-
1.
Analysis benefits of a second Allo-HSCT after CAR-T cell therapy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia who relapsed after transplant
Cao, X. Y., Zhang, J. P., Zhao, Y. L., Xiong, M., Zhou, J. R., Lu, Y., Sun, R. J., Wei, Z. J., Liu, D. Y., Zhang, X., et al
Frontiers in immunology. 2023;14:1191382
-
-
-
Free full text
-
Editor's Choice
Abstract
BACKGROUND Chimeric antigen receptor (CAR) T-cell therapy has demonstrated high initial complete remission (CR) rates in B-cell acute lymphoblastic leukemia (B-ALL) patients, including those who relapsed after transplant. However, the duration of remission requires improvements. Whether bridging to a second allogeneic hematopoietic stem cell transplant (allo-HSCT) after CAR-T therapy can improve long-term survival remains controversial. We retrospectively analyzed long-term follow-up data of B-ALL patients who relapsed post-transplant and received CAR-T therapy followed by consolidation second allo-HSCT to investigate whether such a treatment sequence could improve long-term survival. METHODS A single-center, retrospective study was performed between October 2017 and March 2022, involving 95 patients who received a consolidation second transplant after achieving CR from CAR-T therapy. RESULTS The median age of patients was 22.8 years (range: 3.3-52.8) at the second transplant. After the first transplant, 71 patients (74.7%) experienced bone marrow relapse, 16 patients (16.8%) had extramedullary relapse, 5 patients (5.3%) had both bone marrow and extramedullary relapse and 3/95 patients (3.2%) had positive minimal residual disease (MRD) only. Patients received autologous (n=57, 60.0%) or allogeneic (n=28, 29.5%) CAR-T cells, while 10 patients (10.5%) were unknown. All patients achieved CR after CAR-T therapy. Before second HSCT, 86 patients (90.5%) were MRD-negative, and 9 (9.5%) were MRD-positive. All second transplant donors were different from the first transplant donors. The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24; p=0.003) and OS(HR, 2.67, 95%CI, 1.24-5.74, p=0.012), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24, p=0.021). CONCLUSIONS Our study indicated that CAR-T therapy followed by consolidation second transplant could significantly improve long-term survival in B-ALL patients who relapsed post-transplant. The second transplant should be considered in suitable patients and is recommended to be performed within 90 days after CAR-T treatment.
PICO Summary
Population
Adults with acute lymphoblastic leukaemia who were minimal residual disease-positive after first transplant at a single centre in China (n=95)
Intervention
CAR-T therapy followed by consolidation allogeneic transplant, using a different donor
Comparison
None
Outcome
The median follow-up time was 623 days (range: 33-1901) after the second HSCT. The 3-year overall survival (OS) and leukemia-free survival (LFS) were 55.3% (95%CI, 44.3-66.1%) and 49.8% (95%CI, 38.7-60.9%), respectively. The 3-year relapse incidence (RI) and non-relapse mortality (NRM) were 10.5% (95%CI, 5.6-19.6%) and 43.6% (95%CI, 33.9-56.2%), respectively. In multivariate analysis, the interval from CAR-T to second HSCT ≤90 days was associated with superior LFS(HR, 4.10, 95%CI,1.64-10.24) and OS(HR, 2.67, 95%CI, 1.24-5.74), as well as reduced NRM (HR, 2.45, 95%CI, 1.14-5.24).
-
2.
CD19 CAR T cells are an effective therapy for posttransplant relapse in patients with B-lineage ALL: real-world data from Germany
Bader, P., Rossig, C., Hutter, M., Ayuk, F. A., Baldus, C. D., Bücklein, V. L., Bonig, H., Cario, G., Einsele, H., Holtick, U., et al
Blood advances. 2023;7(11):2436-2448
Abstract
Patients with precursor B-cell acute lymphoblastic leukemia (pB-ALL) who have relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), have relapsed more than once, or are resistant upfront have a dismal prognosis. CD19-targeted chimeric antigen receptor (CAR) T cells have evolved as potent immune therapies. Tisagenlecleucel (Tisa-cel) is a commercially available autologous CD19-directed CAR T-cell product. We performed a retrospective study inviting all CAR T-cell centers in Germany to participate. Eighty-one patients with pB-ALL were included. Twenty-eight days after CAR T-cell infusion, 71 patients (87.7%) were in complete response, and 8 (9.9%) were in nonremission. At 2 years, the probabilities of event-free survival (pEFS), relapse-free survival (pRFS), and overall survival (pOS) were 45.3%, 51.7%, and 53.2%, respectively. pEFS was not different in patients without (n = 16, 55.0%) vs with prior allo-HSCT (n = 65, 43.4%). In patients treated after allo-HSCT, the time to relapse after allo-HSCT was a strong predictor of outcome. Patients relapsing within 6 months of allo-HSCT had a disappointing pEFS of 18.4% (pOS = 16.0%); the pEFS for those relapsing later was 55.5% (pOS = 74.8%). Our study provides real-world experience in pediatric, adolescent, and young adult patients with ALL treated with Tisa-cel, where most patients were treated after having relapsed after allo-HSCT. A total of 45.3% were rescued with a single dose of Tisa-cel. Our novel finding that patients with ALL after allo-HSCT had by far a better pEFS if relapse occurred beyond 6 months might be helpful in clinical decision-making and motivates studies to uncover the reasons.
