Early Immunosuppression As Cytokine Release Syndrome Prophylaxis in Outpatient Haploidentical Transplants: A Randomized Phase II Study.

IntroductionCytokine release syndrome (CRS) is a common complication following haploidentical hematopoietic stem-cell transplantation (haplo-HSCT), manifesting in over 70% of transplantations. Currently, there is no established prophylactic treatment for CRS. However, preliminary non-randomized data suggest that the early initiation of immunosuppressive graft-versus-host disease (GVHD) prophylaxis may reduce CRS incidence.Objectiveto compare CRS incidence with cyclosporine A (CsA) and mycophenolate mofetil (MMF) initiation on day 0 versus starting the regimen in day +5 for outpatient peripheral blood haplo-HSCT.MethodsThis phase II randomized, unblinded clinical trial (NCT04781803) enrolled 32 adult patients undergoing unmanipulated peripheral blood haploidentical transplantation. Patients were randomly assigned to two different GVHD prophylaxis regimens. GVHD prophylaxis included post-transplant cyclophosphamide (PTCY) 50 mg/kg on days +3 and +4, CsA 6 mg/kg for both study arms, and MMF 1 g BID on day +5 (control arm) or day 0 (experimental arm). Conditioning consisted of fludarabine, cyclophosphamide, and melphalan and was the same across groups. CRS was defined and graded using the Lee criteria and the ASTCT consensus criteria.ResultsWe included 16 patients per group. Overall, 20 patients (62.5%) developed CRS, 13 (81.3%) in the control arm, versus 7 (43.8%) in the experimental arm (p = 0.066).Patients receiving early immunosuppressors primarily experienced grade 1 CRS, while patients initiating treatment on day +5 exhibited grade 1 (n = 9) or grade 2 (n = 4) CRS (p = 0.027). The median day of CRS onset was day +2 (range 1-7). CRS incidence was not associated with age, CD34+/kg, DRI score, HCT-CI, survival, or conditioning intensity. Time to neutrophil and platelet engraftment were similar between groups (p = 0.83 and 0.54, respectively). Hospitalization for any reason was required in 10 patients (62.5%) in the control arm and 9 patients (56.25%) in the experimental arm (p = 0.71). CRS was the cause of hospitalization in 6 cases (31.5%), and 8 out of 20 patients with CRS (40%) were managed as outpatients. The median length of hospitalization was 3.5 days (range, 0-90), with no significant difference between groups (p = 0.89). The most common reasons of hospitalization included infection (n=6, 31.5%), CRS (n=6, 31.5%), hemorrhagic cystitis (n=2, 10.5%), transfusion support (n=2, 10.5%) and mucositis (n=2, 10.5%) and cardiogenic shock (n=1, 5.2%).ConclusionThe reduction in CRS incidence, although notable, did not reach statistical significance. However, a statistically significant reduction in CRS grade was observed when GVHD prophylaxis was initiated on day 0. The completely ambulatory conduct of haplo-HSCT was limited by other complications, including infection and mucositis.