Abstract
Introduction Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy defined by the presence of peripheral monocytosis and can occasionally exhibit bone marrow fibrosis (BMF). Myelofibrosis (MF), a myeloproliferative neoplasm (MPN) characterized by BMF, can also exhibit peripheral monocytosis which is associated with a poor prognosis (Tefferi BJH 2017). Although diagnostically distinct, their characteristics and behavior compared to each other is not well reported. We, therefore, aim to compare the clinical features and outcomes of CMML patients to those with MF and monocytosis.
Methods We included patients diagnosed with CMML or MF by 2022 WHO criteria at a single academic institution. Patients with MF were included based on the same absolute and relative monocytosis thresholds as CMML (≥0.5 x 109/L and ≥10%), and if the monocytosis was persistent for at least 3 months. Baseline characteristics were compared with Wilcoxon rank sum, Pearson's Chi Squared and Fisher's exact test. Survival analysis was performed via Kaplan Meier method.
Results We included 66 patients with a diagnosis of CMML and 53 patients with a diagnosis of MF and associated monocytosis. There was no significant difference in age at diagnosis, with a median age of 68 for both CMML and MF patients (p = 0.15). CMML patients had a higher median absolute monocyte count (AMC) at diagnosis compared to MF patients at the time of monocytosis development (4 x 109/L vs 1.6 x 109/L, p <0.001). Patients with CMML had a trend towards lower median hemoglobin (Hgb) (9.7 g/dL vs 10.7 g/dL, p = 0.08) and higher white blood cell (WBC) count (17 x 109/L vs 12 x 109/L, p = 0.06). CMML patients had a lower platelet count (102 x 109/L vs 338 x 109/L, p <0.001). Both groups had a similar percentage of blasts in peripheral blood, with 0.4% in CMML and 0.5% in MF (p = 0.5). There was no difference in the presence of palpable splenomegaly at diagnosis (39% in CMML vs 55% in MF, p = 0.10).
There was no difference in the presence of cytogenetic abnormalities, with abnormalities noted in 48% (32/66) of CMML and in 36% (19/53) of MF patients (p = 0.2), though CMML patients had a higher prevalence of adverse risk cytogenetics (30% vs 11%, p = 0.002). MF patients had higher grade BMF (p <0.001) although 12.5% of CMML patients had MF2-3 fibrosis. CMML patients had a significantly higher prevalence of TET2 mutations (35% vs 17%, p = 0.03) as well as mutations in the RAS pathway (42% vs 15%, p = 0.001). The characteristic MPN driver mutations of JAK2, CALR, and MPL were more common in MF (p <0.001). Of note, JAK2 mutations were present in 6% of CMML patients, while CALR and MPL mutations were exclusive to MF.
Treatment approaches differed between the two groups, as JAK inhibitors were utilized more frequently in MF (79% vs 14%, p <0.001), while the majority of CMML patients were treated with hypomethylating agents (76% vs 40%, p <0.001). While a larger percentage of patients underwent stem cell transplantation in the CMML group, 21% (14/66) compared to 9.4% (5/53) in the MF group, this difference was not significant (p = 0.08). There was no difference in leukemia free survival at 5 years between the two groups (p = 0.16). There was no significant difference in median 5-year overall survival (p = 0.069), although trended towards longer in monocytic MF as compared to CMML (36.6 months in CMML vs 54 months in MF).
Conclusions There is significant overlap in the clinical presentation of CMML and MF with monocytosis, with similar Hgb and WBC counts, percentage of peripheral blasts, marrow fibrosis, overall prevalence of cytogenetic abnormalities, and the presence of splenomegaly. However, there are also considerable differences, with CMML having significantly lower platelet counts and higher frequency of adverse risk cytogenetics. The mutational profile was also distinguishing, with MF patients having a higher prevalence of MPN driver mutations and CMML patients having a significantly higher prevalence of mutations involving TET2 and the RAS activation pathway.
Although these malignancies have a variety of differences in baseline characteristics, there are many clinical similarities challenging the diagnostic differential. Importantly, we found no significant difference in both leukemia free survival and overall survival, although the latter neared statistical significance which favored MF, and larger datasets are required to validate this finding.
