MRD Monitoring in Younger Patients With NPM1 Mutated AML Clinically Relevant

ORLANDO ­– Researchers have confirmed 2 clinically relevant minimal residual disease checkpoints, after double induction therapy and after completion of therapy, in younger patients with acute myeloid leukemia (AML) with nucleophosmin (NPM1^mut) mutations, a study presented at the American Society of Hematology (ASH) 57^th Annual Meeting has shown.¹

Because NPM1^mut represent one of the most frequent gene mutations in AML and can be used for monitoring minimal residual disease, researchers sought to determine clinically relevant checkpoints and a cut-off value to identify patients with a high risk for relapse.

For the study, researchers analyzed data from 499 NPM1^mut patients aged 18 to 60 years with AML. Patients had been treated with double induction therapy with idarubicin, cytarabine, and etoposide with or without ATRA or gemtuzumab ozogamicin, or 1 cycle of daunorubicin plus cytarabine followed by 1 to 4 cycles of high-dose cytarabine, autologous stem cell transplantation, or allogeneic stem cell transplantation.

Results showed that NPM1^mut transcript levels before treatment were not associated with clinical characteristics like age, blood counts, and gene mutations, with the exception of lactate dehydrogenase (LDH) level (P = .006). Researchers also found that pretreatment NPM1^mut transcript levels did not affect event-free, relapse-free, or overall survival.

The study demonstrated that after double induction therapy, the cumulative incidence of relapse at 4 years was 10% for patients with lower NPM1^mut transcript levels vs 45% for those with higher NPM1^mut transcript levels (P < .0001), which translated to a significant improvement in overall survival in patients with lower transcript levels (P = .001). After completion of therapy, 4-year cumulative incidence of relapse was 13% and 56%, respectively (P < .00001), which similarly translated to a significantly better overall survival with lower incidence of relapse (P < .00001).

“Reduction of NPM1^mut transcript levels and achievement of RQ-PCR negativitiy significantly correlated with FLT3^ITD/DNMT3A mutation status, especially in triple-positive patients,” Silke Kapp-Schwoerer, MD, of the University Hospital of Ulm Department of Internal Medicine III in Ulm, Germany, said during her presentation. “Outcome of triple-positive patients compared to patients with NPM1^mut solely is significantly worse.”

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Multivariate analysis showed that NPM1^mut transcript levels were significantly associated with shorter remission duration and shorter overall survival.

In addition, researchers determined that exceeding a cut-off value of > 200 transcript levels was highly predictive of disease relapse and found that concurrent mutations of FLT3^ITD and DNMT3A significantly impact the kinetics of NPM1^mut transcript levels.

“For interpretation of NPM1^mut MRD monitoring, FLT3^ITD and DNMT3A mutation status should be considered,” Dr Kapp-Schwoerer concluded.

Reference

1. Kapp-Schwoerer S, Corbacioglu A, Gaidzik VI, et al. Clinical relevance of minimal residual disease monitoring in NPM1 mutated AML: a study of the AML Study Group (AMLSG). Oral presentation at: 57^th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL.