Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 15
Harry P. Erba, MD, PhD: This has been an amazing discussion. There is so much more to discuss now in AML [acute myeloid leukemia]; the last 3 years have been a whirlwind of new therapies. What I would summarize of our discussion so far is that we still have a whole lot to learn about how to use all of these drugs and a whole lot to learn about how to use some of our methods of detecting measurable residual disease.
I want to turn to an important topic for our patients with myeloid neoplasm, and I know it is a bit outside the scope of AML, but we have Corey Cutler MD, MPH, FRCPC, here today, and Corey presented what is one of the most important practice-changing or educating presentations at ASH [the American Society of Hematology 2020 annual meeting]. It was his oral presentation of the BMT CTN 1102 study looking at reduced intensity allogeneic transplant vs the use of hypomethylating agents [HMAs] in patients with higher-risk MDS [myelodysplastic syndrome]. This is incredibly important because CMS [Centers for Medicare & Medicaid Services] has not been covering allogeneic transplant for our older patients with MDS, and CMS asked for this study to be done. Corey, you and the BMT CTN pulled it off, and I am glad that you are here to discuss it with us today.
Corey S. Cutler, MD, MPH, FRCPC: Thanks for having me. I would like to start by saying how refreshing it is to hear a bunch of leukemia investigators talk so favorably about transplantation by and large. I also believe that the CTN 1102 trial was an important study. We, at the Dana-Farber Cancer Institute, looked at nearly 400 subjects, and we allocated them to donor or no-donor assignment based on the presence of whether they had an HLA [human leukocyte antigen]-matched sibling or HLA-matched unrelated donor. These were all individuals above the age of 50 but below 75 years of age who had intermediate-2 or high-risk MDS at any point in their disease course.
Subjects were treated according to whatever local standard was considered in their best interest at their center, so we did not specify what type of low-intensity transplant to perform or what regimen to use. Similarly, we did not specify what regimen of hypomethylating therapy or other supportive measures they could receive. It was important that we noted that, at the end of 3 years, the median outcome in subjects who were allocated to the donor arm was about 21% higher than subjects who had no donor. There was an almost 48% 3-year overall survival in the donor group, which was significantly better. The leukemia-free survival outcomes matched that, and we looked at an intent-to-treat analysis where we took subjects in the no-donor arm who underwent alternative donor transplant out, and we excluded the subjects in the donor arm who did not undergo transplant, and the results were even more striking. We believe that it was a practice-changing therapy. We think that this is going to solidify the role of allogeneic transplant in transplant-eligible older individuals with high-risk MDS, and we believe that CMS will reconsider its decision on payment for this procedure moving forward.
Harry P. Erba, MD, PhD: Corey, one of the interesting things I found about the assessment was that the benefit in terms of survival was there regardless of whether the patient received HMA or their response to HMA. That caught me by surprise because I have always been told to give the patient azacitidine, get that blast count below my magic number, and then do a reduced intensity transplant. Do you want to comment on that?
Corey S. Cutler, MD, MPH, FRCPC: We looked at subgroups based on whether subjects had received HMA and whether they were responsive to HMA therapy in the past, and the benefit was seen across the board. There were slightly different magnitudes depending on the subject’s prior responsiveness to HMA, but the benefit was seen across the board. Importantly, there were probably not a huge proportion of patients in this trial who had already exhausted many of their treatment options and were using transplant as a therapy of last resort. That is an important consideration here, and one of the main messages from the trial is that transplant should not be the last resort. We would like to meet transplant-eligible patients early in their disease course so that we can do the best donor search that we can and be ready to move to transplant when the patient is medically ready.
Harry P. Erba, MD, PhD: You bring up an important point there, which is the transplant-eligible patient. For the doctors in the community, what do you mean by that? Are these patients 71 years old, 78 years old? What about age or comorbidities? How are they supposed to know what you are looking for?
Corey S. Cutler, MD, MPH, FRCPC: We no longer use age as a fixed cutoff for transplant eligibility. A fit patient who is 71, 72, or 73 years of age is certainly somebody we would consider for transplantation. We look at medical comorbidity as an important factor to determine whether someone is transplant eligible. Measures of geriatric assessments are important in these individuals, but we have transplanted individuals up into their late 70s, but patients in their low 70s, particularly in 2020, are very much fair game for who might be eligible for a reduced intensity transplant. As we get better at matching and as we get better at preventing and treating graft-vs-host disease, transplant outcomes are clearly going up. Individuals at advanced age are not necessarily excluded. Quite frankly, if the community-based physician is not sure, then have that patient come to the transplant center to have a meaningful discussion with the transplant team to learn about the potential downsides of transplant. What are the risks? What are the potential complications? Let the patient decide what is right for them.
Harry P. Erba, MD, PhD: Those are good points. Sasha [Alexander], Eunice, do you agree with early referral for transplant for patients with high-risk MDS?
Alexander E. Perl, MD, MS: Absolutely.
Eunice S. Wang, MD: I agree with that. Only a proportion of my patients decide to go to transplant, and that is interesting because, for most patients, even my own transplant team will say that, if you have a patient with high-risk MDS, they do not have acute leukemia, so we do not have to transplant them right away. They say, “Why don’t you go ahead and give them a few rounds of azacitidine, see how they do, and then get back to us?” I’ll say, “This person has like a TP53 mutation, RUNX1, ASXL1, I don’t know whether they’re going to do great.” We get a little pushback from that saying, “Go ahead and treat them, and then when you get around to it, we’ll do transplant down the line.” Early referral is great because a lot of people do not do that, and we should be pushing our transplant colleagues to say, “It doesn’t matter if they respond to HMA or not. I don’t have to give them 4 to 6 rounds of HMA, so maybe you should just take them now.” I have had those patients who develop complications and never get to 4 or 6 rounds, so that is an important message. The CMS thing has been a deterrent for some of our older patients and their ability to get transplants.
Corey S. Cutler, MD, MPH, FRCPC: In my practice, I definitely use HMA therapy as a bridge to transplantation, and anyone with higher-risk MDS who is being evaluated for transplant should be receiving some form of therapy until the time of transplant has come. I generally do not stand on ceremony, waiting for someone to see 4 or 6 cycles. Give them a round or 2 while we are doing our search. If they are doing great on the HMA therapy, and the blast count is coming down, perhaps give them 1 or 2 more rounds. If things are not going as planned, and the blasts are not coming down or if the patient is not tolerating HMA therapy well, then it might be the right time to move right to transplant then.
You mentioned TP53 status. There are certainly patients in whom reduced intensity transplant is not appropriate, and TP53 status might be one of those factors that one has to take into consideration. For someone with borderline comorbidity and a TP53 mutation, perhaps that is someone in whom transplant is not necessarily the right decision. Again, it is a measure of balancing patient expectations and all sorts of other factors. It is always worth having a conversation.
Harry P. Erba, MD, PhD: That is an important part of this entire discussion. Have the patient decide: they need to have a caregiver, and they need to evaluate their own therapeutic goals for where they are in their life. This is not something that happens in a 5-minute or 10-minute conversation, and it may not be done in 1 clinic visit, but it is an incredibly important part of the entire discussion. I agree with you. This is a discussion that I often have with patients as I am giving them azacitidine as to when I will refer them to transplant, and I try to encourage that early in the process.
Transcript Edited for Clarity