Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia WithNPM1Mutation: A Study by the Acute Leukemia French Association Group

Abstract

Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.

Spontaneous Remission in an Older Patient with RelapsedFLT3ITD Mutant AML

“…While the current definition of complete (and hence spontaneous) remission in AML relies solely on morphologic criteria, there is growing consensus that identification of minimal residual disease (MRD), as assessed by highly sensitive molecular and multiparameter flow cytometry assays in marrow samples at the time of clinical remission, may be a more significant and accurate predictor for leukemic persistence and recurrence than pathology alone. In fact, various recent studies have investigated the role of mutant NPM1 as a tool for MRD assessment in AML [18–25]. The presence of MRD as determined by quantitation of NPM1 -mutated transcripts after two cycles of chemotherapy in standard-risk AML was shown to be a powerful independent prognostic factor for disease relapse and overall survival in one study [22].…”

“…The presence of MRD as determined by quantitation of NPM1 -mutated transcripts after two cycles of chemotherapy in standard-risk AML was shown to be a powerful independent prognostic factor for disease relapse and overall survival in one study [22]. In another study, reduction in postinduction MRD based on peripheral blood NPM1 -mutated transcripts had strong prognostic significance and predicted benefit from allogeneic stem cell transplant [18]. In the subset of patients with FLT3 ITD, only age, white blood cell count, and 4-log reduction in peripheral blood MRD, but not FLT3 ITD allelic ratio, were significantly associated with a higher cumulative incidence of relapse.…”

Minimal Residual Disease in Acute Myeloid Leukemia: Still a Work in Progress?

“…Yet, the best source to analyze (PB or BM), the best time-points and best thresholds for NPM1 are yet to be defined. For instance, Balsat et al analyzed molecular NPM1 MRD, detected by RT-qPCR, in 152 NPM1-mutated AML patients [40]. Multivariate analysis showed higher 3-year CIR ( p < 0.001) and shorter OS (HR: 5.1; p < 0.001) in patients with an NPM1 reduction after induction <4 log.…”

“…In FLT3-ITD+ patients, multivariate analysis identified only age, WBC count and 4 log NPM1 PB reduction, but not FLT3-ITD allelic ratio, as predictors of OS. Interestingly, in those 71 patients where allo-HSCT was performed because of FLT3-ITD or adverse cytogenetics, it determined a survival benefit in patients with a post-induction MRD clearance <4 log (HR: 0.25; p = 0.047 for OS and Disease-free Survival (DFS)), but not in those with a clearance >4 log (HR: 2.11; p = 0.261 for OS, HR: 1.62, p = 0.419 for DFS) [40]. …”

Prognostic Value and Correlation Between WT1 Overexpression and NPM1 Mutation in Patients with Acute Myeloblastic Leukemia

“…Однако оптимальный уровень к настоящему времени не определен. Значения в разных источниках варьируют от 3 до 5 log [14,30,33]. В настоящее время большинство исследователей рассматривают NPM1 как высокоспецифичный [34][35][36] и стабильный маркер оценки МОБ [14,[37][38][39][40][41].…”