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Molecular MRD Testing Identifies Patients with NPM1mut AML Who May Benefit From Allogeneic Transplant

April 18, 2024

May 2024

Lara C. Pullen, PhD

Lara C. Pullen, PhD, is a freelance medical writer in Chicago, Illinois.

New research indicates that post-induction molecular measurable residual disease (MRD) reliably identifies those patients with NPM1-mutated (NPM1mut) acute myeloid leukemia (AML) who benefit from allogeneic transplant in first remission. Likewise, patients who achieve MRD negativity in blood after second induction show no survival benefit from allogeneic transplant in first complete remission (CR1-allo), even if they have FLT3 internal tandem duplication (ITD). Jad Othman, MBBS, a hematologist at Guy’s Hospital and King’s College in London, and colleagues published their results from the largest study to date to examine the role of CR1-allo in NPM1mut AML in Blood.

Approximately one-third of patients with AML have the NPM1 mutation. Hematologists have long recognized that select patients with NPM1mut AML may benefit from a bone marrow transplant, although there is still debate about exactly which patients are most likely to benefit. Approximately 40% of patients with NPM1mut AML have FLT3- ITD, and early research suggested that CR1- allo only improved overall survival (OS) for these patients.

In the current study, the researchers used prospective data from the U.K. NCRI AML17 and AML19 studies to examine the effect of CR1-allo according to peripheral blood NPM1 MRD status measured by real-time quantitative polymerase chain reaction after two courses of induction chemotherapy. They found that 19% of the 737 patients who achieved remission were MRD positive. About half (46%) of MRD-positive patients received CR1-allo, as did 17% of MRD-negative patients. The investigators observed significant heterogeneity of OS benefit from CR1-allo according to MRD status, with substantial OS advantage for MRD-positive patients (3-year OS with CR1-allo of 61% vs. 24% without; hazard ratio [HR] = 0.39; 95% CI 0.24-0.64; p<0.001) but no benefit for MRD-negative patients (3-year OS of 79% vs. 82%; HR 0.82; 95% CI 0.50-1.33; p=0.4). When the investigators restricted their analysis to patients with AML with co-existing FLT3-ITD, they again found that CR1-allo only improved OS for MRD-positive patients. They noted, however, that their findings were limited by the fact that patients were not treated with effective frontline FLT3 inhibitors.

Richard Dillon, MD, PhD, a hematologist at Guy’s Hospital and King’s College and corresponding author for the paper, explained that “bone marrow transplant is a very effective procedure, but it has severe short- and long-term toxicity.” Not only are the side effects significant, but the financial cost is high, in the hundreds of thousands of dollars. Molecular MRD testing is extremely predictive of disease outcome, and his study demonstrated that “it’s only the patients who are MRD-positive (less than one-quarter) who benefit from the transplant.” Moreover, the new data indicate that there is no survival benefit for transplantation in patients who are MRD-negative with co-existing FLT3-ITD AML, which until now has been considered by some to be an indication for transplant.

Dr. Dillon suggested, therefore, that instead of giving patients who are MRD-negative an early transplant, hematologists could perform regular serial molecular monitoring to detect emerging relapse. Transplant can then be reserved for those patients who have early evidence of disease progression. The authors noted, however, that MRD assays are not commonly available.

“It’s not a very complicated lab test, actually,” Dr. Dillon said. “The equipment needed is available in most large molecular labs. However, expertise is essential to avoid generating misleading results, and this requires a degree of centralization. We have six labs in the U.K. who are doing this routinely, but we have worked very closely together to ensure that robust technical controls are in place and have developed an external quality assurance program.” He explained that in Europe, the testing tends to be performed in centralized academic laboratories, whereas in the U.S., it is performed at academic universities and by private providers. “Worldwide, the testing has become widely available,” he said, “but in the U.S. less so because of all of the regulatory requirements.” He hopes that the robust data in the study will add momentum worldwide to the practice of routine MRD testing for this patient population.

“MRD testing has really changed the way we manage our patients for the better,” Dr. Dillon said. He estimated that in the U.K., MRD testing allows hematologists to save hundreds of patients a year from the financial and health burdens of a transplant. He was still surprised by the clarity of the results and by the positive reactions to the data from around the world.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Othman J, Potter N, Ivey A, et al. Post induction molecular MRD identifies patients with NPM1 AML who benefit from allogeneic transplant in first remission [published online ahead of print 2024 February 16]. Blood. doi: 10.1182/blood.2023023096.

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