An independent, multi-center analysis of the post-approval utilization and efficacy of pacritinib and momelotinib in patients with myelofibrosis

Abstract

Abstract Introduction JAK inhibition is the basis of treatment for most patients (pts) with myelofibrosis (MF). Early JAK inhibitors (ruxolitinib (RUX) and fedratinib) result in myelosuppression that often exacerbates disease-related anemia and thrombocytopenia. The FDA-approval of pacritinib (PAC) in 2022 and momelotinib (MOM) in 2023 have extended the benefits of JAK inhibition to pts with cytopenic MF and, via inhibition of non-JAK target kinases, may improve hematologic parameters. PAC and MOM have different labeled indications; the former approved for pts with MF and platelet (plt) count <50 x109/L, and the latter for pts with MF and anemia. We assessed the post-approval utilization of PAC and MOM in an independent, multicenter, retrospective study comparing the demographics, disease features and outcomes of treated pts. Methods IRB approval at each center was obtained prior to identifying pts treated with standard of care PAC and MOM from 7 academic centers from February 2022 to May 2025. Baseline demographic, clinical, genomic, and treatment information and hematologic values at 3, 6, 9 and 12 months (mo) of therapy were collected. Adverse event data was collected from detailed chart review. Results We identified 236 pts who received either PAC (n = 123) or MOM (n = 113); 28 pts received both PAC and MOM with 78% receiving PAC before MOM. Median age at treatment start was 67 years (y) in PAC-treated pts and 69 y in MOM-treated pts. PAC-treated pts started treatment a median of 3.2 y after diagnosis vs. 2.8 y for MOM-treated pts. Prior RUX use was common in PAC (71%) and MOM-treated (68%) pts. Among pts who received prior RUX, 65% of PAC and 63% of MOM-treated pts had discontinued RUX within 2 mo of starting treatment. Among PAC-treated pts, 20% were high-risk (50% INT-2) by DIPSS compared to 12% (58% INT-2) treated with MOM. Median WBC and hemoglobin (hgb) were 6.5 x 109/L and 8.7 g/dL for PAC-treated pts compared to 7.9 x 109/L and 8.5 g/dL for MOM-treated pts. PAC-treated pts had a lower median plt count (54 x 109/L vs. 230 x 109/L, p < 0.01). A similar proportion of PAC- and MOM-treated pts (28% vs. 26%) were RBC transfusion-dependent when starting treatment. PAC-treated pts were more likely to harborJAK2 mutations compared to MOM-treated pts (77% vs 56%, p < 0.01), while MOM-treated pts were more likely to harbor CALR mutations (30% vs. 12%, p < 0.01). A similar proportion of PAC- and MOM-treated pts harbored at least 1 high molecular risk mutation (38% vs 45%). PAC-treated pts were more likely to have abnormal cytogenetics compared to MOM-treated pts (55% vs. 37%, p = 0.02). For both PAC and MOM-treated pts, mean hgb increased from baseline to 3 mo and 6 mo. At baseline, the mean hgb was 8.8 g/dL in the PAC group compared to 8.4 g/dL in the MOM group. At 6 mo, hgb increased to 9.0g/dL in the PAC group and 9.3g/dL in the MOM group; corresponding to a 3% increase with PAC (p=0.79) and an 11% increase with MOM (p<0.01). Pts who discontinued RUX within 2 mo of starting PAC or MOM had more robust increases in hgb from baseline to 6 mo [6% (PAC) and 17% (MOM)]. At 6 mo, the mean plt count decreased from 57 x 109/Lto 56 x 109/Lin the PAC group and from 188 x 109/L to 158 x 109/L in the MOM group (2% decrease with PAC vs. 16% decrease with MOM, p < 0.01). In pts who discontinued RUX within 2 mo of starting PAC or MOM, plt count rose by 12% in PAC-treated pts and decreased by 32% in MOM-treated pts (p = 0.045). The proportion of PAC vs MOM-treated pts discontinuing therapy at 3, 6, and 12 mo was 26% vs 17%, 52% vs 29%, and 70% vs 42%, respectively. The most common reason for discontinuation of PAC and MOM were non-hematologic AEs. MOM-treated pts had longer median duration of treatment compared to PAC-treated pts (15.7 mo vs. 6.0 mo; p < 0.01). Median overall survival was 22.8 mo for PAC treated pts vs. not reached for MOM-treated pts. Conclusion While pts treated with PAC and MOM in clinical practice share some demographic, clinical, and genomic features, several critical differences exist. Differences in treatment duration and survival likely reflect multiple factors including baseline risk score, plt count, and cytogenetic abnormalities. The magnitude of these differences warrants further investigation. Overall, this real-world study highlights clinical nuances in JAK inhibitor selection and emphasizes the opportunity to personalize treatment approach.