The combination of the hypomethylating agent azacitidine and the BCL2 inhibitor venetoclax is an established regimen in older, unfit patients with acute myeloid leukemia (AML). Now, a phase II randomized trial indicates potential for less intensive therapy in the newly diagnosed fit population. In PARADIGM, the results of which were presented in the Plenary Session at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition, the combination significantly improved event-free survival—reducing risk by 43%—compared with conventional intensive induction chemotherapy.¹

Amir Fathi, MD

In 172 previously untreated transplant-eligible patients, the primary endpoint of median event-free survival was 14.5 months with azacitidine plus venetoclax vs 6.2 months with intensive chemotherapy (hazard ratio [HR] = 0.57; P = .0021). At a median follow-up of 16 months, the 1-year event-free survival rates were 53.4% and 36.0%, respectively. Response and transplant rates following study treatment were also higher with azacitidine plus venetoclax, reported Amir Fathi, MD, Associate Professor of Medicine at Harvard Medical School and Program Director of the Center for Leukemia at Massachusetts General Hospital, both in Boston. 

“We believe these data support the use of azacitidine and venetoclax in functionally fit, traditionally transplant-eligible patients with intermediate- or adverse-risk, FLT3 wild-type AML,” said Dr. Fathi. In an interview with The ASCO Post, he added, “Ultimately, what most leukemia physicians hope for is an eventual end to intensive induction chemotherapy for so many reasons. I would like this to be an entrée into the gradual movement of gentler therapy as an alternative in AML.”

Rationale and Endpoints

In explaining the rationale behind the PARADIGM trial, Dr. Fathi pointed out that for about 50 years, the standard upfront treatment for fit patients with AML has been intensive chemotherapy incorporating cytarabine and anthracyclines. “But despite advances for certain AML subsets, intensive chemotherapy continues to yield suboptimal outcomes for most of our patients,” he said. “More than that, it comes with substantial burden in terms of deep and prolonged severe marrow suppression, weeks-long hospitalizations, frequent infections and bleeding complications, mucositis, malnutrition, deleterious psychosocial effects, and increased risks of cardiac injury and secondary malignancies down the line.”

The VIALE-A trial established the superiority of azacitidine plus venetoclax over single-agent azacitidine in patients ineligible for intensive chemotherapy.² Retrospective studies have suggested this combination may also improve outcomes over intensive chemotherapy, but no prospective studies have established an advantage. “This prompted us to design our randomized study,” he commented.

I would like this to be an entrée into the gradual movement of gentler therapy as an alternative in AML.

— AMIR FATHI, MD

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Event-free survival was selected as the primary endpoint, Dr. Fathi said, because an overall survival advantage is likely to be difficult to demonstrate in a study in which one arm involves an intensive treatment and the other does not. “The challenge is that there is a lot of natural crossover” that impacts the interpretation of overall survival, he added. In PARADIGM, “a substantial proportion of patients who failed therapy with 7 + 3 [cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days] or CPX [CPX-351; liposomal daunorubicin/cytarabine] thereafter got a hypomethylating agent and venetoclax ... We didn’t follow them for response to subsequent therapies, but we recorded the next lines of treatment. But in practice, a lot of those patients who respond to these subsequent lines also then go to transplant too. So, there is this natural crossover that is impossible to placebo-control for in a study comparing intensive vs nonintensive arms,” he said.

“Even if we were to do a larger study—a phase III study—overall survival, in my opinion, is fraught with challenge because of this likely extensive crossover in both directions, mainly from intensive therapy to azacitidine and venetoclax,” Dr. Fathi noted. “That is a real challenge, and I think event-free survival serves a good purpose [as] a primary endpoint, however you want to study this.”

PARADIGM Details

The PARADIGM trial was conducted at nine U.S. academic centers and randomly assigned 172 untreated adults who were eligible for intensive induction chemotherapy to receive either azacitidine plus venetoclax or conventional intensive chemotherapy. In the latter arm, 54% of patients received 7 + 3 and 46% received CPX-351 for a median of two cycles; those treated with azacitidine plus venetoclax received a median of four cycles.

