Clinical Correlates, Prognostic Impact and Survival Outcomes in Chronic Myelomonocytic Leukemia Patients with Myeloproliferative Neoplasm Associated-Driver Mutations
Authors: Pophali Prateek , Lasho Terra L. , Finke Christy , Horna Pedro , Ketterling Rhett P. , Gangat Naseema , Begna Kebede H. , Mangaonkar Abhishek A. , Pardanani Animesh , Tefferi Ayalew , Patnaik Mrinal M. 
Published: October 2019

Background : Chronic myelomonocytic leukemia (CMML), a myeloid neoplasm with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms (MPN), is characterized by peripheral blood (PB) monocytosis and a risk for leukemic transformation (LT). Gene mutations commonly seen in CMML include, TET2 (~60%), SRSF2 (~50%) and ASXL1 (~40%). MPN associated-driver mutations such as JAK2V617F (~10%), MPL (<1%) and CALR (<1%) are uncommon, and in fact, the 2016 World Health Organization (WHO) guidelines state that the presence of these mutations tends to support a diagnosis of MPN with monocytosis. We carried out this study to assess the i) clinical correlates and ii) survival outcomes of MPN associated-driver mutations in CMML.

Methods : 323 molecularly annotated patients with WHO-defined CMML were included in the study. All patients had bone marrow (BM) biopsies and cytogenetics performed at diagnosis. Targeted capture assays were carried out on BM DNA specimens obtained at diagnosis for 30 myeloid relevant genes, by previously described methods.

Results: Among the 323 study patients, 67% were males and median age was 71 years (range, 18-95). Twenty five (8%) patients had CMML with MPN associated-driver mutations; 24 (96%) with JAK2V617F and 1(4%) with a MPLW515L mutation. There were no patients with CALR or JAK2 exon 12 mutations. Additional signal-pathway mutations included NRAS (15%), KRAS (4%), CBL (14%), PTPN11 (3%), CSF3R (1%), and SH2B3 (<1%).

i) Phenotypic correlates:

The median age of CMML patients with MPN-associated driver mutations was 71 years and 66% were male. The WHO morphological subtypes included CMML-0 60%, CMML-1 24% and CMML-2 16%; while 91% of patients had a normal karyotype. The distribution of mutations included TET2 75%, SRSF2 54%, ASXL1 48%, RUNX1 20%, NRAS and EZH2 12% each, SETBP1 8%, SF3B1, U2AF1, CBL, PTPN11, FLT3-TKD, & Tp53 4% each, respectively. Risk stratification by the Mayo Molecular Model included high 16%, intermediate-2 32%, intermediate-1 36% and low risk 16%, respectively. In comparison to CMML patients without MPN associated-driver mutations, those with, had a higher hemoglobin (HB, p=0.001) and hematocrit (p=0.001), were more likely to have leukocytosis (p=0.02) and elevated LDH levels (p=0.0002), less likely to have thrombocytopenia (p=0.003), more likely to have a "proliferative" CMML phenotype (p=0.01) with palpable splenomegaly (p=0.0007), and more likely to have mutations involving TET2 (p=0.02). Six (2%) thrombotic events were documented in the cohort; 2 (8%) in patients with MPN-driver mutations and 4 (1%) in those without (p=0.07). There were no differences between the two groups with regards to the degree of monocytosis, PB and BM blasts, BM cellularity, BM megakaryocytic atypia, and BM fibrosis.

ii) Survival outcomes:

At last follow up 219 (68%) deaths and 55 (17%) LT were documented, of which 14 (56%) deaths and 2 (8%) LT occurred in the MPN-driver mutation group. The median OS for the entire cohort was 28 months (22-32); 31 months for CMML patients with MPN associated-driver mutations and 24 months for those without (p=0.4). On a univariate analysis, survival was adversely impacted by low HB (p<0.0001), high white blood count (p=0.0009) and absolute monocyte count (p=0.0004), circulating immature myeloid cells (p=0.02) and blasts (p=0.005), BM blasts (p=0.02), palpable splenomegaly (p=0.03), abnormal karyotype (p=0.001), presence of DNMT3A (p=0.006), ASXL1 (p=0.009), EZH2 (p=0.03) and Tp53 (p=0.02) mutations and the absence of TET2 (p=0.0009) mutations. Survival was not affected by the presence of JAK2V617F (p=0.4) or MPL (p=0.46) mutations. On a multivariable analysis that included the aforementioned significant variables, only HB <10 gm/dl (p=0.0016), presence of PB blasts (p=0.01), presence of DNMT3A (p=0.003) and the absence of TET2 mutations (p=0.02) retained significance. The presence of MPN associated-driver mutations did not impact LFS (p=0.36).

Conclusions: The occurrence of MPN associated-driver mutations in CMML is infrequent (~8%) and is largely restricted to JAK2V617F. CMML patients with MPN-associated driver mutations have a higher HB/hematocrit, are more likely to have proliferative features and palpable splenomegaly, and are less likely to be thrombocytopenic. There was a trend towards an increased thrombotic risk, with no impact of these mutations on overall and leukemia free survival.

Disclosures

No relevant conflicts of interest to declare.