Abstract
Introduction Autologous chimeric antigen receptor (CAR) T cells induce high rate of deep remissions among children with relapsed/refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL). In a significant proportion of cases cure is achieved only with HSCT as post-CAR-T consolidation. Seeking to combine the cytoreductive and curative power of HSCT with the antigen-specific activity of CAR-T we devised an approach with simultaneous infusion of hematopoietic stem cell graft and CAR-T cells, derived from the same donor. Two graft-versus-host disease prevention platforms were used: ex-vivo T cell depletion and post-transplant cyclophosphamide. We report here pooled analysis of prospective trial patients and compassionate use program.
Patients and methods A total of 39 pts with R/R BCP-ALL (n=35), B-NHL/leukemia (n=3) and MPAL (n=1) (16 female, 23 male, median age 9,6 y) were enrolled. All patients had disease relapse after multiple lines of treatment including previous HSCT(n=13), blinatumomab (n=22), inotuzumab (n=2), blinatumomab+inotuzumab (n=6) and CAR-T cell infusion(n=12). The disease burden was above 5% for bone marrow blasts among 16 patients, with a median blast count of 50% (6 – 90%). MRD was detectable by flow cytometry among 13 patients with a median leukemia population of 0.15% (0.002 - 6.9%), and five patients had MRD-negative complete remission. The extramedullary disease was seen among 5 patients. The median proportion of CD19-positive cells in the leukemic population was 100% (0–100%), while the median proportion of CD22-positive cells was 100% (36–100%).
Fourteen (36%) pts received treosulfan-based myeloablative preparative regimen and TBI-based regimen was used in 25 (64%) pts. Twenty-six patients received T-cell depleted graft, 25 from haploidentical donors and one from match related. In this subgroup CAR-T products included CD19 CAR- T (n=3), CD19-22 tandem CAR-T (n=20), and cocktail CD19 and CD22 CAR-T (n=2). Thirteen pts were transplanted with T-replete bone marrow with PtCy-based GVHD prophylaxis, 3 from matched sibling and 10 from haploidentical donors. In this subgroup CAR-T cells were infused on day +5 after HSCT and were represented by either by CD19-22 tandem CAR- T (n=1) or by CD19 and CD22 cocktail product (n=12). In the PtCy group GVHD prophylaxis included abatacept, vedolizumab and CsA or baricitinib
Results There was no suspected conflict between the graft and CAR-T cells. Primary engraftment was observed in 37 of 39 pts (one pt died before engraftment and one relapsed early), the median time to neutrophil and platelet recovery was 13 and 17 days, respectively, all engrafted patients achieved MRD-negative CR at day +28 after HSCT. The median time to CAR-T cell peak expansion was 14 days.
Cytokine release syndrome (CRS) occurred in 22 (56%) patients and only two pts had grade >2 CRS. Also 22 patients had neurologic events (ICANS grade 1, n=14, grade 2, n=6 and grade 3, n=2). Eleven patients had aGvHD, grade 2 (n=9), grade 3(n=1) and grade 4 (n=1), 5 patients had mild chronic GvHD. There were no significant differences in CAR-T toxicity between depletion and PtCy groups.
Leukemia relapse was observed in nine children at a median time of 174 days (range, 95-1641 days) after allograft, 2 pts had CD 19 negative relapse.
Twenty-four (62%) patients are alive (22 in CR, 2 with disease progression) with a median follow-up of 2,6 years (0,34-5,4), 15 patients died. Eight deaths were due to progressive disease. Six were in CR and one before engraftment. Causes of non-relapse mortality were VOD+pneumonia (n=1), CMV (n=1), Mucormycosis (n=1), septic event (n=3) and COVID19 (n=1). EFS and OS at 2,6 years are 59% (95%CI:42- 76) and 56% (95%CI:39- 72), respectively, without differences between T-cell depletion and ptCy groups.
Conclusion Our early experience suggests that allogenic CAR-T cells can be safely infused simultaneously with the hematopoietic stem cell graft both on the platform of T cell depletion and PtCy-based GVHD prophylaxis. The infusions did not compromise engraftment and GvHD control, while specific CAR-T toxicity was mild and manageable. We have documented CAR-T expansion and persistence. Prospective testing of the approach is warranted.
