A distinct immunophenotype identifies a subset of NPM1‐mutated AML with TET2 or IDH1/2 mutations and improved outcome

Abstract

Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in AML. NPM1 mutations often co-occur with FLT3-ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1-mutated AML and correlated sequencing data with immunophenotypic and clinical findings. Of 84 cases (63%) that lacked monocytic differentiation ("myeloid AML"), 40 (48%) demonstrated an acute promyelocytic leukemia-like (APL-like) immunophenotype by flow cytometry, with absence of CD34 and HLA-DR and strong myeloperoxidase expression, in the absence of a PML-RARA translocation. Pathologic variants in TET2, IDH1, or IDH2 were identified in 39/40 APL-like cases. This subset of NPM1-mutated AML was associated with longer relapse-free and overall survival, when compared with cases that were positive for CD34 and/or HLA-DR. The combination of NPM1 and TET2 or IDH1/2 mutations along with an APL-like immunophenotype identifies a distinct subtype of AML. Further studies addressing its biology and clinical significance may be especially relevant in the era of IDH inhibitors and recent work showing efficacy of ATRA therapy in NPM1 and IDH1-mutated AML.

Clinical implications of recurrent gene mutations in acute myeloid leukemia

“…Recent work by flow cytometry and sequencing data has identified a distinct immunophenotypic subset of NPM1-mutated AML with TET2 or IDH1/2 mutations and improved outcome. This subset of NPM1-mutated AML was associated with longer relapse-free and OS, when compared with cases that were positive for CD34 and/or HLA-DR [81]. Targeting mutant IDH by small molecule inhibitors is a rapidly emerging therapeutic approach shown by the recent approval of the first selective mutant IDH2 inhibitor, enasidenib, for the treatment of IDH2-mutated AML [82].…”

Navigating through Mutations in Acute Myeloid Leukemia. What Do We Know and What Do We Do with It?

“…NPM1 mutations are associated with a favorable prognosis in AML with a normal karyotype without other mutations. AML with mutated NPM1 commonly harbors other mutations involving the FLT3 (in 40-50% of patients), DNMT3A, TET2, IDH1, and IDH2 (14) genes. A recent large retrospective study by Ostronoff et al (15) showed that AML patients aged between 55 and 65 years and with NPM1+/FLT3-ITD+ have an improved survival compared to the group without this phenotype.…”

“…A recent large retrospective study by Ostronoff et al (15) showed that AML patients aged between 55 and 65 years and with NPM1+/FLT3-ITD+ have an improved survival compared to the group without this phenotype. Mason et al (14) studied 133 cases with NPM1 mutated AML; 40% of these cases demonstrated an acute promyelocytic leukemia (APL)-like phenotype with lack of CD34 and human leukocyte antigen (HLA)DR expression, suggesting a maturation arrest of myeloid differentiation closer to the promyelocytic stage. Furthermore, these APLlike cases also showed TET2, IDH1, or IDH2 mutations with a superior outcome and lower frequency of DNMT3A mutations.…”

Morphological and Immunophenotypic Clues to the WHO Categories of Acute Myeloid Leukaemia

“…In one large series, the former was seen in about two thirds of patients and the latter in the remaining third [17]. There is correlation between the cytological category and the immunophenotype.…”

“…Overall, about two thirds of cases do not express CD34 and about one third do not express HLA-DR, yielding an “APL-like” immunophenotype [17]. In one large series, 32% of cases were negative for both CD34 and HLA-DR, these falling very largely into the group with myeloblastic differentiation; such cases were more likely to express CD56 and show weak or negative expression of CD13 [17]. The expression of CD4 or CD19 has also been reported in a series of AML patients with mutated NPM1 and normal karyotype [20].…”