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Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study.

ABSTRACT: Background:No effective treatment exist for patients with relapsed and refractory B-cell lymphoma, until the advent of anti-CD19 chimeric antigen receptor (CAR) T-cells. Therefore, this study aimed to explore the factors affecting the efficacy of anti-CD19 CAR T-cell and the adverse reactions of the therapy. Methods:We recruited 11 patients with relapsed and refractory B-cell lymphoma. The number of anti-CD19 CAR T-cells, proliferation, and adverse reactions were recorded in detail, to explore the relationship between the factors affecting the efficacy of anti-CD19 CAR T-cell and the long-term survival of patients. Results:The 11 patients in our study had a total overall response rate of 100%, after receiving anti-CD19 CAR T-cells. The median follow-up was 253 days (range, 130-1,017 days). The median overall survival (OS) and median progression-free survival (PFS) were not reached. After 3 months of treatment, the complete remission (CR) rate was 63.6% (7/11). As of December 7, 2019, 5 patients had maintained CR for a period exceeding 1 year, including 2 patients who had maintained CR for more than 1,000 days. The patients who received 3 or 4 lines of chemotherapy were more likely to have sustained remission than the patients who received <2 or >4 lines of chemotherapy. Each of the 4 patients in the study who had diffuse large B cell lymphoma (DLBCL) progression all had high myc protein expression (positive incidence: 30-80%). The incidence of Grade 2 cytokine release syndrome (CRS) was 36.4% (4/11), and Grade 3 CAR T-cell-related encephalopathy syndrome (CRES) was experienced by 1 patient. The occurrence of adverse reactions was not significantly related to the infusion dose, peak amplification time, or maximum copy amount. The immunoglobulin levels of the four patients who died showed a significant downward trend. Interleukin-1? (IL-1?), interferon-? (IFN-?), interleukin-10 (IL-10), and interleukin-17A (IL-17A) appeared to be associated with the occurrence of CRS and CRES. Conclusions:Anti-CD19 CAR T-cell treatment is a new therapy for patients with relapsed and refractory B-cell lymphoma. Among the small sample size in this study, it demonstrated high efficiency and safety.

SUBMITTER: Huang C

PROVIDER: S-EPMC7575989 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study.

Huang Chen C Wu Lili L Liu Ruixia R Li Weijing W Li Zheng Z Li Jianqiang J Liu Lihong L Shan Baoen B

Annals of translational medicine 20200901 17

<h4>Background</h4>No effective treatment exist for patients with relapsed and refractory B-cell lymphoma, until the advent of anti-CD19 chimeric antigen receptor (CAR) T-cells. Therefore, this study aimed to explore the factors affecting the efficacy of anti-CD19 CAR T-cell and the adverse reactions of the therapy.<h4>Methods</h4>We recruited 11 patients with relapsed and refractory B-cell lymphoma. The number of anti-CD19 CAR T-cells, proliferation, and adverse reactions were recorded in detai ...[more]

PMID: 33145267

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Project description:BackgroundRecent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.MethodsWe generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).ResultsData from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49-24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74-18.08 months) and 6.93 months (95% CI, 3.13-10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017-0.601).ConclusionsThe results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.Trial registrationClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687.

Project description:BackgroundPatients with relapsed or refractory (R/R) lymphomas have benefited from chimeric antigen receptor (CAR)-T-cell therapy. However, this treatment is linked to a high frequency of adverse events (AEs), such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and hematologic toxicity. There has been increasing interest in hematological toxicity in recent years, as it can result in additional complications, such as infection or hemorrhage, which remain intractable.MethodsWe conducted a retrospective, single-institution study to evaluate the patterns and outcomes of cytopenia following CAR-T-cell infusion and potential associated factors.ResultsOverall, 133 patients with R/R lymphoma who received CAR-T-cell therapy from June, 2017 to April, 2022 were included in this analysis. Severe neutropenia, anemia and thrombocytopenia occurred frequently (71, 30 and 41%, respectively) after CAR-T-cell infusion. A total of 98% of severe neutropenia and all severe thrombocytopenia cases occurred in the early phase. Early severe cytopenia was associated with CRS incidence and severity, as well as peak inflammatory factor (IL-6, C-reactive protein (CRP), and ferritin) levels. In multivariate analysis, prior hematopoietic stem cell transplantation (HSCT), baseline hemoglobin (HB), and lymphodepleting chemotherapy were independent adverse factors associated with early severe cytopenia. In addition, 18% and 35% of patients had late neutrophil- and platelet (PLT)-related toxicity, respectively. In multivariate analysis, lower baseline PLT count was an independent factor associated with late thrombocytopenia. More severe cytopenia was associated with higher infection rates and poorer survival.ConclusionsThis research indicates that improved selection of patients and management of CRS may help to decrease the severity of cytopenias and associated AEs and improve survival following CAR-T-cell therapy.Clinical trial registrationhttps://www.clinicaltrials.gov/ct2/show/NCT03196830, identifier NCT03196830.

Project description:Axicabtagene ciloleucel is the first U.S. Food and Drug Administration-approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for the treatment of patients with relapsed or refractory large B-cell lymphoma after ?2 prior systemic therapies. Although axicabtagene ciloleucel is administered only at authorized treatment centers, community oncologists play a critical role in the CAR T-cell treatment journey, recognizing potentially eligible patients for referral and then, after treatment, closely collaborating with treatment centers to monitor and manage patients long term. ZUMA-1, the pivotal, multicenter, phase I/II study of 108 patients treated with axicabtagene ciloleucel, resulted in an objective response rate of 83%, including 58% complete responses. With a 27.1-month median follow-up, 39% of patients had ongoing responses. CAR T-cell therapy is associated with the potentially life-threatening adverse events (AEs) of cytokine release syndrome and neurologic events, which generally occur early after treatment. In ZUMA-1, cytokine release syndrome and neurologic events were generally reversible and grade ?3 cytokine release syndrome and neurologic events occurred in 11% and 32% of patients, respectively. Frequent prolonged AEs included hypogammaglobulinemia, B-cell aplasia, and cytopenias requiring supportive care until recovery of hematopoietic function. Rate of treatment-related mortality was low, at <2%. With appropriate management of common AEs, axicabtagene ciloleucel offers the potential for long-term durable responses in patients who otherwise lack curative treatment options. IMPLICATIONS FOR PRACTICE: Community oncologists should be familiar with key aspects of chimeric antigen receptor (CAR) T-cell indications and eligibility to help recognize and refer potential patients for this paradigm-changing treatment option at the appropriate time during the disease course. To ensure optimal long-term outcomes for patients who have been treated with CAR T-cell therapy, oncologists must also be familiar with common prolonged AEs and their monitoring and management.

Dataset Information

Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study.

Publications

Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study.

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