Thrombosis, bleeding, and progression in JAK2 V617F clonal hematopoiesis Free

JAK2 V617F mutations occur frequently in patients with myeloproliferative neoplasms (MPNs) and are associated with increased thrombosis risk. Patients can also have JAK2 V617F clonal hematopoiesis without an overt MPN (JAK2 CH). Thrombotic, bleeding, and progression outcomes in patients with JAK2 CH are not well characterized.

We conducted a retrospective cohort study of JAK2 CH patients to (1) evaluate clinical, laboratory, and treatment patterns (2) characterize thrombosis, bleeding, progression to MPN, and death, and (3) determine risk factors for thrombosis.

We retrospectively identified patients with JAK2 CH, defined in this study as patients with a JAK2 V617F mutation regardless of variant allele frequency (VAF) who failed to meet World Health Organization 2016 criteria for MPN. Patients were seen at Mass General Brigham (MGB) through (1) the MGB Biobank, a repository of whole exome sequencing performed on 53,000 individuals from 2008-2022 (PMID: 26805891), or (2) referral to the MGB hematology clinic from 2014-2022 for previously noted JAK2 mutation confirmed on clinical molecular testing (PMID: 27339098). All clinical records were reviewed for both groups and patients were included only if there was sufficient data to exclude an MPN. We abstracted labs, treatments, and outcomes after JAK2 sequencing including arterial and venous thrombosis, major and clinically relevant non-major bleeding, progression to overt MPN, and death. We evaluated change in blood counts over time with a mixed effects model. We calculated cumulative incidence rates of thrombosis, bleeding, and progression with death as a competing event. We used univariable and multivariable logistic regression models adjusted for patient source to evaluate risk factors for thrombosis.

We identified 35 patients with JAK2 CH (median age 66, 54% female, 57% from biobank, 43% from clinic). In clinic patients, the most common reasons for referral were abnormal blood counts (60% - transient in 7/9, persistent in 2/9 with normal bone marrow biopsy), thrombosis (27%), or incidentally detected JAK2 on other testing (13%).

JAK2 CH clinic patients had less follow-up (median 25 vs. 95 months, p=0.01) and lower JAK2 VAF (median 1.1% vs. 14.0%, p<.001) compared to biobank patients, but otherwise were similar in demographics, cardiovascular risk factors, and prior history of thrombosis/bleeding. Median blood counts at time of JAK2 sequencing were platelet 329 K/uL, hematocrit 39.0%, white blood cell 7.7 K/uL. Blood counts were not different between groups and did not change significantly over time. Aspirin use at JAK2 sequencing was similar between groups (50% biobank vs. 67% clinic, p=0.49), but most clinic patients were prescribed aspirin for JAK2 CH (70%) vs. for myocardial infarction/stroke prevention in biobank patients (100%).

Cumulative incidence of thrombosis, bleeding, and progression to MPN was 46% (17% venous, 29% arterial), 24%, and 4% respectively, and 5-year overall survival was 81%. Outcomes were not significantly different between groups. Causes of death were non-hematologic malignancy (N=3), renal failure (N=1), septic shock (N=1), and unknown (N=1).

Only prior history of arterial thrombosis was significantly associated with arterial thrombosis after JAK2 sequencing on univariable analysis, and this remained significant when adjusting for patient source (OR 15.43, p=0.03). We found no other significant risk factors for arterial and venous thrombosis, including JAK2 VAF, baseline blood counts, and aspirin use at time of JAK2 sequencing.

There are few detailed characterizations of the clinical features and outcomes of JAK2 CH patients. We present a cohort of JAK2 CH patients at a single institution with cumulative incidence of thrombosis, bleeding, and progression to MPN of 46%, 24%, and 4%. Clinic patients had lower VAFs compared to biobank patients, likely related to differences in sequencing techniques and other sources of bias that deserve further investigation in future studies. However, outcomes were similar between the two groups. Aspirin was used by the majority of clinic patients, although this was not associated with thrombosis. Only prior history of arterial thrombosis predicted risk of subsequent arterial thrombosis. Larger cohorts of JAK2 CH patients are needed to understand their outcomes and guide management.