Rapid and Sustained Recovery of Cellular Immunity in Patients with Myelofibrosis on Momelotinib Therapy
Authors: Makker Jasmine , Thaw Kyaw Htin , Sheikh Amna , Cadman-Davies Llywelyn , Duminuco Andrea , Torre Elena , Woodley Claire , Asirvatham Susan , O' Sullivan Jennifer , Curto-Garcia Natalia , Sriskandarajah Priya , Radia Deepti H. , de Lavallade Hugues , Kordasti Shahram , Harrison Claire , Harrington Patrick 
Published: December 2024

Momelotinib (MMB) is a novel oral JAK1/2 inhibitor (JAKi) and Activin A receptor Type 1 inhibitor that has demonstrated benefits in reducing symptoms, anemia, and splenomegaly in myelofibrosis (MF) patients. While established JAKi therapy with Ruxolitinib (RUX) is linked to notable immunosuppression, the impact of MMB on cellular immunity has not yet been studied.We aimed toevaluate ‘real-world’ MMB efficacy and its effects on immune cell populations in RUX-exposed as well as RUX-naïve patients.

Patients were monitored for 48 weeks after starting MMB. Sequential peripheral blood samples were obtained to assess changes in immune cell frequencies and to evaluate hematological response at baseline, 6, 12, 24, and 48 weeks. 10 healthy subjects were used as controls (HC). For normally distributed data, means, t-tests, and one-way ANOVA were used for statistical analyses; otherwise, medians, Mann-Whitney U, and Kruskal-Wallis were used.

40 MF patients starting MMB (200 mg daily n=36, 100 mg daily n=4), who were RUX-naïve (n=6) or had prior RUX resistance/intolerance (n=34) were included. Total daily dosage of RUX was ≤25 mg in 24 and &gt;25 mg in 7 patients, with a median time of 1.5 years on RUX. Of these, primary MF n=13 and secondary MF n=27, with DIPSS+ intermediate-1 n=3, intermediate-2 n=22, and high n=14. Median age was 70 years (male n=23, 57.5%).

Immune cell recovery: Patients showed significantly reduced frequencies of CD3+, CD4+, and CD8+ T-cells and NK cells at baseline compared to HC (p=&lt;0.001, 0.001, &lt;0.001, 0.01 respectively). At baseline, total lymphocytes were 1183 cells/μL, CD3+ 727, CD4+ 449.7, CD8+ 232, and NK 114; at 6 weeks post-MMB, there was a significant increase to 1556.5 (total lymphocytes), 968 (CD3+), 530.5 (CD4+), 295.5 (CD8+), and 213.5 cells/μL (NK); p=0.007, 0.006, 0.012, 0.08, 0.009 (n=28), returning towards HC levels. This increase persisted at 12 weeks: 1459, 1104, 477, 368, and 192 (p=0.007, 0.03, 0.1, 0.1, 0.008; n=21); 24 weeks: 1720.4, 1131.5, 702.1, 355.5, and 168.5 (p=0.04, 0.02, 0.02, 0.06, 0.01; n=20); 48 weeks: 1772.6, 1025.1, 586.6, 416.9, and 213 cells/μL (p=0.04, 0.1, 0.2, 0.1, 0.03; n=11).

There were no significant differences in immune subset frequencies between RUX-exposed and RUX-naïve patients at any time point. Further, RUX-naïve patients also demonstrated an increase in counts across all immune subsets: total lymphocytes increased from 950.5 cells/μL (baseline, n=4) to 1459 (6 weeks, n=3), 1963.5 (12 weeks, n=2), and 1585.3 (24 weeks, n=3). CD3+ rose from 648.3 to 768.7, 1195.5, 955; CD4+: 412 to 534, 798.5, 420; CD8+: 139 to 228, 367, 301.7; NK cells: 166 to 224.3, 261.5, 349; B-cells: 156.7 to 259.3, 507, 284 cells/μL at the respective time points.

In RUX-exposed patients, no significant differences were observed in immune cell frequencies between those receiving ≤25 mg and &gt;25 mg total daily dosage. Similarly, on stratifying patients by diagnosis (primary vs secondary MF), DIPSS+ score, driver mutation subtype, and additional high-risk mutations, the differences at each time point were not significant.

Hematologic response: At 6 weeks, mean Hb increased from a baseline of 90.5g/L to 102g/L (p=0.005, n=21). At 12 weeks, mean Hb remained significantly higher at 105.5g/L (p&lt;0.001, n=18), which was sustained at 24 weeks (mean Hb=104.9g/L, p=0.004, n=20) and 48 weeks (mean Hb=104.7g/L, p=0.007, n=11). 33% of patients at baseline required no transfusions through follow-up (n=9, 7, 4 at 12, 24, 48 weeks). 67% were either transfusion dependent (n=10; defined as ≥6 units of red blood cell transfusions in preceding 12 weeks) or required occasional transfusions (n=14) initially. Of these, only 3 remained transfusion dependent and 9 became transfusion independent at 12 weeks, 7 more at 24 weeks, and 1 further at 48 weeks, which was maintained until their follow-up (24 weeks n=13; 48 weeks n=7).

Conclusion: We describe a notable recovery in immune cell frequencies as soon as 6 weeks after starting MMB therapy, persisting up to 48 weeks. The degree of contribution from RUX discontinuation remains unclear, however, responses were also observed in a RUX-naïve cohort, suggesting an additional MMB off-target effect. Additionally, we continue to demonstrate that MMB significantly improves anemia and reduces transfusion dependency in a real-world setting. Further studies are required to assess the mechanistic effects of MMB on immune cell proliferation and recovery.