Cytokine Release Syndrome after Peripheral Blood T-Cell Replete Haploidentical Transplantation Is Not Prevented By Dexamethasone and Limits Its Full-Outpatient Conduction

Introduction: Our center has implemented an outpatient-based peripheral blood haploidentical HSCT (haplo-HSCT) program since 2012. Cytokine release syndrome (CRS) associated with T-cell replete haplo-HSCT is characterized by fever and high levels of inflammatory cytokines with symptom onset typically occurring early after cell infusion, coinciding with maximal in vivo T-cell expansion. In this study, we report our analysis of CRS development after T cell-replete haplo-HSCT after using prophylactic dexamethasone and focusing on the impact of CRS on hospitalization and transplant outcomes in our outpatient program.

Methods: In this retrospective study, adult patients undergoing a T-cell replete haplo-HSCT at our transplant center between January 2016-2018 were included. CRS was defined and graded using the criteria described by Lee et. al. Conditioning was based on fludarabine 25 mg/m2/day (day -5 to -3), cyclophosphamide 350 mg/m2/day (day -5 to -3), and oral melphalan 50-100 mg/m2 (day -2 to -1). For graft-versus-host disease (GVHD) prophylaxis we used post-transplant cyclophosphamide (PTCy) 50 mg/kg on days +3 and +4 as well as mycophenolate mofetil and either cyclosporine or tacrolimus starting on day +5. All patients received dexamethasone 8 mg IV on day 0 to +2 as prophylaxis against CRS. Disease-risk index (DRI) and HCT-Comorbidity Index (HCT-CI) were calculated based on established definitions. The primary objective was to evaluate the incidence of CRS with dexamethasone prophylaxis during an outpatient-based peripheral blood haplo-HSCT. Secondary objectives were to describe factors associated with CRS and to determine the impact of CRS on transplant outcomes and hospitalizations.

Results: There were 42 patients included; the median age was 32.5 years (range, 16-66). The median DRI score was 3 (range, 1-4). The most common underlying diagnosis was acute lymphoblastic leukemia (n=14, 33%), followed by acute myeloid leukemia (n=8, 19%), and lymphoma (n=7, 16.6%). Conditioning was myeloablative (n=33, 79%) or reduced-intensity (n=9, 21%). Thirty patients (71.4%) developed CRS. CRS severity was grade 1-2 in 28 patients (66.7%) and grade 3 in 2 patients (4.8%). Median day of onset occurred on day +2 (range 0-4) and usually resolved after PTCy on day +5 (range, 1-11). The incidence of CRS was not associated with recipient age, number of CD34+ cells infused, DRI score, baseline HCT-CI score, and conditioning intensity. Time to neutrophil and platelet engraftment was not different in patients with CRS compared with patients without. Hospitalization was required in 36 cases (87%) while 6 patients (13%) were followed in a fully-outpatient basis, including 2 patients with grade 1 CRS. The median length of hospitalization was 13 days (range, 0-50) for patients with CRS and 8 days for patients without CRS (range, 0-44). The most common signs and symptoms besides fever were gastrointestinal manifestations (36.6%), hypoxemia (30%), fluid-responsive hypotension (16%) while 2 patients required vasopressors.

Conclusion: The completely ambulatory conduct of haplo-HSCT was limited by the development of CRS. However, even in patients who developed CRS median length of hospitalization was short. CRS was common despite dexamethasone prophylaxis although most CRS were of grade 1 or 2. None of the factors evaluated were associated with CRS development in this context, and CRS did not influence time to engraftment, cumulative incidence of acute or chronic GVHD. New strategies are required to prevent CRS and prevent hospitalizations associated with haplo-HSCT.

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