CAR T-Cell Therapy in Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia/Lymphoma: A Retrospective Study

Abstract

Background Patients with relapsed or refractory T cell acute lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) often have limited treatment options available and poor prognoses. Clinical trials of autologous CD7, donor-derived CD7 and donor-derived CD5 CAR T-cell therapy in r/r T-ALL/LBL conducted in our center have showed encouraging efficacy and a shaky safety. To evaluate the safety and efficacy of the three therapies, we conducted a retrospective study and analyzed the results of the clinical trials across three different CAR T-cell therapies. Methods This is a retrospective comparative analysis of CAR T-cell therapies with different targets and sources in r/r T-ALL/LBL, including a phase Ⅰ trial of autologous CD7 CAR T-cell therapy (NCT04840875), a phase Ⅰ trial (ChiCTR2000034762) and a phase Ⅱ trial (NCT04689659) of donor-derived CD7 CAR T-cell therapy, and a phase Ⅰ trial of donor-derived CD5 CAR T-cell therapy (NCT05032599). Adverse events and pharmacokinetics were not collected after patients received stem-cell transplantation. In univariate analysis, Chi-square test and Fisher's exact test were used to compare categorical outcome; in multivariate analysis, linear regression was used for the continuous outcome and Logistic regression was used for the categorical outcome. Results A total of 102 patients were included in this analysis, consisting three cohorts: 20 patients receiving autologous CD7 CAR T cells, 66 with donor-derived CD7 CAR T-cell therapy, and 16 receiving donor-derived CD5 CAR T cells. Although with comparable complete remission rates, patients in the three cohorts had different adverse events. Especially, patients who received autologous CD7 CAR T-cell therapy had a significant lower severe infection rate than those with donor-derived CD7 CAR T cells (odds ratio [OR], 0.06; 95% confidence interval [95%CI], 0.01 to 1.03; P=0.019 by exact method) and donor-derived CD5 CAR T cells (OR, 0.03; 95%CI, 0.01 to 0.60; P=0.006) (Table 1). Despite that all patients developed grade 3-4 cytopenias, more patients who received autologous CD7 CAR T-cell therapy reverted grade 3-4 cytopenias to grade 2 or lower within one month compared with donor-derived CD7 CAR T cells (OR, 13.00; 95%CI, 3.99 to 42.32; P<0.001) and donor-derived CD5 CAR T cells (OR, 27.86; 95%CI, 3.02 to 257.28; P<0.001). Based on the multivariate analyses, CD7 CAR T-cell therapy led to lower severe infection rate compared with CD5 CAR T-cell therapy (OR, 0.08; 95%CI, 0 to 0.56; P=0.015) (Table 2), and it should be noted that in this study, the vector uesd in autologous and donor-derived CD7 CAR T-cell therapy was different from that in CD5 CAR T-cell therapy; larger proportion of patients treated with CAR T cells manufactured from their own T cells retured all grade 3-4 cytopenias to grade 0-2 within one month (OR, 68.08; 95%CI, 3.21 to 1446.20; P=0.005), versus patients receiving donor-derived therapy. No factors were identified as independently influencing CRS, ICANS and CR/CRi rate at one month, including central nervous system leukemia not associated with ICANS. Although the source of CAR T cells has not been shown to be a factor in CRS and ICANS, patients with autologous CAR T-cell therapy had lower peak levels of cytokines than donor-derived, including IL-6, sCD25 and TNF-α with the maximal P value of 0.02 in multivariate analysis. Conclusion Despite the risk of tumor contamination and CAR T-cell manufacture failure in autologous CD7 CAR T-cell therapy, some clinical experience have emerged against for them recently. In addition to the fact that autologous therapy cause no GVHD and the faster recovery from hematologic toxicity, being beneficial for long-term defense against infection, it produces lower levels of several cytokines in vivo compared to donor-derived therapy, providing a guarantee for lower incidence of CRS and ICANS. Hence, given the comparable remission rate and remarkable safety, autologous CD7 CAR T-cell therapy would be prioritized for recommendation for r/r T-ALL/LBL patients with low tumor load and access to collect enough normal T cells from their own body for CAR T-cell manufacture. CD5 CAR T-cell therapy is regarded as an option for patients with CD5 positive encountering treatment failure or relapse after CD7 CAR T-cell therapy.