A less-intensive treatment protocol for adults with newly diagnosed acute myeloid leukemia (AML) is more effective than the current standard of care, according to the results of a phase 2 clinical trial led by investigators at Harvard Medical School, Massachusetts General Hospital, Dana-Farber Cancer Institute, University of Pennsylvania Perelman School of Medicine, and City of Hope National Cancer Center in Duarte, California.
If the findings, published Sept. 2 in the New England Journal of Medicine, are replicated in phase 3 studies, they could change the initial treatment approach for many patients with AML, a blood cancer that starts in the bone marrow.
“Less-intensive treatment does not necessarily mean less-effective treatment,” said co-first author Amir Fathi, HMS professor of medicine at Mass General and director of the Leukemia Program at the Mass General Brigham Cancer Institute. “Our goal is to optimally treat acute myeloid leukemia while reducing serious complications and the amount of time patients spend in the hospital.”
The National Cancer Institute estimates that more than 80,000 people are currently living with AML in the United States, with about 22,720 people predicted to be newly diagnosed in 2026 and about 11,500 people anticipated to die from it this year. About one-third of people survive five years or more after diagnosis. AML is more common in older adults.
The trial found that participants receiving a treatment known as hypomethylating therapy — a combination of the drugs azacitidine and venetoclax — had more than twice as much time before treatment failed, the leukemia returned or worsened, or they died, compared with participants receiving the standard therapy, known as induction chemotherapy.
Induction chemotherapy is a long-standing keystone of AML treatment for patients who can tolerate it. However, it frequently has severe side effects. Hypomethylating therapy is the standard second choice, especially in older patients.
The PARADIGM trial tested whether hypomethylating therapy could work as well — or better — for patients who could receive intensive chemotherapy, including younger patients.
A new PARADIGM for AML
The trial randomly assigned 172 adults eligible for intensive chemotherapy at nine U.S. centers to azacitidine plus venetoclax or intensive chemotherapy. Nearly three-quarters had harder-to-treat forms of AML.
Participants receiving the less-intensive combination went 14.5 months before treatment failed, the leukemia returned or worsened, or they died, compared with 6.2 months for those receiving intensive chemotherapy.
Treatment brought AML into a remission state in 78 percent of participants receiving the combination and 53 percent of those receiving intensive chemotherapy.
Participants receiving the combination also had fewer serious infections and bleeding problems.
In the first 30 days, participants spent 12.5 days in the hospital with the combination versus 27.3 days with intensive chemotherapy.
More patients receiving the gentler combination then proceeded to stem cell transplantation: 60 percent, compared with 40 percent of those receiving intensive chemotherapy.
“For decades, intensive chemotherapy has been the standard upfront treatment for patients considered able to tolerate it,” Fathi said. “Our findings suggest that some of these patients may do better with a less-intensive approach.”
The trial was not designed to show whether either treatment helped patients live longer. Future studies are needed to test less-intensive treatments in excluded groups, including patients younger than 60 with NPM1-mutated AML and those with FLT3-mutated AML.
Additional collaborating institutions are Beth Israel Deaconess Medical Center; University of California, Davis, School of Medicine; Atrium Health Levine Cancer Institute at Wake Forest University School of Medicine; Ohio State University Comprehensive Cancer Center; Stanford Cancer Institute at Stanford University; Yale University School of Medicine; Children’s Hospital Los Angeles; and Fralin Biomedical Research Institute (FBRI) at Virginia Tech Cancer Research Center.
Adapted from a Mass General Brigham news release.
Authorship, funding, disclosures
Alexander E. Perl of Penn Medicine and Geoffrey G. Fell of Dana-Farber are co-first authors with Fathi. Areej El-Jawahri of Mass General Brigham and Ibrahim Aldoss of City of Hope are co-senior authors. Additional authors include B.A. Jonas, B.K. Ragon, A.S. Mims, U. Borate, G.N. Mannis, K. Quillen, M. Stahl, B.J. Aubrey, P. Koller, A.S. Artz, M.M. Al Malki, A.S. Stein, G. Marcucci, M.L.B. Peters, T.A. Graubert, P. Westervelt, P.C. Amrein, H.R. Hock, A.M. Brunner, G. Hobbs, R. Narayan, M.H. Lee, P.G. Miller, A.L. Watson, R. Hao, A.C. Marola, J. Lombardi‑Story, S. Dhaver, M.R. Grunwald, Y.-B. Chen, M.J. Weinstock, A.H. Matthews, I. McGovern, B.L. Wood, C.S. Hourigan, and D.S. Neuberg.
Relevant disclosures include consulting for AbbVie, Genentech, AstraZeneca, Daiichi Sankyo, Astellas, Servier, Bristol Myers Squibb, BeOne Medicines, Azurity Pharmaceuticals, Thermo Fisher Scientific, Kura Oncology, and Syndax.
Funding for the conduct of this investigator-initiated study and the provision of venetoclax was provided by AbbVie and Genentech. The Harvard Cancer Center (support grant 5P30 CA006516) also provided funding for statistical and data support.
