Background: Patients with ALL who have relapsed after allo-HSCT have a dismal prognosis. CAR-T cell therapy has shown great success for treating relapsed/refractory B-ALL. Here we have assessed the initial response, duration of remission, and safety, especially cytokine release syndrome (CRS), graft-versus-host disease (GVHD) incidence after CD19 CAR-T therapy for B-ALL patients who relapsed after transplant.
Methods: From February 2016 to May 2019, 32 patients with B-ALL who relapsed post allo-HSCT were enrolled from four different clinical trials. The median age was 22 (2-55) years old. Median bone marrow blasts were 23.89% (0.03-92.43%) before CAR-T infusion, and 12/32 (37.5%) patients had received at least one prior donor lymphocyte infusion. No patients had active GVHD before CAR-T except for one patient who had limited chronic skin GVHD not requiring treatment.
The second generation CD19 CAR-T cells were produced from purified T cells either from transplant donors (12) or patients (20). They contained either a 4-1BB co-stimulatory signal domain in 23 patients or a CD28 domain in 9 patients.
All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days followed by a single infusion of CAR-T cells with a median dose of 2 x105 (0.083-10x105) cells/kg.
Results: With a median follow-up of 237 (30-789) days, 28/32 (87.5%) patients achieved complete remission (CR) on D30 after CAR-T-cell infusion, and 27/32 (84.4%) were minimal residual disease (MRD)-negative CR. For the 28 CR patients, one-year overall survival (OS) was 44.6% and leukemia-free survival (LFS) was 43.6% (Figure 1). Eight patients who achieved MRD-negative CR underwent a 2nd allo-HSCT at a median time of 76 (39-329) days after CAR-T (2 from matched-unrelated donors, 6 from haploidentical donors). Six out of 8 patients remained in LFS at a median follow up of 333(200-763) days but the other two died from infection. For the remaining 20 CR patients, 5 patients remained in LFS at a median of 386 (270-611) days but 8 patients subsequently relapsed at a median of 165 (46-240) days. Of the 8 relapsed patients, 3/10 (30.0%) patients whose CAR-T-cells were manufactured from donor, and 5/18 (27.8%) from autologous CAR-T-cells. Seven patients died from non-relapse mortality.
Only 24/32 (75.0%) patients had grade I-II CRS, and 3/32 (9.4%) had grade II-IV CRS. Total 5/32 (15.6%) patients developed neurotoxicity with 4 of grade III and 1 of grade IV.
After CAR-T therapy, 9/32 patients developed GVHD including 7 with grade II-III acute GVHD and 2 with localized chronic GVHD. Of note, 5/12 (41.7%) patients whose CAR-T cells were manufactured from transplant donors developed GVHD, versus 4/20 (20.0%) (p=0.24) for those whose CAR-T were autologous.
Conclusions: Our study demonstrates that a high CR rate can still be achieved through CAR-T therapy even for those who relapsed after allo-HSCT without increasing CRS or neurotoxicity. A second consolidation allo-HSCT may be considered for those who achieved MRD-negative CR after CAR-T. Receiving CAR-T cells that manufactured from transplant donors may result in a trend towards higher GVHD rate compared to autologous CAR-T cells. GVHD should be carefully watched and managed.
[Figure 1. OS &LFS of the 28 patients achieved CR after CAR-T therapy]
Clinical Trial Registry: www.clinicaltrials.gov NCT03173417, NCT02546739；www.chictr.org.cn ChiCTR1800016541,ChiCTR-IIh-116008711
Disclosure: Nothing to declare.