Exclusion criteria included core binding factor fusions, FLT3 mutations, and NPM1 mutations (unless NPM1-mutated patients were older than age 60). Following a response to therapy, all patients could proceed to hematopoietic cell transplantation. The median age was 64 years (aged < 65 years: 51%), 67% were male, 78% were White, and 72% had adverse risk factors.

The primary endpoint was event-free survival, with events defined as progressive disease, persistent disease prompting therapy change, relapse, hospice, or death. The median duration of follow-up was 21.9 months.

Other Outcomes Improved

When adjusted for key variables such as age, risk factors, and certain mutations, the event-free survival benefit with azacitidine plus venetoclax vs intensive chemotherapy was found to remain statistically significant (HR = 0.66; P = .0231). The proportion of patients proceeding to transplant was higher (61% vs 40%; P = .009), and although transplant overall appeared to confer a significant protective effect on event-free survival, the benefit of azacitidine plus venetoclax persisted after adjustment for transplant as a time-dependent variable (HR = 0.67; P = .0302).

Patients who received azacitidine plus venetoclax vs intensive chemotherapy also achieved higher overall response (88% vs 62%; P < .0001), complete remission (CR) plus CR with partial hematologic recovery (P = .0450), and composite remission (81% vs 55%; P < .001) rates. However, the CR rates did not significantly differ (59% vs 50%; P = .066), he reported.

Median overall survival with azacitidine plus venetoclax was 21.5 vs 18.6 months with intensive chemotherapy (P = .1873). Significant natural crossover was observed following study treatment: 67.6% of patients in the intensive chemotherapy arm who experienced relapses or were refractory subsequently received hypomethylating therapy plus venetoclax off study, compared with 47.2% of those in the opposite arm crossing over and receiving subsequent induction.

Safety Profile

The study showed that common therapy-related adverse events of grades 3 and 4 were mostly hematologic and occurred at similar rates between the arms. A significantly greater proportion of the intensive chemotherapy vs azacitidine plus venetoclax arm was found to experience grade 3 or higher treatment-emergent infectious complications (20.8% vs 15.1%; P = .04) and bleeding complications (6.3% vs 1.3%; P = .01). The 30- and 60-day mortality rates were both 0% with azacitidine plus venetoclax vs 3.5% and 4.7%, respectively, with intensive chemotherapy.

Additionally, patients treated with azacitidine plus venetoclax had a lower rate of intensive care unit (ICU) admission (0% vs 9.8%; P = .003) and experienced fewer hospitalizations (P < .001) than those who received intensive chemotherapy. Significantly better quality of life (P = .001) and less symptom burden (P = .019) and depression (P = .007) were also reported with azacitidine plus venetoclax.

DISCLOSURE: Dr. Fathi has received compensation for consulting with AstraZeneca, Takeda, Genentech, Syndax, Schrödinger, Servier, AbbVie, BMS, Prelude, Kura, Autolus, Genmab, Daiichi Sankyo, Novartis, Johnson & Johnson, Pfizer, and Astellas; and has received clinical trial support from AbbVie, Genentech, Kura, BMS, and Servier.

REFERENCES

1. Fathi AT, Pert A, Fell G, et al: Results from PARADIGM - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. 2025 ASH Annual Meeting & Exposition. Abstract 6. Presented December 7, 2025.
2. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.

Expert Point of View

Andrew Wei, MBBS, PhD, Hematologist, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, and Metcalf Fellow and Laboratory Head, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, introduced the PARADIGM trial during the Plenary Session at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition. He provided some background for the findings, noting that the 7 + 3 (cytarabine continuously for 7 days, along with short infusions of an anthracycline on each of the first 3 days) chemotherapy backbone has proven effective in younger patients with acute myeloid leukemia (AML) for years, but in older populations, efficacy is reduced, toxicity is increased, and clinical benefit is therefore limited.

