Humanized Anti-CD19 CAR-T Cell Therapy and Sequential Allogeneic Hematopoietic Stem Cell Transplantation Achieved Long-Term Survival in Refractory and Relapsed B Lymphocytic Leukemia: A Retrospective Study of CAR-T Cell Therapy

Abstract

Early response could be obtained in most patients with relapsed or refractory B cell lymphoblastic leukemia (R/R B-ALL) treated with chimeric antigen receptor T-cell (CAR-T) therapy, but relapse occurs in some patients. There is no consensus on treatment strategy post CAR-T cell therapy. In this retrospective study of humanized CD19-targeted CAR-T cell (hCART19s) therapy for R/R B-ALL, we analyzed the patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) or received a second hCART19s infusion, and summarized their efficacy and safety. We retrospectively studied 28 R/R B-ALL patients treated with hCART19s in the Affiliated Hospital of Xuzhou Medical University from 2016 to 2020. After the first hCART19s infusion, 10 patients received allo-HSCT (CART+HSCT group), 7 patients received a second hCART19s infusion (CART2 group), and 11 patients did not receive HSCT or a second hCART19s infusion (CART1 group). The safety, efficacy, and long-term survival were analyzed. Of the 28 patients who received hCART19s treatment, 1 patient could not be evaluated for efficacy, and 25 (92.6%) achieved complete remission (CR) with 20 (74.7%) achieving minimal residual disease (MRD) negativity. Seven (25%) patients experienced grade 3-4 CRS, and one died from grade 5 CRS. No patient experienced ≥3 grade ICANS. The incidence of second CR is higher in the CART+HSCT group compared to the CART2 group (100% vs. 42.9%, p=0.015). The median follow-up time was 1,240 days (range: 709–1,770). Significantly longer overall survival (OS) and leukemia-free survival (LFS) were achieved in the CART+HSCT group (median OS and LFS: not reached, p=0.006 and 0.001, respectively) compared to the CART2 group (median OS: 482; median LFS: 189) and the CART1 group (median OS: 236; median LFS: 35). In the CART+HSCT group, the incidence of acute graft-versus-host disease (aGVHD) was 30% (3/10), and transplantation-related mortality was 30% (3/10). No chronic GVHD occurred. Multivariate analysis results showed that blasts ≥ 20% in the bone marrow and MRD ≥ 65.6% are independent factors for inferior OS and LFS, respectively, while receiving allo-HSCT is an independent factor associated with both longer OS and LFS. In conclusion, early allo-HSCT after CAR-T therapy can achieve long-term efficacy, and the adverse events are controllable.

Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL

“…However, no significant difference in EFS was seen between the CART+HSCT group and the CART2 group in our study. This contradictory result may be explained by the fact that in the study of Chen et al , 35 the timing of the second hCART19 treatment and HSCT following hCART19 treatment was postrelapse and remission, respectively. However, in our study, all patients going on to CD22 CAR-T or HSCT went to planned consolidative therapy while still in primary CAR-mediated remission.…”

“…No relevant studies have been conducted yet. But a retrospective study 35 showed that after hCART19 treatment, patients who received HSCT had longer OS and leukemia-free survival (LFS) than those who received a second round of hCART19 treatment. However, no significant difference in EFS was seen between the CART+HSCT group and the CART2 group in our study.…”

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

“…Several studies have illustrated that disease burden before CAR-T-cell therapy was a remarkable predictor of remission duration and survival. [4,35,36] Wudhikarn et al [35] reported the results of a single-center, phase I study at Memorial Sloan Kettering Cancer Center (MSKCC) that enrolled 56 adult B-ALL patients treated with cluster of differentiation (CD)19-CAR-T cells. They showed that a higher disease burden, as indicated by bone marrow blasts ≥5% or extramedullary disease, rather than MRD prior to CAR T-cell infusion, was the only signi cant risk factor associated with the risk of disease progression (P = 0.02).…”

“…The bene ts of allo-HSCT in r/r B-ALL patients with MRD-positive CR or morphological relapse after CAR-T-cell therapy remain a matter of debate due to limited research data. [36,53] In a study conducted by Song et al [53] , 23 r/r B-ALL patients who were in non-remission (NR) or MRD-positive after CAR-T-cell treatment to evaluate the ef cacy and safety of salvage allo-HSCT. The 1-year OS and LFS values were 85.7% and 35.7%, 68.1% and 40.9%, in NR and MRD-positive groups, respectively.…”

Anti-PD-1 Therapy Enhances the Efficacy of CD30-Directed Chimeric Antigen Receptor T Cell Therapy in Patients With Relapsed/Refractory CD30+ Lymphoma

“…Chimeric antigen receptor (CAR) T-cell therapy offers an effective therapeutic option for patients with lymphoid malignancies (1)(2)(3). CD19 antigen was commonly selected in CAR-T treatment of B cell hematologic malignancies and got a response of 80% overall response rate (ORR) in lymphomas (2,4) and higher than 90% ORR in B acute lymphocytic leukemia (B-ALL) patients (5) with controllable toxicities. However, most patients do not have a durable response, and there remains a room for improvement (6).…”