff for age because we say age is function. So, we do sometimes consider patients up to the age of 75. Most of the data are actually on patients either below 55 or 65, and then obviously the comorbidities, the availability of the donor. The way I discuss it with patients, I say, “What are the goals?” If somebody is young, I think sometimes it’s much easier to say transplant is the only way, with higher risk disease. In somebody who is 50, expected to live without MDS till 80, there’s a 30-year potential gain in survival. But let’s say our average patients are 69 or 70, excellent shape, no comorbidities. The way I discuss it with patients, I say, “We need to set our goals.” In general, somebody who is 70 is expected to live to 80, 82, right? That’s the average population survival without MDS.

With MDS, a higher-risk disease would have maybe a 2-year survival the best. Actually, the median is probably the same, transplant or no transplant. But basically those patients are losing 7, 8 years of survival because of the disease. But then the procedure itself is intense, a month in the hospital, 2 months in an apartment across from the hospital, a 2 or 3 year’s quality of life affected. So, the end gain of a good quality of life could be only 2 or 3 years for somebody in their 70s. I always try to explain that. I tell the patients, what’s your goal? If somebody says, “My goal, I want to make it to 85 because that’s what I want to do, I’m willing to take risks,” I say, “You have your answer.” If somebody says, “No, I value more quality of life and I want to see the graduation of my grandson next year and not be on all those treatments,” you have your answer.

I think it’s always weighing those benefits and risks. But definitely we look at the disease risk. The patient age still matters. Although more data suggest that age per se does not predict the outcome. The functional status of the patient, the comorbidities, and availability of donor are factors (which is also now changing with haploidentical transplants and other things). In general, when we look at our database, as much as we are aggressive in transplant in our MDS patients, less than 10% were transplanted. Fifty percent of the patients that we sent to transplant with intent to transplant ended up not getting a transplant.

Mikkael A. Sekeres, MD, MS: I think that’s a critical message as well. If you look at the population, fewer than 5% of patients with MDS are even approached about a transplant or it is even discussed. Even at our centers—where we’re geared up to transplant and look at it as part of our algorithm as soon as a patient is diagnosed with higher risk MDS to consider transplant—it’s still less than 10% because of a lot of the limitations of factors that you mentioned.

Transcript Edited for Clarity