PI-05. First line single-agent ruxolitinib for grade 3-4 acute graft-versus-host disease in patients with severe infectious complications

Summary

Introduction

Corticosteroid treatment has been the standard of care for acute graft-versus-host disease (GVHD) since 1980s. However, their administration is associated with significant number of infectious complications, including invasive fungal infections, severe bacterial infections and viral reactivations. Ruxolitinib (Ruxo) was demonstrated to be an effective second-line agent for GVHD comparable the best available therapy. Its administration was not associated with increased incidence of bacterial or fungal infections. We hypothesized that, in patients with severe bacterial or fungal infections, Ruxo will not exacerbate the existing anti-infectious control.

Patients and methods

The present pilot study enrolled patients who had poorly controlled severe bacterial or fungal infections defined by presence of febrile fever and CRP>50 mg/l, or procalcitonin levels of >1 mcg/l, despite adequate anti-infectious therapy, or poorly controlled localized infection. The study enrolled 5 patients. Their characteristics are shown in Table 1. All the patients received Ruxo at a starting dose of 5 mg bid and topical therapy in case of skin involvement. The therapy was continued until complete response or treatment failure. The dose was increased by 5 mg in non-responding cases.

Table 1. Clinical characteristics of the patients and GVHD

Results

All five patients did respond to the treatment. Four patients had complete response, and in one patient, partial response was achieved after DLI. Median time to partial response was 12 days (range 8-136), and the median term to complete response was 14 days (range 3-44). Median time to Ruxo discontinuation was 105 days (range 12-150). Attempts of early Ruxo discontinuation in two patients with rapid responses resulted into recurrence of GVHD and overlap syndrome. None of the patients had exacerbation of the above mentioned infectious complications. Three of the five patients had chronic GVHD: two of them, with moderate degree, and severe disease was observed in one case. Only one patient received steroids after Ruxo. Additional treatments of GVHD included ECP, rituximab, fecal transplant. Ruxolitinib was generally well tolerated. Toxicities were predominantly hematological, but were associated with pre-existing cytopenias. Three out of five patients required subsequent intravenous antibiotics, one patient received antifungals intravenously, 4/5 patients had CMV reactivation after Ruxo administration. Two cases of sepsis were documented at >100 days after ruxolitinib initiation. Other viral infections included acute respiratory illness in one case, persistence of HHV6 pericarditis, EBV-associated encephalitis. Three out of 5 patients are alive. None of the patients developed a relapse of underlying malignancy. Two fatalities were associated with persistent severe poor graft function and recurrent infections, despite a response for GVHD.

Conclusion

This pilot study confirmed that single-agent ruxolitinib is a viable option for patients with significant risk from steroid treatment. Prolonged exposure to ruxolitinib, likely beyond day+100, is required to prevent GVHD recurrence and chronic GVHD. Patients with persistent severe poor graft function should be switched to alternative treatments. Larger sample size is required to confirm these preliminary observations.

Keywords

Graft-versus-host disease, recurrent, prevention, ruxolitinib.