ASXL1 Mutation and Leukocytosis Undermine Spleen Response to Pacritinib in Myelofibrosis

Background:

Non-transplant treatment options in myelofibrosis (MF) are palliative in scope and include JAK2 inhibitors (JAKi): ruxolitinib, fedratinib, pacritinib, and momelotinib. All four JAKi are effective in reducing spleen size and alleviating symptoms. In addition, pacritinib and momelotinib exhibit erythropoietic effect, attributed to alleviation of ineffective erythropoiesis through inhibition of activin A receptor type-I. In the current study, we sought to identify molecular or clinical predictors of response to pacritinib in MF patients treated outside of clinical trials.

Methods:

The current study was conducted under an institutional review board approved minimum risk protocol that allowed retrospective collection and analysis of data from patient records (Mayo Clinic, Rochester, MN; Scottsdale, AZ; and Jacksonville, FL). Anemia response assignment was restricted to patients with baseline hemoglobin level of <10 g/dL and required, for transfusion dependent cases, achieving transfusion independence and, for transfusion-independent cases, an increase in hemoglobin of ≥1.5 g/dL, both sustained for a minimum 2 months; spleen response was clinically vetted but was also supported by radiologic imaging when available and required a ≥50% decrease in palpable splenomegaly for spleen size >10 cm or the spleen becoming not palpable for a spleen size 5-10 cm at base line. Symptom response was adjudicated by central review and required a marked or moderate improvement to qualify as response; because of the retrospective nature of the study, symptom burden assessment by formal criteria was not attempted. Leukocyte cutoff level used for response analysis was determined by receiver operating characteristic curve analysis. Conventional statistical methods were applied using JMP Pro 16.0.0 software (SAS Institute, Cary, NC, USA).

Results:

We identified 36 NGS-annotated patients with MF who received pacritinib therapy between April,2022 and June,2023 (median age 66 years; 56% males). Twenty-five (69%) patients had failed previous JAKi therapy while 11 (31%) were JAKi-naïve. Eighteen (50%) patients were transfusion-dependent while the median (range) counts were 106 x 10(9)/L (14-578) for platelets, 6.6 x 10(9)/L (1.2-112.8) for leukocytes, and 9 x 10(9)/L (5-12.4) for hemoglobin; leukocyte count was ≥15 x 10(9)/L in 11 (31%) patients and hemoglobin <10 g/dL in 29 (81%). Karyotype was unfavorable in 12 (34%) patients. Driver mutation distribution was JAK2 55%, CALR 27%, MPL 11%, and triple-negative 5%. NGS revealed mutations involving ASXL1 36%, U2AF1 13%, IDH1 13%, SF3B1 13%, K/NRAS 5%, SRSF2 8%, and EZH2 5%.

Pacritinib was started at 200 mg BID in 9 (25%) patients and at lower doses in the remaining. Median duration of pacritinib therapy was 4 months (range 1-15). Anemia response was documented in 5 (17%) of the 29 patients with baseline hemoglobin <10 g/dL, spleen response in 12 of 28 evaluable (42%) and symptom response in 18 (50%). Improvement in symptoms was always accompanied by both anemia (p=0.008) and spleen (p=0.01) response; by contrast, there was no significant correlation between anemia and spleen responses (p=0.9) (Table 1).

Significant correlations with molecular or clinical variables were mostly apparent for spleen response, which was more likely to occur in the absence of ASXL1 mutation (61% vs 10%; p=0.006), with leukocyte count <15 x 10 (9)/L (55% vs 0%; p=0.005), and in JAKi-naïve vs previously-exposed cases (75% vs 30%; p=0.03; Table 1); significance was sustained by all three risk factors during multivariable analysis; the prognostic impact of ASXL1 (p=0.02 vs 0.01) and leukocytosis (p=0.01 vs 0.07) was apparent in both JAKi-naïve vs JAKi-exposed cases. Anemia response was non-significantly (p=0.27) higher in transfusion-independent (27%) vs dependent (11%) cases, at baseline, and was more likely (p=0.04) to occur in patients starting at lower dose levels. Treatment-emergent adverse events included diarrhea 44%, nausea/vomiting 19%, and grade-3/4 thrombocytopenia 38% or neutropenia (11%).

Conclusions: ASXL1 mutation and leukocytosis (>15 x 10⁹/L) are independently associated with inferior spleen response to pacritinib, in both JAKi-naïve and JAKi-exposed myelofibrosis. These observations are important for individualized treatment selection.