Myeloproliferative neoplasm driver mutations (JAK2/CALR/MPL) in chronic myelomonocytic leukemia are associated with an increased risk of blast transformation Free

Introduction Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Blast transformation (BT) is a frequent complication of CMML with a 3-year risk of approximately 31%. MPN driver mutations (i.e., JAK2, CALR, MPL) are known to occur in CMML but their impact on overall survival (OS) or BT remains uncertain.

Methods The current study was conducted under institutional review board approved minimum risk protocols that allowed retrospective collection and analysis of patient data. Diagnostic criteria were according to the International Consensus Classification (Blood 2022; 140:1200). For survival analysis, patients were censored at the time of allogeneic stem cell transplant (ASCT). All statistical analyses were conducted using JMP Pro 17.0.0 software (SAS Institute, Cary, NC, USA) and Bluesky Statistics Software (Worldwide Headquarters, Chicago, IL, USA).

Results A total of 612 CMML patients were considered (median age 71 years; 68% males). MPN driver mutations (MPN^MUT) were detected in 56 (9%) patients, including 43 (77%) with JAK2, 10 (18%) MPL, and 3 (5%) CALR. The median variant allele frequencies were 44% for JAK2 (range, 0.3–100%), 49% for MPL (range, 0.3–97%), and 50% for CALR (range, 20–80%). Age and sex distributions and CMML-1 vs. CMML-2 representation were similar between CMML patients with and without MPN^MUT. On the other hand, CMML patients with MPN^MUT were more likely to display higher hemoglobin level (p <0.01), platelet count (p <0.01), absolute neutrophil count (p = 0.02) and leukocytosis (≥13 ×10⁹/L; p <0.01); they were also less likely to be red blood transfusion dependent (p <0.01), display platelet counts of <100 ×10⁹/L (p <0.01) or abnormal karyotype (p= 0.03), present with severe anemia (p= 0.03) or harbor NRAS mutation (p = 0.02). Higher Mutational frequencies of SRSF2 (median 53% vs. 41%; p = 0.01), TP53 (median 8% vs. 2%; p = 0.02) and IDH2 (median 13% vs. 4%; p = 0.01) were noted in CMML patients with MPN^MUT.

During a median follow-up of 23 months (inter-quantile range 11-51 months) for all 612 CMML patients, 402 (67%) deaths, 118 (19%) BT and 108 (18%) ASCT were documented. Of these, 36 (9%) deaths, 18 (15%) BT and 13 (12%) ASCT occurred in patients with MPN^MUT. Median OS for the entire group (N=612) was 32 months with 1-, 2- and 3-year OS rates of 78%, 58% and 47%, respectively. There was no significant difference in OS between CMML patients with or without MPN^MUT (median 41 vs 31 months; p = 0.27). Thrombotic events were reported in 53 (9%) patients after diagnosis of CMML, including 48 venous and 5 arterial events. There was no significant difference in arterial (p = 0.10) or venous (p = 0.76) thrombosis-free survival between CMML patients with or without MPN^MUT.

Among all 612 patients with CMML, followed for a median of 18 months for living patients, 118 (19%) experienced BT, with 1-, 3-, and 5-year BT rates of 10.8%, 23.1%, and 31%, respectively. Cumulative incidence analysis function (CIF) was calculated in order to assess the BT-free survival while accounting for death as a competing risk; 3-year CIF was 30% for CMML patients with vs. 18% for those without MPN^MUT (Gray's test; p = 0.01). This observation was confirmed in univariate analysis of time to BT (HR 1.7; p=0.03) as well as the corresponding multivariable analysis involving other mutations and clinical risk factors: MPN^MUT (HR 1.8; 0.036), ASXL1^MUT (HR 2.3; p<0.01), DNMT3A^MUT (HR 2.6; p<0.01), CMML-2 vs. CMML-1 (HR 3.4; p<0.01), and leukocyte count ≥13 ×10⁹/L (HR 2.0; p<0.01). SRSF2, IDH2, and TP53 mutations did not impact BT. Notably, the aforementioned risk factors for BT, including ASXL1^MUT and DNMT3A^MUT, were no longer significant when analysis was restricted to patients with MPN^MUT.

Conclusions The current study suggests a higher risk of BT in CMML patients with MPN^MUT, independent of other molecular or clinical risk factors for BT. On the other hand, overall and thrombosis-free survival did not appear to be similarly influenced. The differential impact of previously recognized risk factors for BT in CMML (e.g., ASXL1^MUT, DNMT3A^MUT, CMML-2, CMML-MP), in the presence (lost significance) vs. absence (remained significant) of MPN^MUT was intriguingly noted.