Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 17
Harry P. Erba, MD, PhD: One of the issues about transplant is how we get patients with AML [acute myeloid leukemia] to transplant. Is transplant the end of the road, or should we be thinking about maintenance for many of our patients, especially those with higher-risk disease? At last year’s ASH [American Society of Hematology Annual Meeting] and ASCO [American Society of Clinical Oncology Annual Meeting], there was an update of the study led by Jeff Lancet, of CPX-351, the liposomal daunorubicin-cytarabine formulation vs standard 7+3 chemotherapy in patients with AML, with myelodysplasia-related changes and therapy-related AML. The 5-year update showed continued improvement in overall survival for the patients who were randomly assigned to CPX-351 [cytarabine, daunorubicin].
What was most impressive in this group is that, at 5 years, if you landmark the survival from the time of transplant, that is when the benefit was most pronounced with 40% of patients still alive compared with 20% in the 7+3 chemotherapy arm, and most of those patients had undergone transplant. The subset analysis and the landmark analysis from this phase 3 study suggested that receiving CPX-351 [cytarabine, daunorubicin] for some reason led to better outcomes postallogeneic stem cell transplantation for these high-risk patients.
Eunice, I want to turn to ask you about patients who you think are going to go to transplant with this high-risk disease. Do you consider CPX-351 [cytarabine, daunorubicin] for them, or are you moving on to using HMA [hypomethylating agent]-venetoclax combinations, which have also been shown to be useful as a bridge to transplant from the phase 1b data that were presented by Keith Pratz? Eunice?
Eunice S. Wang, MD: This is another hotly debated topic, and I have colleagues in my service at Roswell Park Comprehensive Cancer Center that fall on both sides of that argument. My preference is that, if there is a patient who is younger and fit, has a poor prognosis, complex karyotype, and therapy-related AML MRC [myelodysplastic-related changes], who is able to tolerate therapy based on their comorbidities and overall outlook in an intensive regimen, my inclination is to offer CPX-351 [cytarabine, daunorubicin].
It is rare in a leukemia meeting to see 5-year overall survival for any study. Most of our studies, particularly those in the relapsed/refractory setting and even in the up-front setting, only have 2 or 3 years of follow-up because everybody is dead at that time. To have 5-year data showing a significant percentage and an improvement, as well as the compelling landmark data post-transplant, that gives you some hope that, if you can take a patient to CPX-351 [cytarabine, daunorubicin] and then take them to a transplant, you can tell them that there is a 40% 5-year survival. That is remarkable even though the numbers are small.
There are individuals, however, for whom the toxicity of induction chemotherapy, whether it’s in a liposomal formulation or just standard 7+3 chemotherapy, may be prohibitive. There are patients who go into induction looking great, then they get septic, go to the unit, get on pressors, and almost die, and they come on out. With those patients, even though we would love to take them to transplant with Corey Cutler’s group particularly, we would hesitate. There are some patients in whom I now use oral azacitidine, CC-486, as an alternative to transplant, because I feel they would not tolerate a transplant well. There are those who, even in the up-front setting, do not look that great, and you know this person has bad disease—save, for example, complex karyotype TP53-mutant disease.
You know that for 7+3 chemotherapy, even liposomal 7+3 chemotherapy, the subgroup analysis by Coleman Lindsley and colleagues at Dana-Farber Cancer Institute with Dr Cutler says that patients who have TP53-mutant disease do not necessarily benefit in terms of overall survival from a CPX-351 [cytarabine, daunorubicin] induction regimen. There are those patients for whom we utilize that high response rate and tolerability of what I would call an intermediate-dose induction of venetoclax-azacitidine to get to transplant.
Keith Pratz and colleagues at Perelman Center for Advanced Medicine presented a small subset analysis of about 10% of patients receiving venetoclax-azacitidine in the phase 1b trial and in another clinical setting, but that 10% is about 30 patients. They showed that, in that small subset of patients who went to transplant, there were high response rates with subsequent transplant. That was a small subset as I said, and the initial eligibility for the phase 1 trial, as for many of these trials, is that you had to be unfit for transplantation or intensive chemotherapy at the time that you were enrolled in the trial. It raises the question that those patients may have been those who were sick from their disease, so they were clinically judged by the physician not well enough to undergo intensive chemotherapy, but with the achievement of two-thirds of those patients going into CR [complete remission], they improved functionally enough to go to transplant. There are a subset of patients for whom we want the opportunity to do that, so we do not exclude transplant as an option depending on how those individuals do with up-front venetoclax-azacitidine.
Harry P. Erba, MD, PhD: Eunice, you touched on a number of important topics, so I want to come back to some of them because they warrant being fleshed out a bit. Sasha, I am going to put you on the back burner for a second because I am going to come back to you to discuss TP53 mutations and APR-246, which has been shown to have activity in this subset of patients.
Transcript Edited for Clarity