Improvement in Serum Albumin As a Measure of Improved Metabolic Profile in Pacritinib-Treated Patients: A Retrospective Analysis of Patients Treated across Three Clinical Trials

Background: As an acute phase reactant and a marker of nutritional status, serum albumin is a prognostic marker in patients with myelofibrosis (MF), with levels tending to decrease over time. An unfavorable cachexia index, based on albumin <4.3 g/dL and cholesterol <122 mg/dL, is associated with inferior survival in patients with MF. [Tefferi A, et al. Blood Adv. 2018] Retrospective data in patients with MF suggest that the JAK1/2 inhibitor ruxolitinib is associated with increases in albumin and cholesterol. [Kuykendall AT, et al. JCO Precision Oncology, 2024]. However, ruxolitinib is also associated with weight gain in many patients, which may be perceived as bothersome by those without cachexia or may even impact cardiovascular risk. The metabolic profile of the JAK2/IRAK1 inhibitor pacritinib has not previously been described.

Methods: Patients with MF who were treated with pacritinib (200 mg twice daily [BID] or 400 mg once daily [QD]) in prior Phase 2 or 3 clinical trials (PERSIST-1 [NCT01773187], PERSIST-2 [NCT02055781], and PAC203 [NCT04884191]) were included in this analysis. Shifts in albumin and weight were analyzed among patients with available Week 12 or 24 data. Among patients requiring treatment for diabetes, changes in medication dosing were analyzed.

Results: A total of 484 pacritinib-treated patients were included in the pooled analysis. The median age was 68 years, 56% were males, median weight of 71 kg, median body mass index (BMI) of 24.5 kg/m², median hemoglobin of 9.8 g/dL and median platelets of 80 x10⁹/L. At baseline, the vast majority of patients (93%) had normal or high BMI (only about 2% had BMI <18 kg/m²).

Among patients with baseline hypoalbuminemia (<3.5 g/dL), 65% (11/17) had improvement to normal albumin levels at Week 12, and 18% (3/17) had values ≥4.3 g/dL. Among patients with baseline intermediate albumin values (3.5 to <4.3 g/dL), 44% (93/210) improved to ≥4.3 g/dL whereas only 6% (12/210) developed hypoalbuminemia. Among patients starting with higher albumin values, 87% (171/197) maintained values ≥4.3 g/dL. Similar trends were observed among patients at Week 24, with 73% (8/11) of patients with baseline hypoalbuminemia improving to normal levels, 41% (64/156) with baseline intermediate values improving values ≥4.3 g/dL, and 85% (144/170) with baseline values ≥4.3 g/dL maintaining these levels. Among patients with baseline cholesterol levels less than 125 mg/dL, 24% (38/157) experienced an increase to ≥125 mg/dL, and none had an increase over 200 mg/dL at week 24.

Over this interval, weight remained stable, with median change 0 kg (interquartile range [IQR]: -1.3, +1.8 kg) at Week 12 and +0.3 kg (IQR: -1.3, +3.14 kg) at Week 24. Among 26 patients requiring metformin at study start, 19% (n=5) discontinued metformin while on treatment with pacritinib. Among 15 patients requiring insulin at study start, 1 discontinued insulin on study treatment.

Conclusions: Patients with MF treated with pacritinib trend towards improvement in serum albumin while maintaining stable weight and normal cholesterol levels in this retrospective analysis. Further analysis, including from the ongoing PACIFICA study (NCT03165734), is warranted to confirm these findings and assess other metabolic effects.