Donor-Derived CAR-T Cells in Children with B-Lineage Acute Lymphoblastic Leukemia Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: Report of 20 Cases
Authors: Shelikhova Larisa , Molostova Olga , Klimentova Maria , Khismatullina Rimma , Lyudovskikh Evelina , Kozlovskaya Svetlana , Abugova Yulia , Pershin Dmitriy , Vedmedskaya Victoria , Fadeeva Maria , Malakhova Ekaterina , Khachatryan Lili , Muzalevskii Yakov , Kazachenok Alexey , Popov Alexander , Mikhailova Ekaterina , Litvinov Dmitriy , Novichkova Galina , Maschan Alexey , Maschan Michael 
Published: December 2024

Objectives: Patients with precursor B-cell ALL/lymphoma who have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have a dismal prognosis. We evaluated the efficacy and safety of donor-derived CAR-T cell therapy in children with post-HSCT ALL/lymphoma relapse.
Patients and methods:
Twenty children with r/r BCP-ALL/lymphoma were enrolled in a compassionate-use program (m/f ratio=15:5, median age 9,0 years). Eighteen patients had BCPALL, 2 had B cell lymphoblastic Lymphoma with BM involvement, all relapsing after multiple lines of treatment, including previous HSCT(n=20), blinatumomab (n=17), inotozumab (n=4) and CAR-T cell infusion(n=5). Allo-CAR-T were derived from previous HSCT donors (haplo n=16, MRD n=4). The CAR-T cells were targeting CD19 and CD22 (n=14), CD19 (n=5) or CD22 (n=1). At the time of allogeneic CAR-T application, the disease burden was high MRD (n=9), overt leukemia (n=7), and extramedullary lesions(n=4), five patients had extramedullary disease in addition to BM involvement The first CAR-T cell doses were 100х103/kg (n=18), 160х103/kg (n=1), 350х103/kg (n=1), 7 patients received 2nd dose 100x103/kg (n=2), 500x103/kg (n=1) and 900x103/kg(n=4) within median 10 days after first infusion. Lymphodepletion included fludarabine, cyclophosphamide +/- cytarabine, 8 pts received prophylactic tocilizumab at day-1, 12 pts received abatacept at days -1, +7, +14, +28
Results:
Cytokine release syndrome (CRS) occurred in 15 (75%) patients and was grade ≤3; all pts were treated with tocilizumab with good effect. Four patients had neurologic events (ICANS grade 1 n=3, ICANS grade 5 n=1). 5 patients had the signs of aGVHD (skin grade 1, n=4, liver=gut grade 4, n=1). The median time to CAR-T cell peak expansion was 14 days. ORR was 85%, twelve patients achieved complete MRD-negative remission, five had MRD negative remission in BM with CT detectable extramedullary lesion, 3 patients had disease progression, one of them with CD19 loss. Nine patients received consolidative HSCT after CAR-T cells, all from alternative donors, four patients relapsed, one with CD19 loss. Fifteen (75%) patients are alive, 11 (73%) of them in CR (two patients without 2-d HSCT), one with stable disease and 3 with disease progression, 5 patients died (2 due to ICAN and sepsis, 3 in PD). Median time of follow-up for survivors was 1 years (range, 0,2 - 4,6).
Conclusions:
Our early experience suggests that donor-derived lymphoid antigen-directed CAR-T cells expand in vivo and provide CR with manageable safety profile. Prospective testing and further research of the approach is warranted.