Few studies have described chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphoblastic leukemia (B-ALL) patients with central nervous system leukemia (CNSL) due to concerns for poor response and treatment-related neurotoxicity. Our study included 48 relapsed/refractory B-ALL (R/R B-ALL) patients with CNSL to evaluate the efficacy and safety of CD19-specific CAR T-cell-based therapy. The infusion resulted in overall response rate of 87.5% (95% confidence interval [CI], 75.3-94.1) in bone marrow (BM) disease and remission rate of 85.4% (95% CI, 72.8-92.8) in CNSL. With a median follow-up of 11.5 months (range, 1.3-33.3), the median event-free survival (EFS) was 8.7 months (95% CI, 3.7-18.8), and the median overall survival (OS) was 16.0 months (95% CI, 13.5-20.1). The cumulative incidences of relapse (CIR) in BM and CNS diseases were 31.1% and 11.3%, respectively, at 12 months (p=0.040). The treatment was generally well tolerated with 9 patients (18.8%) experiencing grade ≥3 cytokine release syndrome. Grade 3-4 neurotoxic events (NEs), which developed in 11 patients (22.9%), were associated with a higher pre-infusion disease burden in CNS and were effectively controlled under intensive management. Our results suggested that CD19-specific CAR T-cell-based therapy could induce similar high response rate in both BM and CNS diseases. The duration of remission in CNSL was longer than that in BM disease. CD19 CAR T-cell therapy may provide a potential treatment option for those previously excluded CNSL patients with manageable neurotoxicity. Clinical trials were registered at www.clinicaltrials.gov as # NCT02782351 and www.chictr.org.cn as # ChiCTR-OPN-16008526.
Clinical trials have confirmed that chimeric antigen receptor (CAR) T cell therapies are revolutionizing approaches for treating several relapsed or refractory hematological tumors. Cytokine release syndrome (CRS) is an adverse event with high incidence during CAR-T treatment. A further understanding of the characteristics and related risk factors of CRS is important for effective management. A total of 142 patients with relapsed or refractory acute lymphocyte leukemia (ALL), lymphoma, or multiple myeloma (MM) received lymphodepletion chemotherapy followed by infusion of CAR-T cells. The characteristics of CRS at different time points after treatment were monitored and risk factors were analyzed. The incidence of CRS for ALL, lymphoma, and multiple myeloma were 82%, 90%, and 90% respectively. Fever was observed on a median of day 3 for ALL, day 1 for lymphoma, and day 8.5 for MM after CAR-T cell infusion, and the duration was different between grade 1–2 CRS and grade 3–5 CRS. Disease types, peak concentration of IL-6, and CRP were associated with CRS. For patients with ALL, numbers of lymphoblast in bone marrow before lymphodepletion, peak concentration of IL-6, and CRP were independent risk factors of CRS. Clinical stage of lymphoma patients and high tumor burden in marrow of MM patients were independent risk factors of CRS. In conclusion, the characteristics and risk factors of CRS in different B-cell hematological tumors are different and should be managed individually during CAR-T cell therapy.
PURPOSE G protein–coupled receptor, class C group 5 member D (GPRC5D) is considered to be a promising surface target for multiple myeloma (MM) immunotherapy. Here, we report the efficacy and safety of anti-GPRC5D chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory (R/R) MM. METHODS This phase Ⅱ, single-arm study enrolled patients (18-70 years) with R/R MM. Lymphodepletion was performed before patients received 2 × 106/kg anti-GPRC5D CAR T cells. The primary end point was the proportion of patients who achieved an overall response. Safety was also evaluated in eligible patients. RESULTS From September 1, 2021, to March 23, 2022, 33 patients were infused with anti-GPRC5D CAR T cells. At a median follow-up of 5.2 months (range, 3.2‐8.9), the overall response rate was 91% (95% CI, 76 to 98; 30 of 33 patients), including 11 (33%) stringent complete responses, 10 (30%) complete responses, four (12%) very good partial responses, and five (15%) partial responses. Partial responses or better were observed in nine (100%) of nine patients with previous anti–B-cell maturation antigen (BCMA) CAR T-cell therapy, including two patients who had received repeated anti-BCMA CAR T-cell infusions with no responses at the last time. Grade 3 or higher hematologic toxicities were neutropenia (33 [100%]), anemia (17 [52%]), and thrombocytopenia (15 [45%]). Cytokine release syndrome occurred in 25 (76%) of 33 patients (all were grade 1 or 2), and neurotoxicities in three patients (one grade 2 and one grade 3 ICANSs and one grade 3 headache). CONCLUSION Anti-GPRC5D CAR T-cell therapy showed an encouraging clinical efficacy and manageable safety profile in patients with R/R MM. For patients with MM that progressed after anti-BCMA CAR T-cell therapy or that is refractory to anti-BCMA CAR T cell, anti-GPRC5D CAR T-cell therapy might be a potential alternative option.
BackgroundGlucocorticoids (GCs) are often used to treat cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The effects of GCs on the efficacy of CAR-T cell treatment in relapsed/refractory multiple myeloma (RRMM) have not been fully established. We evaluated the impact of GCs on clinical outcomes of RRMM patients treated with CAR-T cells.MethodsThis study involved RRMM patients treated with CAR-T cells at our center between June 2017 and December 2020. Patients were stratified into GC-used group (GC-group) and non-GC-used group (NGC-group). CRS or ICANS was graded on the basis of the American Society of Transplantation and Cellular Therapy consensus grading system. Response status was evaluated by the IMWG Uniform Response Criteria. The duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were calculated.ResultA total of 71 patients were included in this study. In the NGC group (40 patients), 34 (85%) had responses to CAR-T cell therapy, including 16 (40%) stringent complete response (sCR), seven (17.5%) complete response (CR), five (12.5%) very good partial response (VGPR), and six (15%) partial response (PR). The overall response rate (ORR) and complete response rate (CRR) in the NGC group were 85% and 57.5%. In the GC group (31 patients), 29 (93.5%) had responses, including 11 (35.5%) sCR, nine (29%) CR, two (6.4%) VGPR, and seven (22.6%) PR. Differences in ORR and CRR between the two groups were insignificant. The dose, duration, and timing of GCs did not affect ORR and CRR. At a median follow-up of 28.2 months, the median PFS was 20.4 months (95% CI, 7.9 to 32.9) while the median OS was 36.6 months (95% CI, 25.9 to 47.2) for the GC group. The median PFS and OS for the NGC group were 13.7 months (95% CI, 8.8 to 18.6) and 27.5 months (95% CI, 14.1 to 41.0). There were no significant differences in either PFS or OS between the GC group and the NGC group. Differences in median DOR for the patients with CR or better in the GC group and NGC group were not significant (p = 0.17). Earlier, prolonged use and high dose of GCs were not associated with any effects on either PFS or OS. Additionally, GCs had no effects on CAR-T cell proliferation.ConclusionAdministration of GCs, dose, timing, and duration does not influence the clinical efficacy of CAR-T cells in RRMM in this study.
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