The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML

Abstract

Key Points• NPM1 RT-PCR levels .1%are associated with poor overall and disease-free survival in AML patients treated with chemotherapy.• NPM1 MRD levels .10% are associated with poor overall and disease-free survival in AML patients after allogeneic transplantation.Mutations of the NPM1 gene (NPM1 mut ) are among the most common genetic alterations in acute myeloid leukemia and are suitable for minimal residual disease detection. We retrospectively investigated the prognostic impact of NPM1 mut -based minimal residual disease detection from bone marrow for development of relapse by using a newly developed real-time polymerase chain reaction based on locked nucleic acid-containing primers in 174 patients, 155 of whom were treated within prospective protocols. The prognostic value of 5 cutoff values after completion of treatment or after allogeneic transplantation was studied by using cause-specific hazard models. Subsequent validation using cross-validated partial likelihood analysis revealed that an increase of more than 1% NPM1 mut /ABL1 was most prognostic for relapse after chemotherapy, whereas an increase of more than 10% NPM1 mut /ABL1 was most prognostic for relapse after allogeneic transplantation. Univariate and multivariate analysis of disease-free survival and overall survival revealed a significantly worse outcome in patients with >1% NPM1 mut /ABL1 and >10% NPM1 mut /ABL1, respectively, which remained significant after adjustment for FLT3-internal tandem duplication status. Our results in a large data set define and optimize cutoff values for early diagnosis of molecular relapse. These results may be especially important for defining triggers for early therapeutic intervention. (Blood. 2013;122(1):83-92)

Molecular response assessment by quantitative real-time polymerase chain reaction after induction therapy in NPM1-mutated patients identifies those at high risk of relapse

“…Krönke et al, 10 and Shayegi et al 11 analyzed clinically relevant MRD checkpoints in NPM1-mutated patients. They, too, identified MRD assessment after induction therapy, or after the achievement of complete remission, as one of the most important MRD checkpoints.…”

“…1,15 NPM1 mutations are reliable markers for monitoring MRD after conventional chemotherapy, allogeneic HSCT, or during the subsequent follow-up. 10,11,16,17 There has been some discussion on the stability of this MRD marker in relapse, but NPM1 mutations could be detected in at least 91% of all relapsed patients. 10,18 In this study, we analyzed MRD monitoring by RT-PCR in 158 adult patients with NPM1 A, B and D mutations treated with high-dose cytarabine induction therapies within the AMLCG 1999, 2004 and 2008 trials.…”

Longitudinal qPCR monitoring of nucleophosmin 1 mutations after allogeneic hematopoietic stem cell transplantation to predict AML relapse

“…Of interest, these cutoff values are significantly lower than those identified in other studies performed in the transplant setting. [7][8][9] Comparing WT1 with NPM1 mut in the relapse cohort, nine out of the eleven patients (82%) had WT1 overexpression (defined according to the threshold identified by Cilloni et al 11 ) during their follow-up, but most of them (seven out of nine) had just a single over-threshold value before relapse, with approximately 1 month of advance before the clinical event. Besides, in the longterm CR cohort, 11 out of 17 patients showed WT1 overexpression in at least one BM evaluation, suggesting limited leukemia specificity (35%).…”

“…4,5 In line with that, numerous studies have demonstrated the usefulness of landmark analyses and longitudinal monitoring of NPM1 mut in AML patients after chemotherapy. 6,7 However, information on the clinical utility of NPM1 mut quantitative monitoring in the post-transplantation setting are to date more limited, [7][8][9] and thus represent the specific focus of our present study.…”

“…However, it has also to be taken into account that ROC analysis might result suboptimal in this context, in which multiple measurements are performed over time in the same patient. 8 It should also be noted that setting an arbitrary threshold of 10 − 3 NPM1 mut copies/ABL copy for single determination would completely avoid false positives (100% specificity), still maintaining 81% sensitivity in relapse prediction. Of interest, these cutoff values are significantly lower than those identified in other studies performed in the transplant setting.…”