Quantitative Assessment of Minimal Residual Disease Predicts Outcome of Patients of Acute Myeloid Leukemia with Nucleophosmin (NPM) Mutation.

Purpose: In patients of acute myeloid leukemia (AML) with mutations in Nucleophosmin (NPM), minimal residual disease (MRD) can be quantified by real-time polymerase chain reaction (qPCR). However, the validity of MRD detection by qPCR on a long-term basis and its prognostic significance remain undetermined.

Patients and Methods: We quantified NPM mutants by qPCR in genomic DNA of 202 bone marrow samples serially collected during a median follow-up of 21.9 months (range 2.5 to 204) from 40 AML patients bearing this mutation.

Results: With a relatively homogeneous number of mutants at diagnosis, induction chemotherapy resulted in a median of 2.78 logs of reduction (p<0.001). The mutant numbers determined by qPCR matched well with clinical courses: clinical relapse was accompanied by rise of mutants (p<0.001) and mutant numbers at morphological complete remission from patients without any subsequent relapse were significantly lower than others (p<0.001). Detection of mutant signals predicted relapse if no further chemotherapy was administered. Failure to achieve at least 2 logs of mutant reduction after consolidation led to shorter overall survival (OS) (11.3 months vs. not reached, p=0.01) and relapse-free survival (RFS) (3.8 months vs. 21.2 months, p=0.001). Patients with any rise of mutants during serial follow-up relapsed more frequently than those with persistently low or undetectable signals (p<0.001). Along serial follow-up, patients obtaining any mutant reduction to < 0.1% of internal control (INC) after treatment had longer OS (a median of 57.9 months vs. 20.2 months, p=0.002) and RFS (11.3 months vs. 4.0 months, p<0.001). On the other hand, detection of mutants above 1.5% of INC in any post-induction sample predicted a poorer outcome (a median of 22.1 months vs. not reached, p=0.002 for OS and 9.7 months vs. not reached, p<0.001 for RFS).

Conclusion: Quantification of MRD by qPCR on genomic DNA in AML bearing NPM mutation predicts outcomes of this group of patients.