-
3.
CAR-T cell therapy followed by allogenic hematopoietic stem cell transplantation yielded comparable outcome between Ph like ALL and other high-risk ALL
Dai, H. P., Kong, D. Q., Shen, H. J., Cui, W., Wang, Q., Li, Z., Yin, J., Kang, L. Q., Yu, L., Wu, D. P., et al
Biomarker research. 2023;11(1):19
Abstract
It was previously believed that patients with Ph-like ALL had poorer prognosis compared with other B-ALL subgroups due to resistance to conventional chemotherapy and lack of targeted drugs. CAR-T therapy has been successfully applied in the treatment of relapsed and refractory B-ALL. Currently, there are few data on whether CAR-T therapy can alter the outcome of Ph-like ALL. Here we included 17 Ph-like, 23 Ph+ and 51 other B-ALL patients, who received autologous CAR T-cell therapy and subsequently allogenic stem cell transplantation. Patients in the Ph-like group and B-ALL-others group were younger that those in the Ph+ group (P=0.001). Ph-like and Ph+ ALL patients showed higher white blood cell counts at diagnosis (P=0.025). The percentage of patients with active disease before receiving CAR T-cells infusion was 64.7%, 39.1% and 62.7% in the Ph-like, Ph+ and B-ALL-others groups. The response rates to CAR-T therapy were 94.1% (16/17), 95.6% (22/23) and 98.0% (50/51) in the Ph-like, Ph+ and B-ALL-others groups. Measurable residual disease negative CR was achieved in 64.7% (11/17), 60.9% (14/23) and 54.9% (28/51) in the Ph-like, Ph+ and B-ALL-others groups, respectively. The estimated rates of 3-year overall survival (65.9%±16.5%, 59.7%±10.5% and 61.6%±7.3%, P=0.758) and 3-year relapse-free survival (59.8%±14.8%, 63.1%±10.5% and 56.3%±7.1%, P=0.764) were comparable among the Ph-like, Ph+ and B-ALL-others groups. Estimated 3-year cumulative relapse rate was 7.8%±0.6%, 23.4%±0.9% and 29.0%±0.4% (P=0.241). Our findings suggest that CART followed by allo-HSCT results in a comparable prognosis in Ph-like ALL and other high-risk B-ALL.Trial registration ClinicalTrials. gov, NCT03275493, Registered on September 7, 2017, prospectively registered and NCT03614858, Registered on August 3, 2018, prospectively registered.
-
4.
Donor Hematopoietic Stem Cell/Lymphocyte Maintenance Treatment After CAR T-Cell Therapy in Patients With B-Cell Acute Lymphoblastic Leukemia Relapse Following Stem Cell Transplant
Li, Q., Lyu, C., Liu, M., Wang, J., Mou, N., Jiang, E., Zhang, R., Deng, Q.
Cell transplantation. 2023;32:9636897231158155
Abstract
Maintaining the efficacy of anti-CD19 chimeric antigen receptor modified (CAR) T-cell therapy in patients with B-cell acute lymphoblastic leukemia (B-ALL) relapse after allogeneic hematopoietic stem cell transplant (allo-HSCT) is an urgent problem. In this study, we aimed to compare the efficacy of donor hematopoietic stem cell infusion (DSI) therapy and donor lymphocyte infusion (DLI) therapy as a maintenance therapy after R/R B-ALL patients achieved CR in anti-CD19-CAR T-cell therapy but relapsed after allo-HSCT. In total, 22 B-ALL patients who relapsed after allo-HSCT received anti-CD19-CAR T-cell therapy. Patients who responded to CAR T-cell therapy received DSI or DLI as maintenance therapy. We compared the clinical responses, acute graft versus host disease (aGVHD), expansion of CAR-T-cells, and adverse events between the two groups. In our study, 19 patients received DSI/DLI as maintenance therapy. After DSI/DLI therapy, progression-free survival and overall survival were higher in the DSI group than in the DLI group at 365 days. The grades I and II of aGVHD was observed in four patients (36.4%) in the DSI group. Only one patient developed grade II aGVHD in the DLI group. The peaks of CAR T-cells in the DSI group were higher than those in the DLI group. IL-6 and TNF-α levels increased again in nine of 11 patients after DSI but not in the DLI group. Our findings indicate that for B-ALL patients who relapse after allo-HSCT, DSI is a feasible maintenance therapy if CR is obtained with CAR-T-cell therapy.
