Cytokine release syndrome after allogeneic stem cell transplantation with posttransplant cyclophosphamide

Abstract

Cytokine release syndrome (CRS) is a systemic inflammatory response with aberrant immune activation and immune hyperstimulation, that leads to increased cytokine levels and inflammation. CRS has been described after antibody and cellular-based therapies. The use of posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has led to the extension of allogeneic HSCT to patients without HLA-identical donors. Furthermore, PTCy has also been introduced in matched and unrelated donor HSCT. However, description of incidence and clinical impact of CRS on outcomes in these patients is scarce. We retrospectively analyzed 107 consecutive haplo-HSCT and 39 HLA-identical HSCT with PTCy from 2010 to 2017 in our institution. We used published CRS criteria to identify 76% and 14% of patients who developed CRS after haplo-HSCT and HLA-identical HSCT, respectively. Most patients presented CRS grades 1 and 2. Only one patient from the whole series presented grade 3 CRS and required tocilizumab therapy. The use of peripheral blood stem cells (PBSC), as well as total nucleated cells infused were associated with an increased risk of CRS. Patients who presented CRS developed grade II-IV acute GVHD more frequently than those who did not (60% vs 28.6% respectively, P = .012). The development of CRS was not significantly associated with nonrelapse mortality or overall survival. CRS is a frequent complication after PBSC haploidentical T-repleted HSCT, but significantly less frequent after HLA-identical HSCT. Most cases are mild. Prompt identification allows adequate management of severe forms. K E Y W O R D S cyclophosphamide, cytokine release syndrome, haploidentical stem cell transplantation, hematopoietic stem cell transplantation 1 | INTRODUCTION Cytokine release syndrome (CRS) is a systemic inflammatory response that occurs as a result of high-level immune activation. With the extended use of inmune-based therapies CRS has been increasingly recognized. 1 However, the pathophysiology of CRS is still incompletely understood. CRS is triggered by the massive release of IFN-γ by activated Tcells and / or tumor cells after the administration of antibody-based therapies, nonprotein-based cancer drugs such as oxaliplatin and lenalidomide and, recently, the new T-cell engaging immunotherapies including bispecific antibody constructs and chimeric antigen receptor (CAR) T cells. IFN-γ causes activation of different immune cells especially macrophages. Activated macrophages produce a cascade Jose Luis Díez-Martín and Mi Kwon contributed equally to this study.

Cytokine release syndrome after haploidentical hematopoietic stem cell transplantation with antithymocyte globulin: risk factors analysis and poor impact on outcomes for non-remisssion patients

“…They need facemask with oxygen delivered at > 6 L/minute to overcome the oxygenation deficit. In our study, the incidence of CRS was 54.9%, which was markedly lower than prior reports [15,16,28,29,32]. The biggest difference was the use of ATG instead of PTCy for GVHD prophylaxis between our study with others.…”

“…We speculated that this might be due to the continuous expansion of T-cells after the reinfusion of stem cells around d+7. Many studies showed similar results demonstrating that the use of peripheral blood grafts was an independent factor predictive of CRS development after haplo-HCT [29,32,37]. In our series, the source of grafts consisted of PB and PB + BM.…”

“…Abboud et al [16] indicated that the presence of CRS did not alter the rates of aGVHD. However, Solán et al [29] showed that patients with CRS developed grade II-IV aGVHD more frequently than those without CRS (60% vs 28.6% respectively, P = .012). Perhaps the differences in these results could be attributed to the small sample size in the study cohort as well as the limited number of patients with severe CRS.…”

“…CRS is a frequent complication described after unmanipulated haploidentical HSCT. However, the majority of published data have been limited to PTCy-based haplo-HCT [15,16,[29][30][31][32]. In this retrospective study, we reported the development and characteristics of CRS in T-cell replete allogeneic transplant based on ATG.…”

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences

“…Grade 2 ( Table 6 ) has been defined as hypotension that can be handled with fluid or only low-dose treatment with one vasopressor, mild respiratory symptoms responsive to low-flow oxygen, or Grade 2 organ involvement [ 73 ]. Patients with Grade 2 should be considered for immunosuppressive treatment, whereas patients with Grade 3 or more should receive immediate treatment [ 81 ]. The decision whether to start with immunosuppressive treatment should probably be based on a general clinical evaluation, and immunosuppression should be started early especially for elderly patients and patients with comorbidities who are judged not to be able to tolerate the altered hemodynamics and/or organ involvement associated with the syndrome.…”