NEW ORLEANS – Investigators say they were “amazed” by the results of a randomized trial showing that patients with acute myeloid leukemia who respond poorly after induction therapy do just as well in undergoing an immediate allogeneic transplant as if they had received an intensive rescue induction regimen to bring them into remission before the transplant.
The results come from the ASAP Phase 3 trial and were presented here at the annual meeting of the American Society of Hematology.
“We chose this to be in plenary because it completely changes the way we think about acute myeloid leukemia,” commented briefing moderator Mikkael A. Sekeres, MD, of the University of Miami Miller School of Medicine, who also serves as chair of the ASH Committee on Communications.
“When we have a patient who has relapsed or refractory AML, that person is in a very, very difficult situation, and the mortality among these types of patients is incredibly high,” Sekeres commented. “So traditionally we’ve given them very high doses of chemotherapy to try to reduce the tumor burden – at least that’s the theory – and then successfully get them into a transplant.”
This new finding “completely shakes that up, if these results hold,” he said. The clinical implication is that “we no longer have to hospitalize these patients and give them very aggressive chemotherapy…[and] we’re not introducing all the morbidity by giving them very high dose chemotherapy, which can actually prevent a transplant from happening if they get sick enough, and we can get them to a transplant faster.”
The ASAP trial was conducted in patients with adverse risk AML who had either a poor response to the first induction treatment or a relapse after the first induction treatment.
They were randomly assigned to either a remission induction strategy aimed at better response before allogeneic hematopoietic stem cell transplantation (alloHCT) or a disease control strategy consisting primarily of watchful waiting with cytarabine low-dose and single doses of mitoxantrone as needed, followed by sequential conditioning and alloHCT.
Results after 4 years of follow-up showed no difference in leukemia-free survival or overall survival between patients who underwent additional chemotherapy with the remission induction strategy and those who went directly to transplant, reported Johannes Schetelig, MD, MSc, of the DKMS Clinical Trials Unit in Dresden, Germany.
“We expected non-inferiority – that’s what we tested, and of course that was based on the assumption that we could get closer or even a little better on the primary endpoint, survival. disease-free, post-transplant,” he said.
“What we didn’t expect was that the early success, [complete response] day 56 post-transplant also translates to equal long-term benefit, so that’s what really amazed me,” Schetelig said at a press briefing ahead of his presentation.
Less intensive approach
Schetelig explained that the rationale for the study was previous work by his group and others showing that alloHCT in patients with residual aplasia after the first induction is feasible, with favorable results compared to the standard of care, and also evidence that sequential conditioning based on high-dose cytarabine or melphalan combined with reduced-intensity conditioning and alloHCT resulted in long-term control of relapsed or refractory AML.
He also gave details of the two treatment arms of the ASAP trial. The remission-inducing arm consisted of cytarabine (3 g/m2 for younger patients or 1 g/m2 for patients over 60) twice daily on days 1-3 plus 10 mg/m mitoxantrone2 on days 3-5 and following alloHCT. In the other group – disease control before sequential conditioning and alloHCT – watchful waiting was recommended, but low-dose cytarabine (LDAC) and single doses of mitoxantrone were allowed for disease control.
Although, as noted by Schetelig, the statistical objective of the study was to show non-inferiority of the disease control arm, this less intensive strategy met expectations for achieving the primary endpoint of disease-free survival (DFS; one sustained complete response) by day 56 after alloHCT.
In an intention-to-treat and per-protocol analysis, the respective 56-day DFS rates in the disease control group were 83.5% and 84.1%. In comparison, the respective rates in the remission-induction group were 81% and 81.3%.
Additionally, after a median randomisation follow-up of 37 months, there was no difference in leukemia-free survival or overall survival up to 4 years after DSS at day 56.
The disease control strategy was also associated with significantly fewer grade 3 or higher adverse events (23% versus 64%, P < 0.001), and fewer days in hospital before transplant (mean 19 versus 42, P < .001). There were no significant differences between the trial arms in deaths within 28 days of randomisation or time to discharge from hospital (28 days in each arm).
“These data support sequential conditioning and alloHCT without prior remission induction chemotherapy whenever a stem cell donor is readily available,” the researchers concluded.
“These results underscore the importance of facilitating alloHCT as [the] most effective anti-leukemia therapy in patients [relapsed or refractory] AML and stress the need to start the search for donors as soon as the diagnosis is made,” they added.
The study was sponsored by DKMS gemeinnützige GmbH. Schetelig disclosed fees from BeiGene, BMS, Janssen, AstraZeneca, AbbVie and DKMS. Sekkeres did not report any relevant financial relationships.
American Society of Hematology (ASH) 2022 Annual Meeting: Abstract 4. Presented December 10, 2022.
Neil Osterweil, award-winning medical journalist, is a longtime and frequent contributor to Medscape.
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