Prevalence and Outcomes of Opportunistic Infections in Steroid Refractory Graft Versus Host Disease Patients Treated with Ruxolitinib, Ibrutinib, and Belumosudil

Chronic graft-versus-host disease (cGVHD) is the leading cause of late non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HCT). It is characterized by immune dysregulation as well as immunosuppression from treatment and is associated with increased infection risk. Thirty-five percent of deaths among patients with cGVHD are attributed to infection.

Three novel agents have recently been approved for the treatment of steroid-refractory (SR)-cGVHD. In contrast to corticosteroids, these agents have more specific immunomodulatory mechanisms of action, however limited data exists regarding risk of infection and utility of antimicrobial prophylaxis in the real-word setting. The aim of this single-institution study was to characterize the incidence and outcome of infections during treatment with ruxolitinib, ibrutinib, and belumosudil therapy.

This was a retrospective review of adult patients (≥18 years) with cGVHD treated with ruxolitinib, ibrutinib, and/or belumosudil between August 2015 and December 2023. GVHD characteristics, treatment, and details of infections were described and analyzed. An infection was attributed to respective drug only during the period the patient was on the agent and recorded only if an organism was documented. Infections were categorized as bacterial, non-respiratory viral, respiratory viral, or fungal. Descriptive statistics were used to summarize variables and the incidence and outcomes of infections.

Ninety-two patients were identified that met inclusion criteria. Organ cGVHD involvement included: 59 (64%) skin, 36 (39%) mouth, 33 (36%) eyes, 27 (29%) liver, 26 (28%) joints and fascia, 21 (23%) gastrointestinal, and 14 (15%) lungs. Most patients (68, 74%) had multi-organ involvement. During the study period, 86 (94%) were treated with ruxolitinib, 16 (17%) with ibrutinib, 14 (15%) with belumosudil, and 5 (5%) with ruxolitinib and belumosudil concurrently. The median number of previous systemic therapies was 2 (range 0 – 5). Most patients were on concurrent prednisone and additional systemic immunosuppression, most commonly tacrolimus (Tac) or sirolimus (Sir). Of the 86 patients treated with ruxolitinib, 67 (78%) were also on prednisone, and 39 (45%) on Tac or Sir. In ibrutinib treated patients (N=16), 11 (69%) were also on prednisone, and 5 (31%) on Tac or Sir. Of the 14 patients treated with belumosudil, 9 (64%) were on concurrent prednisone, and 4 (29%) on Tac or Sir. Of the 5 patients treated with ruxolitinib/belumosudil combination therapy, 2 (40%) were on prednisone and 1 (20%) on Sir.

In ruxolitinib treated patients (N=86), 35 (41%) experienced one or more infections, with 19 resulting hospitalizations. Sixteen (19%) patients experienced non-respiratory viral infections, 15 (17%) respiratory viral, 15 (17%) bacterial, 5 (6%) fungal. Fifty percent (N=8) of the 16 ibrutinib treated patients experienced one or more infections with 6 resulting hospitalizations. Five (31%) patients experienced respiratory viral infections, 3 (19%) bacterial, 1 (6%) viral, and 1 fungal (6%). Of the 14 patients treated with belumosudil, 5 (36%) experienced one or more infections with 4 resulting hospitalizations. Four (29%) patients experienced bacterial infections and 2 (14%) respiratory viral infections. Two of the 5 patients (40%) treated with ruxolitinib and belumosudil concurrently experienced one or more infections with no hospitalizations. One (20%) patient experienced a viral infection, and 1 (20%) patient experienced a bacterial infection. Infection was the primary cause of death in 5 patients. Median time from the start of treatment to first infection was 62 days, (IQR 11 - 142 days) for patients treated with ruxolitinib, 32 days (IQR 16 – 243) for ibrutinib, 107 days (IQR 77 – 295) for belumosudil, and 182 days (IQR 7 – 357) for ruxolitinib/belumosudil combination therapy.

We demonstrate a significant number of infections, including invasive fungal infections, in this cohort of SR-cGVHD patients treated with the study agents. While several factors and concurrent medications may impact the risk of infection in this population, these analyses demonstrate the need for additional risk assessment and antimicrobial prophylaxis when initiating treatment with the agents.