PB1761 CLINICAL IMPACT OF NPM1 MUTATION SUBTYPES IN A MONOCENTRIC COHORT OF ACUTE MYELOID LEUKEMIA
Authors: Sciumè M. , Fabris S. , Ciceri G. , Freyrie A. , Neri A. , Baldini L. , Fracchiolla N.S. 
Published: June 2019

Background:

Acute myeloid leukemia (AML) with mutated NPM1 was recently recognized as a distinct entity. The most common NPM1 mutation is type A, generally considered of favorable prognosis in the absence of additional internal tandem duplication (ITD) in FLT3 gene. So far little is known about the prognostic relevance of non‐A type.

Aims:

We aimed to evaluate the relevance of A type and non‐A type NPM1 mutations on clinical profiles and outcomes in a monocentric AML cohort.

Methods:

Adult patients with newly diagnosed NPM1‐mutated AML were selected from the institutional database. NPM1 mutations were detected by Sanger sequencing and molecular minimal residual disease (MRD) was determined by real‐time quantitative polymerase chain reaction analysis (sensitivity 10‐5). Genetic risk classification and response to treatment were assessed according to the 2017 European LeukemiaNet guidelines. The chi‐squared test was used for testing relationships between categorical variables; p ≤ 0.05 were considered significant. Overall survival (OS) curve was estimated using the Kaplan–Meier method.

Results:

We identified 32 consecutive patients seen in a 4‐year period. Median age at AML diagnosis was 67 years and male/female ratio was 15/17. Median white blood cell count was 32x109/L. Type A NPM1 mutations was found in 21 (66%) and non‐A type in 11 cases (34%), including B type (4 cases), D type (2 cases) and other rare mutations (5 cases). One of the latter was this following novel mutation c.870_873delGAGGinsCTTCTCCC. Hyperleukocytosis occurred in 4 type A (19%) and 2 non‐A type (18%) cases (p not significant, NS). M4 was the most represented morphology (17 cases, 53%). The karyotype was normal in all cases and favorable genetic risk was found in 15 type A (71%) and 8 non‐A type (73%) cases, whereas intermediate in 6 type A (29%) and 3 non‐A type (27%) cases (p NS). All intermediate risk had a FLT3‐ITD mutation. Sixteen patients (50%) were treated with antracycline‐cytarabine‐based chemotherapy (8 type A, 8 non‐A type) and 3 of them received also midostaurin (all non‐A type). Eleven patients (34%) were treated with hypomethylating agents (9 type A, 2 non‐A type), 5 patients (16%) died before AML treatment start (4 type A, 1 non‐A type). Complete remission (CR) was observed in 13 cases (41%) treated with intensive chemotherapy (6 type A, 7 non‐A type) and in 2 cases (18%) who received a hypomethylating agent (all type A) (p 0.014), without significant difference between the two mutation groups. A relapse occurred in 5 of the 15 patients who achieved a CR, 3 cases treated with intensive chemotherapy (1 type A, 2 non‐A type) and 2 cases with hypomethylating agents (all type A). Molecular MRD was available in 11 cases (4 type A, 7 non‐A type); at the end of first line treatment it was negative for 3 patients (27%, 1 type A, 2 non‐A type), who had also a flow‐cytometry MRD negativity. After a median follow‐up of 26.5 months, median OS and median disease free survival were both 5 months; using the Kaplan–Meier method a significant OS difference was observed between type A and non‐A type cases (Fig. 1), DFS was not significant different between the two groups. During the follow‐up 18 patients died (56%, 14 type A, 4 non‐A type), mainly due to AML progression (9 cases) or hemorrhagic complications (4 cases).

Summary/Conclusion:

Our results in a small retrospective and monocentric series of NPM1 mutated AML showed similar clinical‐biological features among cases with type A and non‐A type mutations, albeit a better OS was associated to non‐A type mutations.

image