Could This Combo Boost Response in Tough AML Cases? | Amir Fathi, MD

So, my name is Amir Fati. I'm a leukemia specialist at Massachusetts General Hospital in Boston, Massachusetts. I direct the leukemia program there. And I am an associate professor of medicine at Harvard Medical School. This year at ASH, we are presenting data from Paradigm, which is a randomized phase two study of azacytidine and vanetoclax versus traditional conventional intensive induction chemotherapy for induction therapy eligible patients with AML. So as a way of background, intensive induction chemotherapy has been the standard of care in AML fit patients for over 50 years. It carries with it much challenge. It's quite marrow suppressive. It's disruptive to life. Patients are in the hospital for 30 to 35 days. Suppresses the marrow system, leading to bleeding and infectious complications in some, and multiple other costs and burdens to both patients, their providers, and the health care system. Nevertheless, it is what we had, and it provided a remission rate and allowed patients to then go from remission to transplant as a curative modality. Several years ago, the phase three Viale A study demonstrated that azacytidine and vanetoclax was superior to azacytidine alone in older patients, induction ineligible AML patients. And that became the standard of care for those induction eligible patients who could not receive intensive therapies. But the regimen was quite impressive in those patients. It led to a high remission rate. It was well tolerated. Less early, much less early mortality than would be expected with intensive therapy. So we thought we have this combination regimen in older patients. It's well tolerated. They do well with it. Chances are that younger patients may even do better with it, and it may compete well with traditional intensive chemotherapy. So we designed the paradigm study to compare azacytidine and vanetoclax to traditional conventional induction chemotherapy and enroll patients who were traditionally induction eligible, many of them younger. So the age cutoff was 18 years and up with a pathologically confirmed diagnosis of AML. We excluded certain subtypes, and this is important because these patients, the data does not refer to them because they were excluded. So patients with FLIT3 mutations were excluded because they had a chance of being randomized to an arm that did not include a FLIT3 inhibitor, which is FDA approved. Patients with core binding factor, a relatively small number of patients in the United States, were excluded because they could be randomized to an arm that did not include an approved antibody drug conjugate. Patients younger with MPM1 mutations were also excluded because they often don't get transplanted, they get consolidation intensive chemo. So these patients were excluded, but the remaining sizable subset of AML patients went on to be randomized one-to-one to azacytidine and vanetoclax versus intensive chemotherapy and received the treatment as per convention and prescription label on both arms. The primary endpoint was EFS, but there were multiple other secondary endpoints, OS, tolerability, safety, quality of life, hospitalization metrics, measurable residual disease, cost, you name it. The two arms were relatively equal, the median age was 64 and a half, most patients were male, most patients were adverse risk, although a sizable minority, almost 30%, were intermediate and favorable risk. They were fairly well matched. Overall, the study accrued well, 86 to each arm in a phase two study, and the primary endpoint was met. Event-free survival was markedly statistically significantly superior for ACEVN. Even after multivariable analysis where we addressed for variables such as age, risk classification and mutations, still ACEVN was protective for event-free survival. Overall survival was not statistically significant, but the challenge with overall survival is that many patients who progress on intensive chemotherapy on that arm end up getting azacytidine and vanetoclax or the cytobines. There is a lot of natural crossover which complicates the interpretation of overall survival. Response rates significantly improved with ACEVN, overall response, composite remission, CR plus CRI. CR not statistically different, but numerically improved with ACEVN. Transition to transplant, if a patient received azacytidine and vanetoclax, they're more likely to get to transplant than intensive chemotherapy on study. Quality of life, depression scales, anxiety scales, all better, probably not surprisingly, significantly so, .001 P value for azacytidine and vanetoclax. Time in the hospital, during the initial hospitalization and during the first six months, much less, significantly less, fewer days in the hospital for patients who got azacytidine and vanetoclax. Admission to the ICU in the first 30 days, 10% for intensive chemotherapy, zero for azacytidine and vanetoclax. 60-day mortality, 5% for intensive chemotherapy, zero for azacytidine. So overall, the favorability, the tolerability, and the EFS activity of azacytidine and vanetoclax in this patient population and their better transition to transplant, which is our ultimate goal, favors the use of azacytidine and vanetoclax in this patient population, intermediate adverse risk, transplant-eligible, induction-eligible patients who do not have flit-through mutation. So I'm hopeful that this will help transform the field, make things better for our patients. If our videos have helped you in any way, and you're able to, please consider making a donation to help us continue this important work. 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