-
5.
CD19/CD22 dual-targeting chimeric antigen receptor T-cell therapy bridging to allogeneic haematopoietic stem cell transplantation for B-cell acute lymphoblastic leukaemia delays platelet recovery and increases risks of cytomegalovirus and Epstein-Barr virus viremia after transplantation
Li, S., Ge, J., Zhou, S., Zhu, W., Han, Y., Chen, S., Xue, S., Wang, Y., Qiu, H., Wu, X., et al
Clinical and translational medicine. 2023;13(10):e1459
-
6.
Outcomes of Second Anti-CD19 CAR T-Cell Therapy (CART2) in Acute B Lymphoblastic Leukemia and the Impact of Allo-HSCT on Efficacy
Xu, Q., Shi, Y., Xue, L., An, F., Xu, H., Liu, X., Zhu, X., Sun, Z., Zhai, Z., Wang, X.
Cell transplantation. 2023;32:9636897231204724
Abstract
For patients exhibiting a suboptimal response to the first chimeric antigen receptor (CAR) T-cell therapy (CART1) or relapse after remission, secondary CAR T-cell therapy (CART2) for the same target may be an option. We retrospectively analyzed patients with acute B-cell lymphoblastic leukemia (B-ALL) receiving CD19 CART1 at our center (n = 84) to report the clinical outcomes of CART2 and to identify the factors that may influence the outcomes. Twenty-six patients received CART2 for suboptimal response or relapse post-CART1. The incidence of cytokine release syndrome (CRS) after CART2 was 65.4% (17/26), with 11 cases classified as grade 1 (42.3%), four cases as grade 2 (15.4%), and two cases as grade 3 (7.7%). Neurotoxicity was observed in one patient (3.8%) after CART2 infusion. Fourteen patients (53.8%) achieved complete remission (CR) after CART2. CART2 exhibited an inferior response rate (CART2: 53.8%, 14/26; CART1: 81.0%, 64/79; P = 0.006) and a lower incidence of severe CRS (CART2: 7.7%, 2/26; CART1: 30.4%, 24/79; P = 0.020) compared with CART1, with a median progression-free survival (PFS) and a median overall survival (OS) of 6.2 months and 11.2 months, respectively. In particular, patients who progressed after consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CART1 and then received CART2 demonstrated promising outcomes with a response rate of 80.0% (8/10), a median PFS of 7.9 months, and a median OS of 25.1 months. After adjusting for the confounding factors, the response rate (85.7%, 6/7) of CART2 administered to this cohort was better than those who did not bridge to allo-HSCT receiving CART2 (28.6%, 2/7) or non-CART2 treatments (13.3%, 2/15). The median OS after CART2, which was not reached, was significantly better than the median OS after CART2 (3.9 months, P = 0.014) and non-CART2 treatments (6.0 months, P = 0.012) administered in patients who did not undergo consolidative allo-HSCT post-CART1. Our results indicated that, although less effective than CART1, a subset of patients can still benefit from CART2 with mild adverse effects. For patients who relapsed after consolidative allo-HSCT post-CART1, treatment with CART2 is a viable option.
-
7.
Donor-derived CD19-targeted chimeric antigen receptor T cells in adult transplant recipients with relapsed/refractory acute lymphoblastic leukemia
Aldoss, I., Khaled, S. K., Wang, Y., Wang, X., Palmer, J., Clark, M. C., Wagner, J. R., Paul, J., Vyas, V., Brown, C. E., et al
Blood cancer journal. 2023;13(1):107
-
8.
Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy
Yang, T. T., Meng, Y., Kong, D. L., Wei, G. Q., Zhang, M. M., Wu, W. J., Shi, J. M., Luo, Y., Zhao, Y. M., Yu, J., et al
Frontiers in immunology. 2022;13:934442
Abstract
INTRODUCTION Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) markedly improves the long-term survival of patients with refractory/relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL). METHODS We performed a parallel comparison of transplant outcomes in 168 B-ALL patients undergoing haplo-HSCT after achieving minimal residual disease (MRD)-negative complete remission (CR) from CAR-T therapy (n = 28) or chemotherapy (n = 140) between January 2016 and August 2021. We further divided the chemotherapy group into the first CR group (chemo+CR1, n = 118) and a second or more CR group (chemo+≥CR2, n = 22). RESULTS With a median follow-up period of 31.0 months, the 2-year overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM), and relapse rates in the CAR-T and chemotherapy groups did not differ significantly (OS, 87.9% vs. 71.5 %; LFS, 72.0% vs. 66.8%; NRM, 3.9% vs. 13.7%; relapse, 24.1% vs. 19.4%). Multivariate analysis confirmed that ≥CR2 at transplantation following chemotherapy was an independent risk factor associated with poor OS (hazard ratio (HR) 4.22 [95% CI, 1.34-13.293], p = 0.014) and LFS (HR 2.57 [95% CI, 1.041-6.343], p = 0.041). The probabilities of OS and LFS at 2 years in the CAR-T group were comparable to those in the chemo+CR1 group but significantly higher than those in the chemo+≥CR2 group (OS, 87.9% vs. 37.8%, p = 0.007; LFS, 72.0% vs. 41.7%, p = 0.043). No significant differences in the incidences of NRM were noted among the three groups. CONCLUSIONS Our results demonstrated that patients with R/R B-ALL receiving haplo-HSCT after CAR-T therapy achieved comparable outcomes to patients transplanted post-chemotherapy-based MRD-negative CR1, without increased risk of transplant-related mortality and toxicity.
-
9.
Comparisons of Long-Term Survival and Safety of Haploidentical Hematopoietic Stem Cell Transplantation After CAR-T Cell Therapy or Chemotherapy in Pediatric Patients With First Relapse of B-Cell Acute Lymphoblastic Leukemia Based on MRD-Guided Treatment
Hu, G., Cheng, Y., Zuo, Y., Chang, Y., Suo, P., Jia, Y., Lu, A., Wang, Y., Jiao, S., Zhang, L., et al
Frontiers in immunology. 2022;13:915590
Abstract
Measurable residual disease (MRD) positivity before haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an independent prognostic factor in determining outcomes in patients with B-cell acute lymphoblastic leukemia (ALL). In this study, we conducted a parallel comparison of the efficacy and safety in patients with suboptimal MRD response after reinduction who underwent haplo-HSCT after chimeric antigen receptor T-cell (CAR-T) therapy or chemotherapy. Forty B-cell ALL patients who relapsed after first-line chemotherapy and with an MRD ≥0.1% after reinduction were analyzed. The median pre-HSCT MRD in the CAR-T group (n = 26) was significantly lower than that in the chemotherapy group (n = 14) (0.009% vs. 0.3%, p = 0.006). The CAR-T group exhibited a trend toward improved 3-year leukemia-free survival and a significantly improved 3-year overall survival compared to the chemotherapy group [71.8% (95% confidence interval (CI): 53.9-89.6) vs. 44.4% (95% CI: 15.4-73.4), p = 0.19 and 84.6% (95% CI: 70.6-98.5) vs. 40.0% (95% CI: 12.7-67.2), p = 0.008; respectively]. Furthermore, no increased risk of graft-versus-host disease, treatment-related mortality, or infection was observed in the CAR-T group. Our study suggests that CAR-T therapy effectively eliminates pre-HSCT MRD, resulting in better survival in the context of haplo-HSCT.
-
10.
Three-year results from phase 1 of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia
Wayne, A. S., Huynh, V., Hijiya, N., Rouce, R. H., Brown, P. A., Krueger, J., Kitko, C. L., Ziga, E. D., Hermiston, M. L., Richards, M. K., et al
Haematologica. 2022
Abstract
The 3-year results are presented for ZUMA-4, a phase 1/2 multicenter study evaluating the safety and efficacy of KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory (R/R) Bcell acute lymphoblastic leukemia (B-ALL). Phase 1 explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Of 31 enrolled patients, KTE-X19 was administered to 24 (median age 13.5 years, range 3-20; median follow-up 36.1 months). No DLTs were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33%, 75%, 27%, and 22% in the all-treated, 2×106, 1×106 (68 mL formulation), and 1×106 (40 mL formulation) CAR T cells/kg groups; 21%, 25%, 27%, and 11% of patients experienced grade ≥3 neurologic events, respectively. Overall complete remission (CR) rates (including CR with incomplete hematologic recovery) were 67%, 75%, 64%, and 67% in the all-treated, 2×106, 1×106 (68 mL), and 1×106 (40 mL) CAR T cells/kg groups, respectively. Overall minimal residual disease (MRD)-negativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplant (alloSCT). In the 1×106 (40 mL) group (recommended phase 2 dose), median duration of remission censored at alloSCT and median overall survival were not reached. Pediatric/adolescent patients with R/R B-ALL achieved high MRD-negative remission rates with manageable safety profile after a single dose of KTE-X19. Phase 2 is ongoing at the 1×106 CAR T cells/kg (40 mL) dose.