Presence of MRD After Chemotherapy May Predict Benefit From Donor Transplant in NPM1-Mutated AML

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Among patients who have acute myeloid leukemia (AML) with genetic mutations in NPM1, those with no residual leukemia cells in the blood based on high-sensitivity testing after two cycles of chemotherapy achieved high rates of overall survival at 3 years and saw no additional survival benefit from undergoing a donor stem cell transplant. Conversely, among patients who had residual leukemia cells in the blood, those who received a donor stem cell transplant had improved survival compared with those who did not undergo a transplant. These findings were presented at the 2023 ASH Annual Meeting & Exposition (Abstract 425).

“To our knowledge, this is the largest study to examine whether measurable residual disease (MRD) after two cycles of chemotherapy could identify which patients with NPM1-mutated AML would benefit from a transplant,” said presenting investigator Jad Othman, MBBS, of Guy's and St. Thomas' NHS Foundation Trust. “In all of the disease subgroups we looked at, the answer is yes, it did—and it was the only thing that did.” 

In the current study, patients who were MRD-positive had improved survival when they received a stem cell transplant, whereas among patients who were MRD-negative, researchers could not identify any subgroup that showed a survival benefit from a transplant, Dr. Othman explained.

AML is classified as favorable-risk, intermediate-risk, or adverse-risk based on the presence or absence of certain genetic mutations, he said. While a transplant of healthy blood cells from a donor can sometimes be a cure for AML, studies have shown that patients with favorable-risk disease generally do well with chemotherapy and that the risks and side effects of a transplant outweigh the benefits. On the other hand, patients with adverse-risk AML generally do poorly with chemotherapy and are likely to benefit from a transplant. For patients with intermediate-risk AML, Dr. Othman said, the relative benefits of chemotherapy and donor stem cell transplantation are unclear. 

The NPM1 mutation is the most common genetic risk factor seen in adult patients younger than age 60 with AML. Patients with the NPM1 mutation are generally deemed to be favorable-risk, whereas those with the FLT3 mutation are considered intermediate-risk. For the subgroup of patients with both mutations, however, it’s been unclear whether chemotherapy alone or chemotherapy followed by a transplant is the best approach.

Current Analysis: AML17 and AML19

Dr. Othman and his colleagues analyzed MRD data from 737 patients with NPM1-mutated AML who had achieved a complete response after being treated in one of two large phase III randomized clinical trials—AML17 and AML19—that were conducted in the United Kingdom, Denmark, and New Zealand. Both trials enrolled newly diagnosed adult patients with AML who were fit for intensive chemotherapy. A subset of 238 patients had both NPM1 and FLT3 mutations. The researchers compared patients’ outcomes based on their mutation status (NPM1 only or both NPM1 and FLT3), whether or not they underwent a donor transplant, and whether they were MRD-positive or MRD-negative when tested after two rounds of chemotherapy. 

Across both trials, among MRD-negative patients, 3-year overall survival was 75% for those enrolled in AML17 and 83% for those in AML19. Receiving a donor transplant did not further improve survival for patients who were MRD-negative. By contrast, 3-year overall survival among MRD-positive patients who underwent a donor transplant was 61%, compared with 24% for those who did not receive a donor transplant. 

In the subset of patients with both NPM1 and FLT3 mutations who were MRD-positive, 3-year overall survival was 22% in AML17 and 31% in AML19, and patients undergoing transplant had improved survival. Among those with both mutations who were MRD-negative, 3-year overall survival was 75% in AML17 and 80% in AML19. Again, for those who were MRD-negative, undergoing a donor transplant did not improve survival. 

“Patients who are MRD-negative after two courses of chemotherapy have a low risk for relapse,” Dr. Othman said. “We saw no evidence that donor transplantation was of benefit to MRD-negative patients, including those with the FLT3 mutation. By contrast, we saw a significant survival benefit for MRD-positive patients who underwent a donor transplant after achieving a complete response to chemotherapy. We think this supports making MRD status after two rounds of chemotherapy a major part of the process for selecting patients who are likely to benefit from transplantation.”

A limitation of the study findings, he said, is that there are several methods of high-sensitivity testing for MRD, and it’s unclear whether the use of a different testing method would have produced the same results. Moreover, not all cancer treatment centers currently have access to high-sensitivity testing. 

Disclosure: The study was funded by the Cancer Research UK. For full disclosures of the study authors, visit

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