scholarly journals Integrating CAR T-Cell Therapy and Transplantation: Comparisons of Safety and Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation After CAR T-Cell or Chemotherapy-Based Complete Remission in B-Cell Acute Lymphoblastic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan-Li Zhao ◽  
De-Yan Liu ◽  
Rui-Juan Sun ◽  
Jian-Ping Zhang ◽  
Jia-Rui Zhou ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Patients often undergo consolidation allogeneic hematopoietic stem cell transplantation (allo-HSCT) to maintain long-term remission following chimeric antigen receptor (CAR) T-cell therapy. Comparisons of safety and efficacy of allo-HSCT following complete remission (CR) achieved by CAR-T therapy versus by chemotherapy for B-cell acute lymphoblastic leukemia (B-ALL) has not been reported. We performed a parallel comparison of transplant outcomes in 105 consecutive B-ALL patients who received allo-HSCT after achieving CR with CAR-T therapy (n=27) or with chemotherapy (n=78). The CAR-T-allo-HSCT group had more patients in second CR compared to the chemotherapy-allo-HSCT group (78% vs. 37%; p<0.01) and more with complex cytogenetics (44% vs. 6%; p<0.001) but the proportion of patients with pre-transplant minimal residual disease (MRD) was similar. The median follow-up time was 49 months (range: 25-54 months). The CAR-T cohort had a higher incidence of Grade II-IV acute graft-versus-host disease (aGVHD 48.1% [95% CI: 46.1-50.1%] vs. 25.6% [95%CI: 25.2-26.0%]; p=0.016). The incidence of Grade III-IV aGVHD was similar in both groups (11.1% vs.11.5%, p=0.945). The overall incidence of chronic GVHD in the CAR-T group was higher compared to the chemotherapy group (73.3% [95%CI: 71.3-75.3%] vs. 55.0% [95%CI: 54.2-55.8%], p=0.107), but the rate of extensive chronic GVHD was similar (11.1% vs.11.9%, p=0.964). Efficacy measures 4 years following transplant were all similar in the CAR-T vs. the chemotherapy groups: cumulative incidences of relapse (CIR; 11.1% vs.12.8%; p=0.84), cumulative incidences of non-relapse mortality (NRM; 18.7% vs. 23.1%; p=0.641) leukemia-free survival (LFS; 70.2% vs. 64.1%; p=0.63) and overall survival (OS; 70.2% vs. 65.4%; p=0.681). We found that pre-transplant MRD-negative CR predicted a lower CIR and a higher LFS compared with MRD-positive CR. In conclusion, our data indicate that, in B-ALL patients, similar clinical safety outcomes could be achieved with either CD19 CAR T-cell therapy followed by allo-HSCT or chemotherapy followed by allo-HSCT. Despite the inclusion of more patients with advanced diseases in the CAR-T group, the 4-year LFS and OS achieved with CAR T-cells followed by allo-HSCT were as remarkable as those achieved with chemotherapy followed by allo-HSCT. Further confirmation of these results requires larger, randomized clinical trials.

scholarly journals How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

2020 ◽  
Vol 11 ◽  
Author(s):  
Mingming Zhang ◽  
He Huang
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has made tremendous progress in the last few decades and is increasingly being used worldwide. The success of haploidentical HSCT has made it possible to have “a donor for everyone”. Patients who received transplantation in remission may have a favorable outcome, while those who were transplanted in advanced stages of disease have a poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy is currently a milestone in the immunotherapy of relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) and has demonstrated high remission rates in patients previously treated in multiple lines, the relatively high relapse rate remains a barrier to CAR-T cell therapy becoming an excellent cure option. Therefore, combining these two approaches (allo-HSCT and CAR-T cell therapy) is an attractive area of research to further improve the prognosis of R/R B-ALL. In this review, we will discuss the current clinical practices of combining allo-HSCT with CAR-T cell therapy based on available data, including CAR-T cells as a bridge to allo-HSCT for R/R B-ALL and CAR-T cell infusion for post-transplant relapse. We will further explore not only other possible ways to combine the two approaches, including CAR-T cell therapy to clear minimal residual disease peri-transplantation and incorporation of CAR technology to treat graft-versus-host disease, but also the potential of CAR-T cells as a part of allo-HSCT.

scholarly journals Consolidative allogeneic hematopoietic stem cell transplantation after chimeric antigen receptor T-cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia: who? When? Why?

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Huiwen Jiang ◽  
Yu Hu ◽  
Heng Mei
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
Therapeutic Window ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

AbstractAlthough anti-CD19 chimeric antigen receptor (CAR) T-cell therapy shows good efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL), it fails to improve long-term leukemia-free survival (LFS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CAR T-cell therapy has emerged as a promising strategy to prolong LFS. Nevertheless, which patients are likely to benefit from consolidative allo-HSCT, as well as the optimal therapeutic window, remain to be explored. Recent clinical data indicate that patients with complex karyotypes, adverse genes, and high pre-infusion minimal residual disease (MRD) by flow cytometry in the bone marrow, were at high risk of relapse after CAR T-cell therapy. High pre-lymphodepletion lactate dehydrogenase, low pre-lymphodepletion platelet count, absence of fludarabine in lymphodepletion, persistent leukemic sequence by high throughput sequencing in bone marrow after CAR T-cell infusion, and early loss of CAR T cells have also been linked to relapse after CAR T-cell therapy. In patients having these risk factors, consolidative allo-HSCT after CAR T-cell therapy may prolong LFS. Allo-HSCT provides optimal clinical benefit in patients with MRD-negative complete remission, typically within three months after CAR T-cell therapy. Herein, we summarize the clinical data on consolidative allo-HSCT after anti-CD19 CAR T-cell therapy, as well as the potential factors associated with allo-HSCT benefit. We also discuss the optimal therapeutic window and regimen of consolidative allo-HSCT. Finally, and most importantly, we provide recommendations for the assessment and management of r/r B-ALL patients undergoing anti-CD19 CAR T-cell therapy.

scholarly journals Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

2018 ◽  
Vol 8 (8) ◽  
pp. 958-971 ◽  
Author(s):  
Bianca D. Santomasso ◽  
Jae H. Park ◽  
Darin Salloum ◽  
Isabelle Riviere ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features

2020 ◽  
Vol 4 (10) ◽  
pp. 2325-2338 ◽  
Author(s):  
Xian Zhang ◽  
Xin-an Lu ◽  
Junfang Yang ◽  
Gailing Zhang ◽  
Jingjing Li ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Therapy ◽  
Tp53 Mutation ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.

Pseudoprogression of extramedullary disease in relapsed acute lymphoblastic leukemia after CAR T-cell therapy

Immunotherapy ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 5-10
Author(s):  
Jie Huang ◽  
Liucheng Rong ◽  
Enxiu Wang ◽  
Yongjun Fang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Background: CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy in relapsed or refractory B-cell acute lymphoblastic leukemia. The changes in extramedullary (EM) disease in pediatric relapsed or refractory B-cell acute lymphoblastic leukemia after CAR T-cell therapy have rarely been reported. Materials & methods: A child with relapsed B-ALL was treated with CAR T-cell therapy. Bone marrow morphological examination, minimal residual disease, fusion mutation and radiological evaluation of the EM disease were performed before and after CAR T-cell infusion. Results: Radiological assessment revealed a distinct asymptomatic pseudo progression of EM involvements on day 16 after CAR T-cell infusion. Conclusion: Pseudoprogression of EM disease indicates heterogeneous immune-related patterns of response in patients treated with CAR-T therapy. Such patients should be closely monitored and practical immune-related response criteria should be developed for them.

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