乌鸦传媒

SAN DIEGO -- Measurable residual disease (MRD) after induction therapy can guide the use of allogeneic transplant in patients with NPM1-mutated acute myeloid leukemia (AML) in first remission, regardless of whether FLT3 internal tandem duplication (ITD) mutations are present as well, according to an analysis of two randomized trials.

Of more than 700 patients in the pooled dataset, those who remained MRD-positive after their second course of induction therapy experienced a significant survival advantage if they received transplant (HR 0.39, 95% CI 0.24-0.64), with 3-year survival rates increasing from 21% to 60% with transplant, reported Jad Othman, MBBS, of King's College London.

But no significant benefit with allogeneic transplant was observed for patients attaining MRD-negativity in the blood after induction (HR 0.82, 95% CI 0.50-1.33), he detailed at the American Society of Hematology annual meeting here.

NPM1 is the most commonly mutated gene in AML, present in about a third of all cases. It is generally considered a favorable-risk marker, but patients are considered intermediate-risk if they also have FLT3 ITD mutations and adverse-risk if rare adverse karyotypes are present.

"The role of allogeneic transplant in these patients with NPM1-mutated AML in first remission has always been controversial," said Othman during a press briefing. "And there's always been significant variation in practice worldwide."

Typically, transplant is offered in adverse-risk AML but not in favorable-risk disease, and remains controversial for intermediate-risk patients.

While prior studies have suggested that performing a transplant will benefit patients with FLT3 ITD mutations with a high allelic ratio, MRD status was not taken into account, Othman said. MRD in the AML17 trial has been shown to be in patients with NPM1 mutations.

In the current analysis, Othman reported that FLT3 ITD made no difference. In patients with both mutations, transplant still only benefited the patients who remained MRD-positive after induction chemotherapy:

• MRD-positive: HR 0.52 (95% CI 0.29-0.93)
• MRD-negative: HR 0.80 (95% CI 0.37-1.72)

The study gives very clear guidance, said press briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine, who was not involved in the research.

If "MRD is still present, a bone marrow transplant should be recommended -- clear separation of those curves," he said. "But if the MRD is negative, I am much more comfortable not offering a bone marrow transplant to my patients."

Sekeres noted that tracking MRD in NPM1-mutated AML has been standard since 2016.

"I was particularly excited by this abstract because I do treat patients with AML, and we always reach a decision point after the initial round -- or rounds -- of chemotherapy on whether or not we should offer a bone marrow transplant," he told 乌鸦传媒. "We tend to offer transplants to patients who either have residual disease on some level, or those patients who have high-risk disease, where it's much more likely their leukemia will return if we stick with traditional chemotherapy as opposed to transitioning those patients to a bone marrow transplant."

Subgroup analysis of the overall study population confirmed that MRD accounted for about 77% of the variance in transplant benefit (P=0.038), said Othman. Furthermore, the study identified no subgroup in the MRD-negative population with a survival advantage from allogeneic transplant.

The findings presented by Othman came from an analysis of 737 AML patients from two U.K. National Cancer Research Institute (NCRI)-led trials: (conducted from 2009-2014) and (conducted from 2015-2020). MRD testing in both trials were performed by quantitative PCR at the same reference laboratory.

Importantly, he noted, selection for transplant was very different in the two studies. In AML17, patients were selected based on a validated risk score that incorporated age, sex, cytogenetic risk, white cell counts, treatment response after the first cycle of chemotherapy, and whether the leukemia was secondary or de novo. In AML19, patients were selected for transplant based entirely on MRD -- i.e., only recommended if MRD was positive in the peripheral blood after two courses of chemotherapy; otherwise transplant was not recommended, regardless of baseline risk factors.

A total of 27% of the MRD-positive patients received a transplant in AML17, as compared with 60% in AML19.

All patients included in the current analysis had NPM1-mutated disease, were in remission, and had a valid peripheral blood sample taken after the second course of induction treatment. They had a median age of 52 years, 55% were female, 39% had FLT3 ITD mutations, and very few had prior myeloid malignancies (4.1%) or adverse cytogenetic risk (1.2%).

Most patients had received a "7+3"-style regimen for induction (cytarabine plus an anthracycline such as daunorubicin or idarubicin), 52% also received gemtuzumab (Mylotarg) with induction, and 40% received an allogeneic transplant during their disease course.

Limitations to the analysis included that no frontline FTL3 inhibitors were used in the trials, regimens that likely would lead to deeper MRD responses, said Othman. Findings also may not be generalizable to patients over 60; only 16% were included in the present analysis, as the two trials largely enrolled fit patients.

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