Tocilizumab Is Effective Therapy for Cytokine Release Syndrome after Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

Haploidentical related-donor (HRD) hematopoietic stem cell transplantation (SCT) is an increasingly important therapeutic option for patients with high-risk hematologic malignancies, with post-transplant cyclophosphamide (PT-Cy)-induced tolerance mitigating life-threatening graft rejection and graft-versus-host disease (GVHD) without disabling immune suppression. Optimal conditioning and graft sources remain unknown. While reduced-intensity conditioning and bone marrow grafts (BMT) are often employed, comparable rates of engraftment and GVHD have been reported with use of peripheral blood stem cells (PBSC), with potentially lower relapse risk. Cytokine release syndrome (CRS), a sepsis-like hyper-immune state driven by interleukin 6, is observed after HRD graft infusion and generally resolves with PT-Cy administration; CRS may be more prominent after PBSCT than BMT. Neither the effect of conditioning on the incidence and severity of CRS nor the contribution of CRS to tumor eradication are known. Tocilizumab, an IL-6 specific antibody, might reduce CRS toxicity while preserving tolerogenic effect of PT-Cy. We reviewed CRS and outcomes in 19 patients treated with HRD SCT with PBSC and PT-Cy. Patients were conditioned with myeloablative (MAC) cyclophosphamide/total-body irradiation (Cy/TBI-900) or reduced-intensity (RIC)fludarabine/cyclophosphamide/TBI-200. CRS was observed in 10/19 patients (7/8 MAC, 3/11 RIC), 3 requiring intensive care. Signs of CRS manifested within 48 hours post-allograft infusion. C-reactive protein (CRP) elevation on Day 0 correlated with development of CRS, with higher CRP corresponding to earlier development of CRS. Tocilizumab was administered in 4 patients, with prompt resolution of signs and symptoms of CRS in each, including decreases in CRP. At median follow-up of 12 months, 17 of 19 achieved prompt full-donor chimerism. Acute GVHD occurred in 9/19 patients, all Stage III skin and steroid-responsive and resolved by 9 months. Chronic GVHD occurred in 3 patients, 2 mild; 1 severe de novo chronic GVHD/overlap with death from fungal pneumonia. 3 patients have relapsed. Tocilizumab-treated patients exhibited comparable outcomes.Tabled 1MAC (n=8)RIC (n=11)Tocilizumab (n=4)Age in Years, median (range)30 (24-62)61 (25-70)53 (25-70)CRS734Neutrophil Engraftment Day, median (range)16 (14-22)17 (11-61)19.5 (15-21)Full-Donor Engraftment7103Acute/Late-Acute GVHD ≥ 2453Chronic GVHD210Relapse1 (7M)2 (4M, 5M)1TRM1 (11M)00HRD PBSCT with PT-Cy yielded adequate engraftment and few early relapses without excessive TRM. Toxicities were acceptable with myeloablative Cy/TBI conditioning; CRS was frequent but tocilizumab therapy was effective. Further investigation of preemptive tocilizumab therapy on the tolerogenic effects of PT-Cy and HRD transplant outcomes is warranted. Open table in a new tab HRD PBSCT with PT-Cy yielded adequate engraftment and few early relapses without excessive TRM. Toxicities were acceptable with myeloablative Cy/TBI conditioning; CRS was frequent but tocilizumab therapy was effective. Further investigation of preemptive tocilizumab therapy on the tolerogenic effects of PT-Cy and HRD transplant outcomes is warranted.