Submitted March 27, 2009
Accepted June 24, 2009
Minimal residual disease levels assessed by NPM1 mutation specific RQ-PCR provide important prognostic information in AML
Susanne Schnittger*, Wolfgang Kern, Claudia Tschulik, Tamara Weiss, Frank Dicker, Brunangelo Falini, Claudia Haferlach, and Torsten Haferlach
MLL Munich Leukemia Laboratory, Munich, Germany
Institute of Hematology, University of Perugia, Perugia, Italy
* Corresponding author; email: susanne.schnittger{at}mll-online.com.
NPM1-mutated AML, recognized as provisional entity in the WHO-2008 classification of myeloid neoplasms, accounts for 30% of AML. We analyzed 1227 diagnostic and follow-up samples in 252 NPM1-mutated AML patients with 17 different NPM1 mutation specific RQ-PCR assays. Paired diagnostic/relapse samples of 84 patients revealed stable NPM1 mutations in all cases suggesting that they are pathogenetically early events and thus applicable for MRD detection. 47 relapses were early predictable due to NPM1 mutation level (%NPM1/ABL1) increase of at least 1 log or in 15 cases due to NPM1 mutation levels not dropping less than three log ranges. A high prognostic value of NPM1 levels was shown for four different intervals after starting therapy. Furthermore, thresholds of 0.1 and 0.01 %NPM1/ABL1 during/after treatment discriminated between prognostic subgroups. Univariate analyses including age, WBC, blast count, CD34 positivity, FLT3-mutations status, FAB-type, karyotype, NPM1 mutation type, and pretreatment NPM1 mutational level showed that only age and FLT3-LM mutation status were prognostically significant for EFS. Multivariate analysis including age, FLT3-LM status and NPM1 mutation level at different time points demonstrated NPM1 level as the most relevant prognostic factor during first-line treatment. Similar results were obtained in patients undergoing second-line chemotherapy or allogeneic stem cell transplantation.
