Researchers have found that screening for residual disease prior to a bone marrow transplant may help physicians identify which adult patients in remission from acute myeloid leukemia (AML) are at risk of relapsing after the procedure, according to a novel study published by Dillon et al in JAMA. The findings support ongoing research aimed at developing precision medicine and personalized posttransplant care for these patients.
Background
AML accounts for 1% of all new cancer cases, and adults aged 65 years and older may be more likely to receive a diagnosis.
About 20,000 adults in the United States are diagnosed with the disease each year, with a 5-year survival rate of approximately 33%. While bone marrow transplants often improve patient survival, studies have shown that lingering traces of AML can make a transplant less effective.
Study Methods and Results
In the new study, the researchers used ultra-deep DNA sequencing technology to screen the blood samples of 1,075 adult patients in remission from AML in order to assess whether screening patients for evidence of low levels of AML could better predict their 3-year risk of relapse and survival. All of the patients involved in the study were preparing to have a bone marrow transplant.
After screening those with variants commonly associated with AML, the researchers established that its two most common genetic mutations—NPM1 and FLT3-ITD—could be used to track residual AML in the bloodstream. Among the 822 patients with NPM1 and FLT3-ITD mutations detectable at initial diagnosis, 17% of them (n = 142) still had residual traces of AML after therapy, despite being classified as in remission.
The researchers found that when compared with patients who did not have the NPM1 and FLT3-ITD mutations, the patients who did have the mutations demonstrated a 70% vs 21% rate of relapse and a 39% vs 63% rate of survival after 3 years.
“If I’m one of six [patients] waiting in a doctor’s office and we’re all being told we’re going in for a transplant and we’ve got the same risk, I want to know if I’m actually one of those five who has a 21% chance of relapse or if I am the one with a 70% chance of relapse,” emphasized senior study author Christopher S. Hourigan, MD, DPhil, a senior investigator and Chief of the Laboratory of Myeloid Malignancies at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH). “Having this increased risk for relapse may not impact a [patient’s] decision about having a bone marrow transplant, but it could influence their next steps in care. For that one [patient] out of six, the transplant often isn’t going to be enough. Other options might include also enrolling in a clinical research trial or considering additional or different therapies,” he added.
In their analysis, the researchers also observed that patients younger than age 60 who had persistent mutations—and received higher doses of chemotherapy and/or radiotherapy as part of their transplant preparation—were more likely to remain cancer-free after 3 years compared with those receiving lower doses.
They also found that patients who didn’t receive stronger treatment before the transplant had better prognoses when their lower-dose therapy included the chemotherapy melphalan. However, more research is needed to evaluate the potential benefits of melphalan and other treatments—including targeted therapy for patients with FLT3-ITD–mutated disease.
Conclusions
“This study confirms prior research and provides new important data showing why testing for residual disease before a transplant is critical,” highlighted Richard Childs, RADM, Clinical Director and Acting Scientific Director of the National Heart, Lung, and Blood Institute at the NIH. “This information can also empower physicians to tailor transplant strategies—including considering different pretransplant conditioning regimens and chemotherapies—to reduce [the] risk [of] relapse and improve the long-term chance [of] survival [in patients with AML].”
Disclosure: The research in this study was funded by the National Heart, Lung, and Blood Institute; the National Cancer Institute; the National Institute of Allergy and Infectious Diseases; the Health Resources and Services Administration; the Office of Naval Research; and the NIH Director’s Challenge Innovation Award. The Laboratory of Myeloid Malignancies also received additional funding from Sellas Life Sciences Group and the Foundation of the NIH AML Measurable Residual Disease Biomarkers Consortium. For full disclosures of the study authors, visit jamanetwork.com.
