New research from the real-world setting supports key thresholds of measurable residual disease (MRD) negativity in NPM1-mutated acute myeloid leukemia (AML) that can predict disease relapse.

The thresholds can provide important guidance to potentially spare patients from unnecessary stem cell transplantation (SCT) and better guide decision-making for optimal treatment.

The study underscores “that polymerase chain reaction [PCR] test for NPM1-mutated MRD is a powerful tool that can help [clinicians] accurately predict relapse months before its occurrence, providing enough time to take measures in order to prevent it,” first author Panagiotis Tsirigotis, MD, of the Division of Hematology, ATTIKON University Hospital in Athens, Greece, told Medscape Medical News.

The real-world findings show that “patients with a negative MRD test during follow-up can be safely followed without any intervention,” he added.

The study was published on April 10 in the American Journal of Hematology.

NPM1 mutation, among the most common mutations in adult AML, is known to occur in approximately 30% of patients with de novo AML. While the mutation is associated with favorable prognosis, its effect on disease outcomes can vary with confounding factors, including the concurrent presence of FLT3-ITD mutation, linked to adverse outcomes.

With NPM1 mutations known as true “founder mutations” that re-emerge prior to the time of relapse in most patients, they represent an ideal target for MRD monitoring, as is supported in clinical guidelines, the authors explained.

However, with real-world evidence on the issue, including optimal MRD thresholds for the prediction of relapse, lacking, the authors further investigated, analyzing data from the Hellenic AML Registry, and identifying 141 patients with newly diagnosed NPM1-mutated AML.

Of the patients, all were in complete remission or complete remission with incomplete hematologic recovery (CR/CRi) after the second cycle of induction, and all had results available from bone marrow MRD assessment, performed with the highly sensitive reverse transcription-quantitative PCR.

The findings showed that the threshold of < 0.1% mutNPM1/ABL after the second cycle of chemotherapy was a clear cutoff of relapse risk, defined as major MRD reduction.

Specifically, the cumulative incidence of relapse was 67% in patients with MRD ≥ 0.1% mutNPM1/ABL vs just 26% in patients with MRD < 0.1% mutNPM1/ABL (P < .001).

Conversely, early intervention to avoid imminent relapse is recommended with high-level MRD positivity of ≥ 0.1% mutNPM1/ABL at the end of treatment, the authors noted.

For those with undetectable or very low-level MRD at the end of treatment (< 0.01% mutNPM1/ABL), “safe monitoring with no further intervention” is recommended.

For those with low-level MRD positivity levels, defined as between ≥ 0.01% and < 0.1%, close MRD monitoring is recommended due to a high risk for progression to high-level MRD positivity.

In the study, none of the patients who had a positive MRD result below the threshold of 0.01% mutNPM1/ABL relapsed, whereas the cumulative incidence of relapse during the following 6 months after MRD detection was 39% for those with MRD levels between 0.01% and 0.1% mutNPM1/ABL.

SCT in CR1 Shows Little Survival Benefit With MRD Below Cutoff

Notably, allogeneic SCT (allo-SCT) performed in the first complete remission (CR1) showed no significant improvement in terms of recurrence-free survival or overall survival among patients who achieved a major MRD reduction (< 0.1% mutNPM1/ABL) after the second cycle of chemotherapy.

In contrast, for patients who did not achieve major MRD-reduction after the second cycle of chemotherapy, consolidation of CR1 with allo-SCT resulted in significantly improved recurrence-free and overall survival, further suggesting the < 0.1% mutNPM1/ABL cutoff to “possibly guide optimal use of allo-SCT,” the authors noted.

“ Only patients who failed to achieve major MRD reduction after the second cycle of therapy experienced substantial benefit from allo-SCT in CR1, while for molecular responders, allo-SCT offered no additional value,” they wrote.

MRD Insights in Concurrent NPM1 and FLT3-ITD Mutations

Of note, as many as 57% of patients in CR1 after two cycles of chemotherapy achieved a major MRD reduction regardless of the presence of concurrent FLT3-ITD mutation, which carries an intermediate risk, with the risk for relapse of approximately 40%-50% at 3 years, Tsirigotis noted.

“In the subgroup of patients with concurrent FLT3-ITD mutations, NPM1-mut MRD retained its prognostic value, a finding consistent with previous reports consistent with findings observed in previous studies,” Tsirigotis said.

Importantly, while allo-SCT improved recurrence-free survival in that population overall, a significant survival advantage was also not observed among those achieving major MRD reduction in the higher risk FLT3-ITD population.

The findings are notable because “even in the best hands, allo-SCT is associated with significant morbidity and mortality,” Tsirigotis said.

However, “with this tool, you can identify those patients who are and are not in real need for allo-SCT,” he said. “Patients who remain MRD negative can be safely followed.”

The findings make the study one of the very few to demonstrate “that allo-SCT in patients in first complete remission offers no significant survival benefit in patients with NPM1- and FLT3-ITD-mutated AML who achieve major MRD response after the completion of the second cycle of chemotherapy,” the authors added.

“Overall, our findings reinforce the recommendations of international MRD guidelines, which underscore the central role of molecular monitoring in AML management,” the authors noted.

“However, unlike the previous studies that were conducted in a controlled trial setting, our results are derived from a national registry, reflecting real-world clinical practice, thereby supporting the practicality of implementing MRD assessment at the end of the second cycle of induction chemotherapy.”

Molecular Insights Helpful; Caution Urged Pending Broader Validation

Commenting on the study, Mikkael Sekeres, MD, chief of the Division of Hematology at Sylvester Comprehensive Cancer Center, University of Miami Health System in Miami, noted that the stratification of MRD positivity into three tiers “is helpful in advising which patients are unlikely to relapse, are very likely to relapse, and which should be monitored more closely.”

Of note, caveats include that the study “focused on patients who received traditional, intensive chemotherapy, as opposed to patients who receive combinations of venetoclax and a hypomethylating agent,” Sekeres told Medscape Medical News.

“It is therefore not known if these results can be applied to other types of therapies for AML,” he said.

Ultimately, the role of assessment of molecular markers like NPM1 mutations is clearly important beyond what may be suggested by morphologic evidence, Sekeres underscored.

“If a patient has a mutation or biologic marker that can be followed and assessed at a very deep level, we should be exploring the value of monitoring those levels over time and possibly intervening when those levels start to trend upwards,” he said.

“We need to exercise some caution in this approach, though, until methods of measuring these low levels of residual disease are standardized and validated for accuracy across the world.”

The authors and Sekeres had no disclosures to report.