Andrew Wei, MBBS, PhD

“In the last decade, there have been at least a dozen new agents approved for AML, and these have targeted the various hallmarks of cancer underpinning AML biology. BCL2 was the first oncogene identified as having pro-survival activity, and the first drug to target this was venetoclax. Venetoclax given with the hypomethylating agent azacitidine has delivered tremendous benefits to older patients, producing clinical responses comparable to that with intensive chemotherapy and a toxicity intermediate between azacitidine and 7 + 3,” he said.

“When we first see a patient with AML, the central question is whether that patient is fit for intensive chemotherapy. However, with the very high response rates observed for patients receiving venetoclax, a new clinical question has emerged: Is my patient who is otherwise fit for intensive chemotherapy potentially suitable for a less intensive option?” Dr. Wei said. “PARADIGM is an attempt to address some of the unanswered questions and also challenge one of the most established clinical regimens in AML, 7 + 3.”

Speaking with The ASCO Post, Dr. Wei commented that the study provides “more reassurance,” especially for patients older than age 60 or of borderline fitness, that there is now a “realistic alternative.” He said, “There is more work to be done regarding whether azacitidine–venetoclax is appropriate in specific subgroups, but I think that for certain situations now, the pendulum is moving more toward not delivering intensive therapy for everyone.”

Also commenting for The ASCO Post was Alison Walker, MD, MPH, MBA, Chief of the Medical Oncology Service and an AML specialist at Moffit Cancer Center, Tampa. “Dr. Fathi and colleagues presented important data at the ASH Plenary Session that attempts to answer a very important clinical question: Can we treat patients with newly diagnosed AML who are eligible for intensive chemotherapy with a hypomethylating agent plus venetoclax and achieve an equal or better response as with intensive chemotherapy?”

Alison Walker, MD, MPH, MBA

She highlighted that the trial reported a higher overall response rate with azacitidine plus venetoclax, comparable complete remission rates between the arms, and a lower rate of severe infection, improved quality of life, and less time in the hospital or intensive care unit, concluding, “Ultimately, we will need additional information about minimal residual disease and transplant outcomes as well as overall survival to further understand how to incorporate these data into treatment planning for patients, but these findings are potentially a step toward lower toxicity for all patients with AML.”

In closing, Dr. Wei highlighted key considerations that could influence interpretation of the trial results: “Patients under the age of 60 were excluded if a FLT3 mutation, NPM1 mutation, or core binding factor AML was present. Therefore, the utility of less intensive vs intensive therapy remains uncertain in these subgroups. It should also be noted that, despite randomization, imbalances in molecular profiles were present between the less intensive and intensive treatment arms for NPM1/IDH2 (35% vs 16%) and TP53 (11% vs 19%) mutations. We know that patients with NPM1/IDH2 mutations respond particularly well to azacitidine–venetoclax, and all patients have poor outcomes in the presence of mutated TP53. Another aspect of this trial was that patients in the intensive arm had a day 14 marrow [check], followed by a second induction if residual disease was present. It will be important to see the full details of the trial to determine the impact of this practice on event-free survival and complications related to therapy.”

DISCLOSURE: Dr. Wei has served on advisory boards and as a consultant for Johnson & Johnson, AbbVie, Servier, Gilead, Molecular Partners, BeOne Medicines (formerly BeiGene), Astellas, BMS, Pfizer, Geron, and Syndax; has received institutional research funding from Novartis, STORM Therapeutics, AbbVie, Servier, Johnson & Johnson, Syndax, Mendus, Dimericon, and AstraZeneca; and receives financial benefits related to milestone and royalty payments associated with the development of venetoclax received by the Walter and Eliza Hall Institute. Dr. Walker reported no relevant conflicts of interest.

MORE INFORMATION

To hear more from Amir Fathi, MD, on the results of the PARADIGM trial from the 2025 ASH Annual Meeting & Exposition, see a video on The ASCO Post Newsreels at ascopost.com/videos.