Cytokine Release Syndrome Is an Independent Risk Factor Associated With Platelet Transfusion Refractoriness After CAR-T Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

Abstract

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care.Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy.Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023).Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions.

Efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy in hematologic malignancies: a living systematic review on comparative studies

“…One RCT was reclassified as NRSI and another one was classified as an ongoing RCT and was not still included because of its preliminary status only providing immature data for its primary outcome. 28 Therefore, two RCTs 29 , 30 and nine NRSI (two quasi-experimental studies 31 , 32 and seven cohort studies) 33 – 39 assessing the use of CAR-T in 1221 participants with B-cell lymphoma or T or B-cell acute lymphoblastic leukemia were included in the review. A detailed list with reasons for exclusion is presented in Supplemental Appendix 2 .…”

“…Finally, five cohort studies also reported incidence of CRS, ranging from 5% to 15% in the CAR-T groups 33 , 35 , 37 – 39 None of the above studies but Wang et al 39 provided explicit information on the incidence of CRS in their comparator groups, being assumed as zero events for these arms. We did not rate the certainty of evidence for this outcome due to insufficient information for the assessment.…”

“…There was not enough information to perform pre-planned subgroup analyses. All the outcomes remained unchanged after carrying out sensitivity analyses excluding studies with serious risk of bias 34 – 36 ( Supplemental Appendix 3 ). Both RCTs and none of the quasi-experimental/cohort studies were industry-sponsored.…”

“…30 The two quasi-experimental studies were both globally rated as 'no information', due to the lack of data on two domains: confounding 31,32 and selection of participants. 31 Regarding most of the estimated outcomes (OS, ORR, CR, PR, relapse from CR, PFS, CRS, TtT, GvHD, neurotoxicity, SAE), the overall risk of bias in the cohort studies was judged as moderate 33,34,[37][38][39] or serious, 35,36 mainly due to concerns related to the first domain (confounding). However, when other outcomes with a higher subjective profile were considered (e.g.…”

“…Locke et al 29 Bishop et al 30 Wang et al 31 Hua et al 32 Zhao et al 33 Schulthess et al 34 Liu et al 35 Muffly et al 36 Avivi et al 37 Hu et al 38 Wang et al 39…”