In patients with NPM1-mutated acute myeloid leukemia (AML), the presence of molecular measurable residual disease (MRD) in the peripheral blood following induction chemotherapy can aid decision-making about postremission therapy. More specifically, MRD status in the peripheral blood can identify patients, including those with FLT3 internal tandem duplication (ITD), who are likely or not to benefit from allogeneic stem cell transplant in first remission, investigators from the United Kingdom report.

MRD-positive patients had improved outcomes when allogeneic transplantation was utilized in first morphologic remission. Conversely, patients who were MRD-negative after two courses of induction derived no benefit from transplant, even those with a concomitant FLT3-ITD mutation. In that subset, MRD-negative status alone conveyed a favorable outcome.

“The headline result of our analysis is that the impact of transplant on survival was determined by MRD status after induction…. This is the primary determinant of benefit.”

— JAD OTHMAN, MBBS

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“The headline result of our analysis is that the impact of transplant on survival was determined by MRD status after induction…. This is the primary determinant of benefit,” said Jad Othman, MBBS, of King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, who presented the findings at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

The study evaluated the impact of allogeneic transplant after first complete remission in patients with NPM1-mutated AML, according to MRD status and baseline clinical and molecular features. Investigators used data from the NCRI AML17 trial (2009–2014) and AML19 trial (2015–2020), which were sequential prospective randomized controlled trials of intensive chemotherapy for younger adults with newly diagnosed AML. Both occurred before the availability of midostaurin and the FLT3-ITD MRD assay, and both evaluated MRD by quantitative reverse transcription polymerase chain reaction at the same reference laboratory.

Study Background

As Dr. Othman explained, the NPM1 mutation conveys a generally favorable risk, but if co-mutated with FLT3-ITD the risk becomes intermediate. The role of allogeneic transplant after first complete remission in NPM1-mutated AML is controversial, and the management of such patients varies in the clinic. While allogeneic stem cell transplant has been considered beneficial in the presence of FLT3-ITD (especially with high allelic frequency), early studies found no benefit for allogeneic transplant after first complete remission in NPM1-mutated AML with wild-type or low allelic FLT3-ITD. In addition, research has suggested that patients deemed at favorable risk generally fare better with chemotherapy and that the risks associated with transplant outweigh the potential benefits. On the other hand, high-risk patients generally derive less benefit from chemotherapy and transplant is deemed warranted.

“The question of offering transplant in intermediate-risk patients has always been one that has been controversial.”

— JAD OTHMAN, MBBS

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“In general, an allogeneic transplant is offered in first remission to patients with AML who have an adverse risk. It is not offered to favorable-risk patients. The question of offering transplant in intermediate-risk patients has always been one that has been controversial,” Dr. Othman said.

Study Population

A total of 737 clinical trial patients who achieved complete remission and had a valid MRD result were evaluated. The selection of patients for allogeneic transplant differed between the studies. In AML17, patients were selected based on a validated risk score using age, sex, secondary disease, cytogenetics, white cell count, and response after one course of chemotherapy. In AML19, patients underwent transplant only if they were MRD-positive following the second chemotherapy cycle.

In AML17, 60 patients (17%) were MRD-positive, 16 of whom (27%) achieved a complete response and underwent transplant. In AML19, which selected patients for transplant using MRD status, 83 patients (21%) were MRD-positive, of whom 50 (60%) achieved remission and underwent transplant. Among the MRD-negative patients of both trials, 18% and 16%, respectively, also underwent transplant.

Transplant in MRD-Positive Patients

Patients who remained MRD-positive after two induction cycles derived significant benefit from transplant vs no transplant (hazard ratio [HR] = 0.39); at 3 years, overall survival rates were approximately 60% for transplant recipients vs 21% for patients without transplant. Patients who became MRD-negative, on the other hand, derived no additional benefit from transplant (HR = 0.82); at 3 years, approximately 80% of these patients, regardless of transplant, were alive, Dr. Othman reported.

In the analysis of patients with NPM1-mutated FLT3-ITD, a subset for whom allogeneic transplant is traditionally performed, the results were consistent with the overall findings. In this population, patients who were MRD-positive benefited from transplant vs no transplant in first remission (HR = 0.52), whereas transplant was not of value in MRD-negative patients (HR = 0.80). There was no subgroup of MRD-negative patients for whom chemotherapy followed by transplant provided a benefit. 

DISCLOSURE: Dr. Othman reported no conflicts of interest.

REFERENCE

1. Othman J, Potter N, Ivey A, et al: The benefit of allogeneic transplant in 1st complete remission in NPM1-mutated AML with or without FLT3 ITD is restricted to those testing MRD-positive after induction: An analysis of the UK NCRI AML17 and AML19 studies. 2023 ASH Annual Meeting & Exhibition. Abstract 425. Presented December 10, 2023.