Abstract
Background:CAR T-cell therapy for B-cell leukemia has matured significantly. However, studies on the safety and efficacy of CAR-cell in T-cell acute lymphoblastic leukemia (T-ALL), particularly long-term follow-up data, remain scarce.
Aim:We previously reported the short-term (6-month) and long-term (2-year) safety and efficacy of a phase I trial, which donor-derived CD7-directed chimeric antigen receptor (CAR) T cell therapy in patients with refractory or relapsed T-cell acute lymphoblastic leukemia (r/r T-ALL). (Trial registration ChiCTR2000034762). This study aims to report the 5-year long-term safety and efficacy of this therapy.
Methods:As previously reported of 2-year follow-up，a total of 20 patients with r/r T-ALL received infusion therapy with CD7 CAR T-cells. Among them, 19 patients showed responses, and 2 patients withdrew from the treatment; 7 patients underwent transplantation after CD7 CART-cells therapy,2 relapsed and died,1 died due to transplantation-related complications; 10 patients did not receive SCT, 4 died of infection, and 3 relapsed and died. After the 2-year follow-up period, 7 patients(3 patients without SCT and 4 with bridging SCT) were followed up 5 years continuously until July 31,2025. Survival,disease remission status,lymphocyte subsets, infections, hematologic toxicitiesand and graft-versus-host disease (GVHD)were evaluated. Statistical analyses included descriptive statistics, Kaplan-Meier estimates.
Results:After a median follow-up time of 56.2(range, 32.1-60.6) months.Six patients (33.3%) had a relapse (four CD7-negative, and two CD7-positive), is the same as the result of the 2-year follow-up. 5-year PFS rate and OS rate were 24.5% (95% CI, 3.9-45.8%) and 24.1% (95% CI, 3.5-44.7%), respectively , and the median PFS and OS were 11.0 (range, 7.3-14.6) months and 18.2 (range, 10.8-25.6) months, respectively. For patients without SCT, 5-year PFS and OS rates were 10.6% respectively, and the median PFS and OS were 11.0 (range, 7.8-14.2) months and 18.3 (range, 6.9-31.8) months, respectively. For patients with SCT, 5-year PFS and OS rates were 42.9% respectively. The 5-year PFS and OS rates in the non-transplant group were significantly lower than those of the 2-year follow-up(PFS 10.6% vs. 31.8%; OS 10.6% vs. 35%), although there were no statistical difference. Late-onset GVHD occurred in 2 (66.7%) of 3 patients who did not receive SCT consolidation, and 2 (50%) of 4 patients who with SCT consolidation, experienced grade 1 or 2 skin GVHD, mild lung or liver GVHD, these complications were mostly mild and all manageable. All three (100%) non-transplanted patients experienced recurrent severe infections. Two (66.7%) of them died from the infections. At 15 months after the administration of CART cells, a patient developed a lung infection due to treatment for GVHD of the skin, liver, intestine and lungs, and died of the lung infection at 32 months. A patient was infected with the novel coronavirus after CART cells infunions and the infection remained positive. Subsequently, bacterial pneumonia, aspergillus sinusitis occurred, and died due to aspergillus sinusitis infection at 56 months. The third patient had a grade 3 CMV and EBV infection. After reinfusion of purified CD34+ cells and donor peripheral blood stem cells, the infection was reduced to a grade lower than 3. The two died patients had CAR transgenes detectable by quantitative polymerase chain reaction (PCR) , and CD7+ T cells remained undetectable until the time of the last assessments, the duration time of CAR T-cell persistence were 56 months and 32 months after CD7 CAR T-Cell infusion. The third patient who receiving infused purified CD34+ stem cells and donor peripheral blood stem cells, had recovery of CD7+T and NK cells 13 months post-infusion, and loss of CD7 CAR T cells by PCR. All three patients had late-onset grade 3 cytopenias, which were suspected to be related to the preceding infection events. Among the 4 transplant patients, 1 (25%) patient experienced cytopenias, infection, and died due to treatment after recurrence.
Conclusions This 5-year follow-up confirms durable efficacy of donor-derived CD7 CAR T-cell therapy in a subset of r/r T-ALL patients. However, severe late infections emerged as the primary toxicity and leading cause of treatment failure. Bridging to SCT or strategies promoting T-cell recovery (e.g., early CD34+ stem cell infusion, KO-lymphocytes) may be crucial to mitigate infection risk.
