ASH 2025 | Results from PARADIGM: aza-ven versus conventional chemo for newly diagnosed fit adults with AML

So at this year’s ASH meeting, I’ll be happily presenting the results of PARADIGM, which is a randomized phase two study that compares azacitidine and venetoclax versus traditional intensive chemotherapy for acute myeloid leukemia, fit patients with acute myeloid leukemia. For over five decades, the treatment of fit patients with AML has been intensive induction chemotherapy, which is quite toxic and quite challenging and hard for patients, requiring long hospitalizations, marrow suppression, bleeding, infectious complications are quite common, and finding an alternative has been challenging. Several years ago, the VIALE-A Phase III study showed that azacitidine and venetoclax combination was better than azacitidine in older induction ineligible patients. So that became the standard of care for those folks. But the composite remission, the activity, the tolerability of that combination made us think that perhaps in younger patients, the results would be even more promising and could potentially compete with intensive chemotherapy. That regimen can also be given in the outpatient setting and has very low early mortality and morbidity. 

So we designed a phase two study to compare traditional intensive chemo to this combination of azacitidine and venetoclax. It is important to note that the patients that were enrolled were induction eligible, traditionally transplant eligible patients. We did exclude certain patients for good reasons. So patients with FLT3 mutations were excluded because they potentially could be randomized to an arm that did not include an FDA approved FLT3 inhibitor. Patients with core binding factor alterations were excluded, relatively small proportion of patients, but they could have been randomized to an arm that did not include gemtuzumab ozogamicin, which is also approved in combination with intensive chemotherapy. We excluded younger patients with NPM1 mutations, but not older patients with NPM1 mutations because these younger patients oftentimes receive not transplant, but consolidation chemo as an intensive therapy. So these groups were excluded. And therefore, the results and data and outcomes that emerged do not apply, in my opinion, to those groups, but still to a sizable proportion of intensive induction chemotherapy patients. 

The eligible patients were then randomized one-to-one to intensive chemotherapy, and the following paradigm of intensive induction followed by intensive consolidation was followed as needed. And patients that received the aza-venetoclax received repeating cycles of azacitidine-venetoclax. And upon response, patients on both arms could come off and go to stem cell transplant, which we actually encouraged when able. 

In terms of the results, the patient populations on both arms were pretty equal. The median age was around 65. Most patients were male. The majority were adverse risk because of the eligibility criteria, but about somewhere around 30%, maybe a little bit less, a sizable minority had favorable intermediate risk disease. So a good proportion of these patients were also in that population. The event-free survival, which was the primary endpoint of this study, was superior for azacitidine and venetoclax, and significantly so. Even after multivariable analysis, looking at age, adverse risk profiles, as well as mutations, azacitidine and venetoclax remain protective of EFS. Overall survival, we’re presenting that it was not statistically significant. My opinion possibly related to a lot of crossover. This type of thing where you’re comparing a low-intensity regimen to a high-intensity regimen, you can’t really do a placebo control. So many patients who get intensive chemotherapy and do not respond to it ultimately go and receive azacitidine and venetoclax. So the interpretability of OS is challenging in that type of setting. 

Response rates were quite impressive. Overall response for azacitidine and venetoclax significantly better. Composite remission significantly better. CR plus CRi significantly better. I’m sorry, CR plus CRh. CR by itself, numerically favoring azacitidine-venetoclax, but not significantly different. Transition to transplant. So patients who got azacitidine-venetoclax on study, more likely to go to transplant than those patients who received intensive chemotherapy which I believe is a very important secondary endpoint. Quality of life metrics anxiety depression all of those things significantly improved probably not surprising for patients who received azacitidine and venetoclax. Hospitalization metrics the duration the duration of time in the hospital, hospitalized, within the first index hospitalization as well as six months out, fewer for patients with azacitidine and venetoclax, also probably not surprising. Admission to the intensive care unit during the first 30 days: 10% for intensive chemo, zero for azacitidine and venetoclax. Dying, chance of dying within the first 60 days: 5% for intensive chemotherapy, zero for azacitidine venetoclax. 

So overall, when you look at all of this data together, I think in terms of both the primary endpoint EFS as well as tolerability and other important secondary endpoints, this supports the use of azacitidine and venetoclax in induction-eligible, traditionally transplant-eligible, intermediate adverse risk AML patients without a FLT3 mutation.

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