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Monitoring of minimal residual disease in acute myeloid leukemia with frequent and rare patient‐specific NPM1 mutations

Nucleophosmin (NPM1) mutations in exon 12 are the most common genetic alternation in cytogenetically normal AML (CN‐AML). Although mutation types A, B, and D represent the majority of cases, rare mutation variants of the NPM1 gene in individual patients do occur. In this study, we have evaluated a novel, DNA‐based real‐time quantitative polymerase chain reaction (RQ‐PCR) for the detection of three of the most commonly occurring mutations and for six rare patient‐specific mutation types, which represent 28% of all of the NPM1 mutations in our group of 25 CN‐AML patients. Furthermore, the prognostic relevance of NPM1‐based monitoring of minimal residual disease (MRD) in peripheral blood (PB), bone marrow (BM), and in specific cell subsets (CD34+, CD34−, CD34dim) of BM were evaluated. In 80% of the evaluable patients, a molecular relapse preceded a hematological relapse. Moreover, in this subset of patients, the molecular relapse occurred at a median of 97 days before the hematological relapse. Our compartment analysis showed a strong correlation between BM and PB (r = 0.907, P < 0.001) as well as a high copy number of mutated NPM1 in CD34+ BM cells. In conclusion, we have demonstrated applicability of our presented RQ‐PCR method for a large percentage of mutated NPM1 patients with CN‐AML as well as the usefulness for long‐term follow‐up monitoring of MRD and the prediction of hematological relapse. Am. J. Hematol., 2010. © 2010 Wiley‐Liss, Inc.