Investigators from the Mass General Brigham Cancer Institute have found that adults with newly diagnosed acute myeloid leukemia (AML) receiving a less-intensive combination of azacitidine and venetoclax had more than twice as much time before treatment failed, the leukemia returned or worsened, or they died, compared with patients receiving intensive chemotherapy. Published in The New England Journal of Medicine , the findings could change the initial treatment approach for many patients with AML.
"Less-intensive treatment does not necessarily mean less-effective treatment," said lead author Amir T. Fathi, MD, 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 less-intensive combination is already used in older patients or those unable to tolerate intensive chemotherapy. The PARADIGM trial tested whether it could work as well—or better—for patients who could receive intensive chemotherapy, including younger patients.
The phase 2 clinical 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.
Patients receiving the 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 leukemia into a remission state in 78% of patients receiving the combination and 53% of those receiving intensive chemotherapy. Patients receiving the combination also had fewer serious infections and bleeding problems. In the first 30 days, patients 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%, compared with 40% 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 should test less-intensive treatments in excluded groups, including patients younger than 60 with NPM1-mutated AML and those with FLT3-mutated AML.
Authorship: In addition to Fathi, Mass General Brigham authors include Brandon J. Aubrey, Timothy A. Graubert, Peter Westervelt, Philip C. Amrein, Hanno R. Hock, Andrew M. Brunner, Gabriela Hobbs, Rupa Narayan, Michelle H. Lee, Peter G. Miller, Alyssa L. Watson, Richard Hao, Abigail C. Marola, Jennifer Lombardi-Story, Shilton Dhaver, Yi-Bin Chen, Ian McGovern and Areej El-Jawahri.
Additional authors include Alexander E. Perl, Geoffrey G. Fell, Brian A. Jonas, Brittany K. Ragon, Alice S. Mims, Uma Borate, Gabriel N. Mannis, Karen Quillen, Maximilian Stahl, Paul Koller, Andrew S. Artz, Monzr M. Al Malki, Anthony S. Stein, Guido Marcucci, Mary Linton B. Peters, Michael R. Grunwald, Matthew J. Weinstock, Andrew H. Matthews, Brent L. Wood, Christopher S. Hourigan, Donna S. Neuberg and Ibrahim Aldoss.
Paper cited: Fathi AT et al. "Azacitidine–Venetoclax or Induction Chemotherapy for Acute Myeloid Leukemia" N Engl J Med DOI: 10.1056/NEJMoa2602804
