Abstract
Patients with refractory or relapsed (R/R) T-cell lymphoblastic lymphoma/leukemia (T-LBL/ALL) face dismal prognoses. To address this unmet need, we conducted a phase I clinical trial evaluating the safety and efficacy of CD7-targeted chimeric antigen receptor (CAR) T-cell therapy in this population(NCT05290155). Among 23 enrolled patients, 14 received CAR-T infusion (median age 25y; 15-52; M:F=12:2), including 5 post-transplant relapses and 9 primary refractory cases. Notably, 100% exhibited aggressive disease phenotypes: universal extramedullary involvement (14/14), mediastinal masses (5/14), and visceral infiltration (pancreas/kidney/lung; 9/14). Robust CAR-T expansion occurred in 13/14 patients (92.9%), with one case showing undetectable pharmacokinetic activity. Peak CAR-T concentration (Cmax) reached 62,389.69 copies/μg DNA (range: 3,175.94-326,482.67), achieved at median 12 days post-infusion (range: 10-21). Hematologic toxicities included universal leukopenia, thrombocytopenia, and neutropenia. Predominant non-hematologic toxicity post infusion was infection (viral: varicella-zoster virus [VZV], Epstein-Barr virus [EBV], cytomegalovirus [CMV], parvovirus B19; bacterial: 1 foodborne case). Cytokine release syndrome (CRS) occurred in 12 patients (85.7%; grade 3: n=1), while immune effector cell-associated neurotoxicity syndrome (ICANS) developed in 2 (14.3%, grade 1 and 2). Complete remission (CR) and overall response rates (ORR) were 100% for bone marrow disease, and ORR were 78.5% (64.2% CR) for extramedullary disease. With median follow-up of 8 months (range: 2-37), the 6 months overall survival (OS) and progression-free survival (PFS) was 70.7% (95% CI, 50.1–99.6), and 35.7% (95% CI, 17.7–72.1). Subgroup analysis revealed patients receiving consolidative allogeneic stem cell transplantation(allo-SCT) had a superior survival compared with those receiving salvage and no allo-SCT, the 6 months OS was 100% (95% CI: 100%-100%), 60.0% (95% CI: 23.1%-88.5%) , and 57.1% (95% CI: 28.6%-85.7%), respectively(P=0.047). Patients without visceral extramedullary diseases had a lower risk of relapse compared to those with visceral involving, the 6 months PFS was 50.0% (95% CI: 22.5%-100%) compared with 25.0% (95% CI: 7.5%-83.0%) (P=0.05). Two cases with early T-precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) relapsed after CAR-T therapy. Both selectively lost the CD7, CD3, and cCD3 epitope. One of them was positive of MPO , and POX staining ranging from (+/-) to (++), accounting for 94%. PAS staining was negative. NGS analysis demonstrated mutations in NOTCH1, JAK3, ASXL1, CEBPA, PHF6, RUNX1 and WT1, and were identified with a lineage switch.
These findings demonstrate that CD7 CAR-T therapy is a promising treatment option for R/R T-ALL/LBL, with improved outcomes in patients responded and bridging allo-SCT. Patients with visceral EMDs had higher risk of relapse. Close monitoring of lineage switch relapse should be done especially for ETP-ALL/LBL patients.
