Gvhd Therapy with Ruxolitinib Is Frequently Associated with Cytopenias, but Significant Decline in Hemoglobin Level Was Only Observed in Non-Responders at Day 28

Background. Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic cell transplant (allo-HCT). Ruxolitinib (a JAK 1/2 inhibitor) has become the standard of care for the treatment of steroid refractory acute GVHD (SR-aGVHD). However, cytopenias are a frequent adverse event (AE), as JAKs are necessary for hematopoietic growth factor signaling. Furthermore, GVHD itself is also associated with bone marrow suppression. Little is known about hematologic trends in GVHD patients who achieve response to JAK1/2 inhibitor therapy.

Methods. We conducted a retrospective study evaluating 57 allo-HCT patients with steroid-dependent (SD) or SR-aGVHD who were treated with ruxolitinib from 02/2017 to 05/2023. Patients were classified clinically as standard or high-risk aGVHD, and counts were assessed pre-treatment and at day 28. CBCs at baseline and day 28, along with change in CBC from baseline, were compared across groups using either a t-test or a paired t-test. Significance was defined as a p-value <0.05.

Results. Most patients received a peripheral blood stem cell graft with calcineurin inhibitor-based GVHD prophylaxis for the treatment of hematologic malignancies. At the time of ruxolitinib initiation, 30 patients (53%) had standard-risk and 27 patients (47%) had high-risk aGVHD. Counts were first assessed at baseline, prior to ruxolitinib initiation. While high-risk patients had a lower median hemoglobin (hgb) at baseline (10.3 vs. 8.8, p= 0.011), median platelet (plt) counts were similar between the two cohorts (120,000 vs. 87,000, p= 0.14). WBC, ANC, and ALC did not differ between high-risk and standard-risk patients. We next assessed counts 28 days after ruxolitinib initiation and found that standard-risk patients maintained stable hgb counts (p= 0.95), while high-risk patients exhibited a significant decline (p= 0.034). Both standard and high-risk patients had overall decreases in their plt counts (standard-risk p= 0.001; high-risk p= 0.009). Finally, we analyzed count trends in patients stratified by response to ruxolitinib therapy. Baseline hgb and plt counts were not significantly different between complete and non-responders; however, non-responders showed an average drop in hgb at day 28 (average delta hgb -0.60), while complete responders showed an average increase (average delta hgb 0.60) (p= 0.011). Both complete and non-responders showed an average drop in platelet count (-12 vs. -82, p= 0.13).

Conclusion. Patients with SD- or SR-aGVHD often have cytopenias prior to treatment with ruxolitinib. Our results show that standard-risk patients tend to maintain stable hgb during ruxolitinib therapy, while high-risk patients show significant declines in their hgb level. When patients were stratified by response (rather than risk), this effect was primarily seen in non-responders. Both standard and high-risk patients are at risk for worsening thrombocytopenia, regardless of response. Worsening hemoglobin level may therefore serve as a biomarker for treatment failure. Further prospective studies and cellular/molecular analyses are needed to better elucidate the complex interaction between JAK1/2 inhibitor therapy and bone marrow suppression in GVHD.

Perales:VectivBio AG: Consultancy; OrcaBio: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; ImmPACT Bio: Consultancy; Caribou Biosciences: Consultancy; Allogene: Consultancy, Research Funding; Adicet: Consultancy; ADC Therapeutics: Consultancy; Nektar Therapeutics: Consultancy; Sanofi S.A.: Consultancy; Novartis: Consultancy; Miltenyi Biotec Incorporated: Consultancy; Kite Pharmaceuticals: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; NexImmune: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Omeros: Current equity holder in publicly-traded company; OrcaBio: Current equity holder in publicly-traded company; Miltenyi Biotec: Consultancy, Research Funding; Sellas Life Sciences: Research Funding. Ponce:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; OncLive: Consultancy; Evive: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.