Is Additional Treatment Needed Pretransplant in R/R AML?

Neil Osterweil

September 11, 2023

HOUSTON ― Should patients with acute myeloid leukemia (AML) for whom induction therapy fails to induce complete remission proceed to allogeneic hematopoietic stem cell transplant anyway? Or do these patients fare better when they receive an intensive salvage induction regimen to bring them into remission before transplant?

This critically important question was debated at the annual meeting of the Society of Hematologic Oncology (SOHO), held in Houston, Texas, and online.

Johannes Schetelig, MD, argued in favor of proceeding to transplant, even without a complete remission.

"In the past, I've told many patients with relapsed or refractory AML that we do need to induce a [complete remission] prior to transplantation," said Schetelig, from the Clinical Trials Unit at DKMS in Dresden. "But is it true?"

According to findings from a recent randomized trial, it may not be. The trial, led by Schetelig, found that patients with AML who received immediate allogeneic transplant without first having achieved a complete response following induction therapy did just as well as those who received intensive salvage induction therapy to establish remission before transplant.

If this finding holds, it "completely upends" how experts have traditionally approached patients with AML, Mikkael A. Sekeres, MD, from the University of Miami Miller School of Medicine, said at a conference press briefing last year.

The phase 3 ASAP trial, presented at last year's American Society of Hematology (ASH) meeting, included patients with AML who had had a poor response or who had experienced a relapse after first induction therapy. Patients were randomly assigned to a remission-induction strategy prior to allogeneic stem cell transplant (alloHCT) or a disease-control approach of watchful waiting followed by sequential conditioning and alloHCT. The primary endpoint was treatment success, defined as a complete response at day 56 following alloHCT.

In an intention-to-treat analysis, 83.5% of patients in the disease control group and 81% in the remission-induction group achieved treatment success. Similarly, in the per-protocol analysis, 84.1% and 81.3%, respectively, achieved a complete response at day 56 after alloHCT. After a median follow-up of 4 years, there were no differences in leukemia-free survival or overall survival between the two groups.

Another advantage to forgoing an intensive salvage induction regimen: Patients in the disease-control arm experienced significantly fewer severe adverse events (23% vs 64% in the remission induction arm) and spent a mean of 27 fewer days in the hospital prior to transplantation.

At last year's press briefing, Schetelig said his team did not expect that a complete response on day 56 after transplantation would translate into "equal long-term benefit" for these groups. "This is what I was really astonished about," he said.

Delving further into the findings, Schetelig explained that in the remission-induction arm, patients who had had a complete response prior to transplantation demonstrated significantly better overall survival at 4 years than those who had not had a complete response at that point: 60% vs 40%.

The study also revealed that in the disease-control arm, for patients under watchful waiting who did not need low-dose cytarabine and mitoxantrone for disease control, overall survival outcomes were similar to those of patients in the remission-induction arm who achieved a complete response.

These findings suggest that patients who can be bridged with watchful waiting may have a more favorable disease biology, and chemosensitivity could just be a biomarker for disease biology. In other words, "AML biology matters for transplant outcome and not tumor load," Schetelig explained.

A recent study that found that having minimal residual disease (MRD) prior to transplant "had no independent effect on leukemia-free survival" supports this idea, he added.

Overall, Schetelig concluded that data from the ASAP trial suggest that watchful waiting prior to alloHCT represents "an alternative" for some patients.

Counterpoint: Aim for Complete Remission

Ronald B. Walter, MD, PhD, argued the counterpoint: that residual disease before transplantation is associated with worse posttransplant outcomes and represents a meaningful pretransplant therapeutic target.

The goal of intensifying treatment for patients with residual disease is to erase disease vestiges prior to transplantation.

"The idea is that by doing so, you might optimize the benefit-to-risk ratio and ultimately improve outcomes," said Walter, from the translational science and therapeutics division at the Fred Hutchinson Cancer Research Center in Seattle.

Several reports support this view that patients who are MRD negative at the time of transplant have significantly better survival outcomes than patients with residual disease who undergo transplant.

A 2016 study from Walter and colleagues at Fred Hutchinson, for instance, found that 3-year overall survival was significantly higher among patients with no MRD who underwent myeloablative alloHCT: 73% vs 26% of those in MRD-positive morphologic remission and 23% of patients with active AML.

Another study, published the year before by a different research team, also revealed that "adult patients with AML in morphologic [complete remission] but with detectable MRD who undergo alloHCT have poor outcomes, which approximates those who undergo transplantation with active disease," the authors of the 2015 wrote in a commentary highlighting findings from both studies.

Still, providing intensive therapy prior to transplant comes with drawbacks, Walter noted. These downsides include potential toxicity from more intense therapy, which may prevent further therapy with curative intent, as well as the possibility that deintensifying therapy could lead to difficult-to-treat relapse.

It may, however, be possible to reduce the intensity of therapy before transplant and still achieve good outcomes after transplant, though the data remain mixed.

One trial found that a reduced-intensity conditioning regimen was associated with a greater risk of relapse post transplant and worse overall survival compared with standard myeloablative conditioning.

However, another recent trial in which patients with AML or high-risk myelodysplastic syndrome were randomly assigned to either a reduced-intensity conditioning regimen or an intensified version of that regimen prior to transplant demonstrated no difference in relapse rates and overall survival, regardless of patients' MRD status prior to transplant.

"To me, it's still key to go into transplant with as little disease as possible," Walter said. How much value there is in targeted treatment to further reduce disease burden prior to transplant "will really require further careful study," he said.

The ASAP trial was sponsored by DKMS. Schetelig has received honoraria from BeiGene, BMS, Janssen, AstraZeneca, AbbVie, and DKMS. Walter reported no relevant financial relationships.

Society of Hematologic Oncology (SOHO) Annual Meeting: Debate conducted on September 6, 2023.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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