A new paper published in the Journal of Clinical Oncology investigates how ultra-deep next-generation DNA-sequencing in patients with acute myeloid leukemia (AML) for measurable residual disease (MRD) could optimize effectiveness of allogenic transplant for patients who have gone into remission.
“We know that MRD before transplant predicts AML coming back after a transplant,” said Christopher S. Hourigan, DM, DPhil, of the National Heart, Lung, and Blood Institute, part of the National Institutes of Health. He is also the lead author of this paper. “The question we had is can we do anything about it? We can measure beyond a conventional clinical remission and find traces of leukemia in the body but will that just tell us what is coming next or can we intervene and actually do something about that fate?”
The paper titled “Impact of Conditioning Intensity of Allogenic Transplantation for Acute Myeloid Leukemia with Genomic Evidence of Residual Disease” looked at blood samples taken before myeloablative conditioning or reduced-intensity conditioning in patients treated on the Blood and Marrow Transplant Clinical Trials Network randomized phase 3 clinical trial 0901. Researchers used error-corrected DNA sequencing to look for detectable variants in 13 commonly mutated genes in AML. Of the patients who relapsed after transplantation, 71% had a mutation detectable in blood before conditioning.
They found those with detectable mutations responded differently based on the conditioning intensity they received. The central hypothesis was that the “benefit of myeloablative conditioning in preventing relapse in patients with AML in morphologic complete remission would be greatest for those with genomic evidence of residual leukemia,” according to their paper. They confirmed that patients in remission with detectable AML-associated mutations before an allogeneic hematopoietic cell transplant had a higher relapse rate and lower overall survival after transplantation when randomized to reduced intensity rather than myeloablative conditioning.
Hourigan said this is particularly important because it could give physicians a better insight into the treatment plan necessary for the best results. The biggest takeaway from the study is that detection of MRD in an AML patient in clinical remission before allogenic transplantation is not just fate, but that extra treatment can be effective in improving outcomes.
For Hourigan, it’s the first step in designing a test that could transform the way we treat AML. With the advent of targeted therapy for AML genetic subtypes, this research—and other studies like it—point to a future where doctors might use their understanding the genetic basis of an individual’s leukemia to personalize transplant therapy; “If you know what’s causing that particular person’s leukemia, then you can potentially track it and treat it,” he said.
The biggest question now is exactly what genes to test, and what to do with those results. While identifying mutations before transplant can help assess relapse risk, Hourigan said it’s important to realize that some of these mutations occur in aging adults without myeloid malignancy and those who had non-AML cancer after chemotherapy.
“I think the key thing we do now is use this same kind of testing on many more patient samples so we can figure out when it’s optimal to go to transplant or whether a patient also needs some additional therapy” he said. “I suspect it will go both ways once we start personalizing treatment on the basis of both the quantity and quality of any residual leukemia: some people will need more therapy than they are currently getting, but I think some people will be able to avoid some of it too.”
“We’re talking about the 1 in 10,000 cancer cells left in your body and we’re going after that. This is what MRD testing could help with—making sure we’re doing the right thing for each person individually.”