Measurable Residual Disease in AML Ups Post-HSCT Relapse Risk

Nancy A. Melville

June 14, 2019

For patients with acute myeloid leukemia (AML), the presence of measurable residual disease (MRD) prior to bone marrow transplant significantly increases the risk for relapse among patients who receive a reduced-intensity conditioning regimen, compared to those with no MRD. This suggests that patients for whom there is evidence of MRD should receive higher-intensity conditioning, say researchers reporting a new analysis from the phase 3 trial known as 0901.

"This is the first demonstration from a randomized clinical setting that choosing different therapy for AML patients with MRD can improve survival," Christopher Hourigan, DM, DPhil, of the Laboratory of Myeloid Malignancies, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, told Medscape Medical News.

"For patients with no genomic evidence of residual disease pretransplant, survival for reduced-intensity conditioning and high-intensity myeloablative conditions was not different," he added.

Previous studies have shown that use of a conditioning regimen of reduced intensity prior to allogeneic hematopoietic stem cell transplant, instead of the usual high-intensity myeloablative regimen, yields encouraging outcomes for some patients and lessens toxicity for AML patients in remission.

However, in the previously reported phase 3 0901 clinical trial, the Blood and Marrow Transplant Clinical Trials Network included AML patients in remission and found a substantially higher relapse rate with the lower-intensity approach.

That study was stopped early, owing to a clear survival benefit for those who received high-intensity myeloablative conditioning.

"Strikingly, over half of AML patients receiving reduced-intensity conditioning relapsed within 18 months after transplant," Hourigan said.

The new analysis of data from this trial, presented by Hourigan here at the European Hematology Association (EHA) 2019 Annual Meeting, examined the factors that played a role in the increased relapse risk.

Hourigan and his colleagues evaluated preconditioning samples from 188 AML patients in the 0901 trial. The patients were well matched with respect to baseline characteristics, including age, sex, disease risk, donor type, donor match, and graft type.

They found that 31% of patients in the high-intensity myeloablative group and 33% in the reduced-intensity group had no genomic variants indicative of MRD. Subsequent survival rates did not differ among those groups (3-year overall survival: 58% vs 65%; P = .98).

However, among the patients who did have detectable variants indicative of MRD prior to conditioning, the 3-year overall survival rate was significantly better for the patients in the high-intensity conditioning group than for those in the reduced-intensity group (61% vs 44%; P = .02).

Overall, of patients who experienced relapse, 76% had at least one detectable variant prior to conditioning.

After adjusting for factors that included the level of disease risk and donor group, patients with detectable variants indicating MRD who went on to receive the reduced-intensity conditioning had a nearly six times greater risk for relapse (hazard ratio [HR], 5.98; 95% confidence interval [CI], 3.19 – 11.26; P < .001).

For these patients, disease-free survival was also significantly decreased (HR, 2.80; 95% CI, 1.76 – 4.44; P < .001), as was overall survival (HR, 2.16; 95% CI, 1.30 – 3.60; P = .003), when compared to the higher-intensity conditioning group.

Although in the original trial, mortality related to toxicity from the treatment itself was significantly higher among the patients who received the high-intensity regimen, the new findings suggest the risk/benefit balance may be offset by this MRD finding, say the researchers.

"We show that overall increased toxicity for those in the high-intensity myeloablative arm was balanced by a reduced risk of AML relapse in those with genomic evidence of residual disease pretransplant," Hourigan said.

The findings provide important evidence that MRD can play a key role in allowing a more personalized approach to therapy, Hourigan added.

"As a physician who treats acute leukemia patients, these findings for me open up many interesting questions and some obvious opportunities for potentially improving the therapeutic outcomes for our AML patients," he said.

"[A question], for example, is whether maintenance therapy with recent approved targeted agents, such as FLT3 [fms-like tyrosine kinase 3] or IDH [isocitrate dehydrogenase] inhibitors, have a role in reducing relapse in those receiving reduced-intensity conditioning prior to transplant," Hourigan said.

The researchers assessed MRD using a next-generation ultra-deep error-corrected genomic sequencing technology that is currently available only for research purposes, Hourigan explained. But he said the findings underscore a role for MRD testing in the future.

"It is easy to imagine a future where transplant physicians routinely integrate information regarding AML residual disease into their therapeutic decision making," he said.

The European Leukemia Network's international AML MRD expert consensus committee (of which Hourigan is a member) recently released guidelines on clinical testing of MRD in AML using existing technologies, such as polymerase chain reaction and flow cytometry.

"Potentially Practice Changing," but Needs Confirmation

Approached for comment on the study, Charles Craddock, MD, MPH, a professor of hemato-oncology at the Center for Clinical Hematology, Queen Elizabeth Hospital, Birmingham, United Kingdom, agreed that the study leaves open the question of whether other assessment tools would show similar results.

"It would be extremely interesting to see if the same effect of relapse would be seen using bone marrow assessment with standard flow cytometry," he told Medscape Medical News.

The study offers valuable insights that need further validation, he said.

"This is an important study because it's one of the first prospective analyses of the impact of measurable residual disease on the outcome of a transplant," Craddock said.

"These are potentially practice-changing data, but they need to be confirmed in further prospective randomized trials," he added.

"Unlike how we assess new drugs, with large, randomized controlled trials conducted before a drug is approved, there are very few good, large, prospective trials assessing innovations in transplantation, so the authors are to be applauded," he commented.

Hourigan has research relationships with Merck, Sellas Life Sciences, Qiagen, Archer, Janssen, and Novartis as an NIH official on advisory boards. Craddock has disclosed no relevant financial relationships.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract LB2600. Presented June 14, 2019.

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