Response: NPM1-mutated AML is an entity irrespective of whether or not chromosomal aberrations are present

We thank Micol et al for their critical comments. NPM1-mutated AML,¹  a new provisional entity of 2008 World Health Organization (WHO) classification of myeloid neoplasms,²  usually carries a normal karyotype (NK).¹  The main goal of our paper³  was to ascertain whether concomitant chromosomal aberrations may influence its features. Our findings clearly supported the view that NPM1-mutated AML is a single disease entity, independently of whether it carries a NK or abnormal karyotype (AK). In fact, chromosomal aberrations occurring in NPM1-mutated AML emerged as secondary genetic lesions and clinicopathologic features, immunophenotype and gene expression profiles overlapped whether NPM1-mutated AML carried a NK or AK.³  In addition, prognosis of NPM1-mutated AML did not appear to be influenced by a concomitant chromosomal aberration.³  These findings have the potential to impact how we classify and treat AML patients.

Micol et al reported that NPM1-mutated AML with NK and AK exhibited the same complete remission rate, overall survival, and event-free survival, thus providing further evidence in support of our view. Unlike our results, however, Micol et al found that event-free survival, but not overall survival, was negatively influenced by the presence of a cytogenetic abnormality in the subset of NPM1-mutated/FLT3-ITD⁻ patients. Several explanations may account for these diverging results. Micol et al's conclusions may be biased because of the small number of NPM1-mutated/FLT3-ITD⁻ cases they investigated: a total of 95 cases (79 NK, 16 AK) compared with our 355 patients (295 NK; 60 AK). It should be also underlined that our results were confirmed in 2 large independent clinical studies, Munich Leukemia Laboratory and GIMEMA/EORTC.

It may be also possible that differences in event-free survival in the 2 studies may be due to occurrence of a few “unfavorable” chromosomal aberrations in the small cohort of patients analyzed by Micol et al. Unfortunately, the authors provide no information about the type of cytogenetic abnormalities that were identified in their patients. In our paper,³  we demonstrated that the pattern of chromosome aberrations observed in addition to NPM1 mutation overlaps with the aberration pattern occurring in addition to t(8;21), t(15;17), inv(16), and 11q23/MLL rearrangement, which are regarded as distinct entities irrespective of whether or not additional chromosome aberrations are present.²  Overall, accompanying chromosome abnormalities had no prognostic impact in AML with t(8;21) and inv(16), respectively, as we showed for NPM1-mutated AML, and only in a large meta-analysis by Schlenk et al⁴  could distinct aberrations be identified that had an impact on prognosis. We agree with Micol et al that a comparable meta-analysis is necessary to clarify whether single additional aberrations may influence the prognosis in NPM1-mutated AML.

In conclusion, a large bulk of evidence,^5-10  including findings from our study,³  points to NPM1-mutated AML as a distinct leukemia entity, irrespective of whether or not chromosomal observations are present. Accordingly, the impact of secondary genetic alterations, such as FLT3-ITD or additional chromosomal aberrations, on survival should be considered in the context of the entity, that is, “NPM1-mutated AML,” comparable with other genetically defined entities such as AML with t(8;21), inv(16), t(15;17), or 11q23/MLL rearrangement.