Treatment of Myeloproliferative Neoplasms with Janus Kinase Inhibitors: A Meta-Analysis of Cardiovascular Safety

BACKGROUND:

Myeloproliferative neoplasms (MPN) are characterized by excess proliferation of hematopoietic cells, and include entities such as myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET). Thrombosis is a significant cause of mortality and morbidity for MPN patients. Janus kinase (JAK) inhibitors have transformed the treatment of MF and PV over the last decade. However, they are known to increase weight and cholesterol, and have been shown to increase major adverse cardiovascular events (MACE) in the context of rheumatoid arthritis. Here we conducted a first-of-a-kind narrative review and meta-analysis of cardiovascular events in MPN patients treated with JAK inhibitors.

METHODS:

A systematic search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) using medical subject headings and key terms for MPNs, JAK inhibitors and cardiovascular disease. The search was performed on the following databases: Pubmed, Ovid Embase, Ovid Medline, Cochrane Library and Clinicaltrials.gov from inception to January 2024. The title, abstract and full-text report were screened by two researchers independently, and any conflicts were resolved by consensus. Clinical trials and retrospective studies were eligible for inclusion provided they had a control group which did not include a JAK inhibitor.

MACE was defined as a composite of myocardial infarction, cerebrovascular events, heart failure and cardiovascular death. Hypertension was included as an adverse event due to its proven association with cardiovascular disease. MACE, hypertension, and thrombosis were recorded as rate per 100 patient-years in tabular format. Incidence rate ratios (IRR) were calculated for each study. IRRs were pooled using a random effects model, to account for the different JAK inhibitors and MPN subtypes within the meta-analysis. Heterogeneity across studies was assessed using Cochran Q and I² indices: low heterogeneity (I²<30%), moderate heterogeneity (I²=30-60%), high heterogeneity (I²>60%). The ‘meta’ package on R was employed to perform all analyses (version 2024.04.2). Data concerning MACE, hypertension and thrombosis was available for 10, 6 and 9 studies, respectively.

RESULTS:

The criteria for inclusion were met by 23 publications including 11 studies, 9 clinical trials and 2 retrospective analyses. Studies included patients with MF (n=6), PV (n=4) and ET (n=1). The analysis of MACE included ruxolitinib (n=8) and pacritinib (n=2); the analysis of hypertension included ruxolitinib (n=4), momelotinib (n=1), and pacritinib (n=1); and the analysis of thrombosis included ruxolitinib (n=8) and momelotinib (n=1). Median follow-up for the control group was between 17.3 to 122 weeks and 20 to 260 weeks for the JAK inhibitor group. Study heterogeneity was low in all analyses.

In the analysis of thrombosis, the pooled IRR was 0.52 (95% CI: 0.28-0.98, p=0.04) (I² = 53.9%) suggesting a significant reduction in thrombotic events with JAK inhibitor treatment. This finding was primarily driven by studies investigating the use of ruxolitinib in MF and PV (n=7). When a subgroup analysis of ruxolitinib in MF and PV was performed, an even more significant reduction was found (IRR 0.378, 95%CI: 0.22-0.66, p=0.0006) (I²=27.4%). Collectively, JAK inhibitor treatment did not significantly increase the risk of MACE (IRR 0.97, 95% CI: 0.52-1.82, p=0.93) (I² = 8.8%), or hypertension (IRR 0.81, 95%CI: 0.48-1.35, p=0.42) (I²= 11.3%).

CONCLUSION:

These findings suggest that ruxolitinib significantly reduces the risk of thrombosis in patients with PV and MF and may show a similar effect in ET alongside momelotinib in MF. As thrombosis is a major cause of mortality in MPNs, a reduction in thromboembolic events should be considered an additional clinical benefit of JAK inhibitors. Moreover, our analysis suggests that the use of JAK inhibitors in the treatment of MPNs is not associated with an increase in MACE, adding to the existing body of evidence which demonstrates the safety of JAK inhibitors in the treatment of MPNs. Further prospective clinical trials are warranted to explore the potential thrombosis risk reduction with other JAK inhibitors and in other types of MPNs.

Harrison:Keros: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy; Geron: Consultancy; Galecto: Consultancy; MorphoSys/Constellation: Consultancy, Honoraria, Other: Research: PI, Research Funding, Speakers Bureau; Sobi: Consultancy; MSD: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; IMAGO: Consultancy, Honoraria, Speakers Bureau; AOP: Consultancy, Honoraria, Speakers Bureau; CTI: Ended employment in the past 24 months; BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Other: Teaching and Speaking; Research: PI, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Teaching and speaking; Research: PI, Research Funding, Speakers Bureau; MPN voice: Other: Leadership role.