Pacritinib Therapy for JAK2 Inhibitor-Naïve or -Experienced Patients with Myelofibrosis: Mayo Clinic Series of 60 Consecutive Patients Treated Outside of Clinical Trials

Background

Pacritinib (PAC) is a relatively selective JAK2 vs. JAK1 inhibitor (JAKi) and is one of four FDA-approved JAKi for use in myelofibrosis (MF). PAC is indicated for MF patients with thrombocytopenia (Platelets <50 x 10⁹/L). In a previously published controlled study of MF patients with platelet count <100 x 10⁹/L (PERSIST-2), including JAKi-naïve and ruxolitinib-experienced, PAC therapy at the recommended dose of 200 mg BID was associated with a ≥35% spleen volume reduction rate of 22%; response rate was lower in ruxolitinib-experienced patients for both 200 mg BID (9.3%) and 100 mg BID (1.8%) dosing (JAMA Oncol 2018;4:652); a more recent post-hoc analysis suggested an additional benefit in anemia with 25-37% of transfusion-dependent patients achieving a ≥12-week transfusion-free period (Blood Adv 2023;7:5835). Herein, we describe our experience with the drug outside of a clinical trial setting.

Methods

Study patients were retrospectively recruited from Mayo Clinic (USA) databases, after approval from IRB. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Study inclusion criteria included documentation of PAC therapy outside of a clinical trial setting. Spleen response was adjudicated by the 2013 International Working Group-European LeukemiaNet (IWG-ELN) response criteria (Blood 2013;122:1395). Anemia response was rated by the revised 2024 IWG-ELN criteria (manuscript submitted; transfusion-free period x 12 weeks and/or 12-week average increase in hemoglobin ≥1.5 g/dL). Conventional statistical methods were employed.

Results

A total of 60 MF patients (median age 70 years; males 62%; primary MF 63%) received PAC upfront (N=19; 32%) or after failing treatment with another JAKi (N=41; 68%), including ruxolitinib (N=39; 65%): JAK2 60%, CALR 27%, MPL 10%. Reasons for discontinuation of previous JAKi treatment included drug intolerance (41%), relapse after initial response (33%), and suboptimal response (26%). Median interval between diagnosis and treatment with PAC was 4 years (range 0-22). At PAC treatment initiation, DIPSS-plus risk distribution was high in 48%, intermediate-2 47%, and intermediate-1 (5%). Transfusion-dependent anemia (TDA; ≥3 units during 12 weeks prior to enrollment) was present in 40% of patients, platelet count <50 x 10⁹/L 25%, leukocyte count >11 x 10⁹/L 40%, spleen size >15 cm 76%, constitutional symptoms 55%, complex/monosomal karyotype 27%, and mutations in SRSF2 11% or ASXL1 33%.

PAC initial dose was 100 (N=41) or 200 (N=19) mg BID. Dose was increased in 44% of patients started at 100 mg BID and decreased in 55% of those started at 200 mg BID. Among 47 patients evaluable for anemia response, only one of 23 with non-TDA (2% overall and 4.3% at 200 mg BID dosing) and none of 24 with TDA responded. In evaluable patients, spleen response rate was 13% (95% CI 5.9-24.7) overall and higher in JAKi-naïve (29%; 95% CI 11.7-54.7) vs. JAKi-experienced (6%; 95% CI 1.6-19.1; p=0.04). Spleen response rate was higher in the absence of leukocytosis (21% vs. 0%; p=0.01) or complex/monosomal karyotype (17% vs. 0%; p=0.05) but similar between 100 and 200 mg BID initial dosing (p=0.9).

At a median follow-up of 14 months (range 1-27), PAC was discontinued in 80% of the patients: intolerance 58%, suboptimal response 54%, transition to allogeneic stem cell transplants (ASCT) 10%. Major side effects were more frequent with 200 vs. 100 mg BID dose and included diarrhea 43%, nausea/vomitting 17%, dyspnea 25%, peripheral edema 28%, allergic reaction 13%, grade 3/4 neutropenia 22%, and grade 4 thrombocytopenia 34%. Up to the time of this writing, 17 deaths (28%), 11 (18%) ASCT, and 3 (5%) leukemic transformations were documented. In multivariable analysis, post-PAC survival was adversely affected by TDA (HR 11.9; p<0.01), platelet count <50 x 10⁹/L (HR 7.4; p<0.01), and SRSF2/ASXL1 mutations (HR 10.7; p<0.01), all independent of ASCT, which was independently associated with longer survival (HR 9.0; p<0.01).

Conclusions: The observations from the current real-world study, regarding the moderate activity of PAC for reducing spleen size, are consistent with those of the aforementioned controlled clinical trial (PERSIST-2). However, despite recent suggestions of the drug’s mechanistically unique erythropoietic activity, the anemia response rate seen in the current study was underwhelming.