DNMT3A mutations are associated with inferior overall and leukemia‐free survival in chronic myelomonocytic leukemia

Abstract

DNMT3A mutations are seen in~5% of patients with chronic myelomonocytic leukemia (CMML) and thus far, have had an indeterminate prognostic impact on survival. We carried out this study to assess the prognostic impact of DNMT3A mutations on a larger informative cohort of CMML patients (n 5 261). DNMT3A mutations were seen in 6% (n 5 16); 56% (n 5 9) male, with a median age of 64 years. Eighty-one % of DNMT3A mutations were missense, with the Arg882 mutational hot spot accounting for 63% of all changes. Five (31%) patients had an abnormal karyotype whereas concurrent gene mutations (SF3B1/SRSF2/U2AF1256%, TET2250%, and ASXL1225%) were seen in all patients. Apart from a higher frequency of SF3B1 (P 5 0.0001) and PTPN11 (P 5 0.005) mutations and a lower frequency of SRSF2 (P 5 0.004) mutations, there were no significant differences between DNMT3A mutated patients and their wildtype counterparts. In univariate analysis, survival was shorter in DNMT3A mutated (median 8 months) versus wildtype (median 27 months) patients (P 5 0.0007; HR 2.9, 95% CI 1.5-5.7); with other variables of significance including lower hemoglobin (P 5 0.002), higher leukocyte count (P 5 0.0009), higher monocyte count (P 5 0.0012), circulating blast % (P 5 0.001), circulating immature myeloid cells (P 5 0.01), bone marrow blast % (P 5 0.045), abnormal karyotype (P 5 0.02), and ASXL1 (P 5 0.01) mutations. In a multivariable model that included the aforementioned variables, when both DNMT3A and ASXL1 mutations were added, only DNMT3A (P < 0.0001) and ASXL1 (P 5 0.004) mutations remained significant. DNMT3A mutations were also predictive of a shortened leukemia-free survival. These findings warrant inclusion of DNMT3A mutations in molecularly integrated CMML prognostic models.

Monocytosis is a powerful and independent predictor of inferior survival in primary myelofibrosis

“…In order to address concerns regarding confounding from inadvertent inclusion of patients with chronic myelomonocytic leukaemia (CMML), we recently employed a multiparametric flow cytometry‐based approach and demonstrated qualitative differences in monocytes between CMML and myeloproliferative neoplasm (MPN)‐associated monocytosis; the classic monocyte fraction (CD14‐positive and CD16‐negative) was <92% in all MPN cases versus ≥94% in 93% of CMML patients (Patnaik et al , ). Furthermore, in the current study, the driver mutational frequency was similarly high in the presence or absence of monocytosis, which strongly argues against significant contamination of our study population by cases with CMML; reported mutational frequencies for JAK2 , CALR and MPL in CMML were only 7%, 0·5% and 0·5%, respectively (Patnaik et al , ). The findings from the current study suggest that the AMC should be included in future prognostic models for PMF.…”

Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients

“…6 A 29-gene panel targeted exome capture assay was carried out on BM DNA specimens obtained at CMML diagnosis in 85 (62%) patients, for the following genes; TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF, ETNK1 and SETBP1, by previously described methods. 5,16 Azacitidine and DAC were dosed according to the FDA approved dosing schedules, with dose adjustments carried out at physician discretion, based on response and tolerability. Responses to HMA therapy were assessed retrospectively using the 2006, IWG MDS response criteria and the 2015, IWG MDS/MPN overlap syndrome response criteria.…”

Nucleophosmin 1 (NPM1) mutations in chronic myelomonocytic leukemia and their prognostic relevance

“…[8] NPM1 mutations are infrequent in CMML (<5%) and MDS (<5%) and have an unclear prognostic impact. [9-11] We carried out this study to assess the i) frequency and clinical correlates, ii) prognostic impact and iii) survival outcomes related to NPM1 mutations in CMML.…”

“…A 29 gene panel next generation sequencing assay was carried out on BM DNA specimens obtained at diagnosis for the following genes; TET2, DNMT3A, IDH1, IDH2 , ASXL1, EZH2, SUZ12 , SRSF2, SF3B1, ZRSR2, U2AF1 , PTPN11, Tp53, SH2B3, RUNX1, CBL, NRAS, KRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL , NPM1, CEBPA, IKZF,ETNK1 and SETBP1, by previously described methods. [5, 11] Statistical analyses considered parameters obtained at time of CMML diagnosis. Differences in the distribution of continuous variables between categories were analyzed by either Mann-Whitney or Kruskal-Wallis tests.…”