To the Editor: For recipients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) often fails to provide them with a satisfactory prognosis. The chimeric antigen receptor T (CAR-T) cells are proven to be safe and effective for these patients.[1] But there are few published studies assessing the advantages of CAR-T compared to traditional chemotherapy as a bridging treatment followed by HSCT. Consequently, we conducted this study to confirm whether children and young adult R/R B-ALL patients with CAR-T therapy could expect a better post-HSCT prognosis, compared to R/R patients only receiving traditional chemotherapy before transplantation.
We performed a retrospective cohort study of consecutive eligible patients in Peking University People's Hospital between January 2016 and December 2020, who (1) were diagnosed as R/R CD19-positive B-ALL; (2) were children and young adult patients <60 years; and (3) received allo-HSCT in our institution. Exclusion criteria included severe cardiovascular, hepatic, or renal dysfunction. R/R patients with bridging CAR-T before allo-HSCT were identified to the CAR-T group, and R/R patients without CAR-T were identified to the control group. The study was approved by the Ethics Committee of Peking University People's Hospital (No. 2022PHB070-001). All patients' legal guardians provided written informed consent in accordance with the Declaration of Helsinki.
In CAR-T group, the novel therapy included 4-1BB CAR-T cells and CD28 CAR-T cells (Beijing Imunopharm Technology Co., Ltd., Beijing, China; Beijing Yongtai Reike Biotechnology Co., Ltd., Beijing, China).[2] All patients in CAR-T group received lymphocyte-reducing chemotherapy of fludarabine-cyclophosphamide (Flu/Cy) regimen before CAR-T infusion. The patient management followed the published guideline.[3]
Whether the recipient received a human leukocyte antigen (HLA)-identical or haploidentical HSCT was based on the donor selection criteria of our institution [Supplementary Methods, http://links.lww.com/CM9/B667].
After transplantation, the donor stem cell engraftment, immune reconstitution, infections, and acute graft-versus-host disease (aGvHD) were routinely detected [Supplementary Methods, http://links.lww.com/CM9/B667].
During follow-up, the progression of disease included the positive alteration of fusion genes or high-risk gene mutations, positive alteration of multiparameter flow cytometry-minimal residual disease (MFC-MRD), B-ALL relapse, and death due to disease. The gene-progression-free survival (gPFS) was defined as the period from HSCT to occurrence of fusion genes or positive high-risk gene mutations. The definition of MFC-MRD-progression-free survival (mPFS) was the period from HSCT to MFC-MRD re-positive status. Disease-free survival (DFS) was defined as the period from HSCT to relapse. Overall survival (OS) was defined as the survival period after HSCT.[4]
The basic characteristics were compared between the CAR-T group and control group. The chi-squared test and Mann–Whitney U test were respectively used for categorical and continuous variables, respectively. The Kaplan–Meier (KM) method was used to compare the risk of progression. The univariate and multivariate analyses were respectively performed using the competing risk model adjusted with confounding factors, in which the treatment-related mortality (TRM) acted as a competing risk for aGvHD, transplantation-related mortality PFS, and relapse.[5] All factors with P <0.20 in univariate analysis were identified into multivariate model. The Statistical Program for Social Sciences (SPSS) 26.0 (SPSS Inc., Chicago, IL, USA) and R version 4.2.2 (https://www.r-project.org/) were used for data analysis and figure production.
We consecutively enrolled 82 children and young adult R/R B-ALL patients, of whom 37 patients with CAR-T therapy were identified into CAR-T group, and 45 patients without CAR-T were identified into control group [Supplementary Table 1 and Supplementary Figure 1, http://links.lww.com/CM9/B621]. The proportion of children (<14 years old) was higher in CAR-T group than that in control group (62.2% [23/37] vs. 24.4% [11/45], P <0.01). The univariate and multivariate analyses showed that age was not associated with post-HSCT prognosis in children and young adult patients [Supplementary Table 2, http://links.lww.com/CM9/B621]. The median follow-up of surviving patients was 30 months in CAR-T group and 24 months in control group, respectively.
During the first month after HSCT, bridging CAR-T showed a privilege in donor stem cell engraftment in R/R patients. Recipients with bridging CAR-T had a higher rate of platelet engraftment than those in control group (86.5% [32/37] vs. 55.6% [25/45], P <0.01). And the time from HSCT to neutrophil engraftment was shorter for patients in CAR-T group [Supplementary Table 1, http://links.lww.com/CM9/B621].
Besides engraftment, there was a significant difference in immune reconstitution of T lymphocyte subsets over the first 3 months after HSCT. During the first 3 months, patients in CAR-T group had a remarkably higher proportion of CD3+, CD4+, and CD8+ T-cell subsets in nuclear cells than those in control group [Supplementary Figure 2, http://links.lww.com/CM9/B621]. The proportions of T-cell subsets in different groups became comparable at the 6-month follow-up after HSCT [Supplementary Figure 2, http://links.lww.com/CM9/B621]. However, such a significant difference was not observed in CD19+ B cell reconstitution, possibly because the recovery of B lymphocytes was late after transplantation. The T cells made up a larger proportion of nuclear cells in CAR-T group than in control group early after HSCT. However, whether the larger proportion was due to the T cell immune reconstitution of donor cells or the existence and expansion of infused external CAR-T cells remained unclear.
On account of the deficient immune system, patients were at risk of infection for several months post-HSCT. In our study, the incidence of infectious fever was similar in CAR-T group and control group (75.7% [28/37] vs. 68.9% [31/45], P = 0.50). The viral infection rates in the first 6 months were similar between the groups as well (67.6% [25/37] vs. 75.6% [34/45], P = 0.42). In addition, a similar fungal infection rate was also observed in two groups (40.5% [15/37] vs. 44.4% [20/45], P = 0.72).
Our data revealed that CAR-T had a positive impact on releasing the burden of aGvHD. In our study, the aGvHD prevention strategy was similar in both groups and patients with grade II–IV aGvHD needed to be treated systemically. In CAR-T group, 18 patients had aGvHD after HSCT, among whom ten had grade I aGvHD, and eight had grade II–IV aGvHD. In control group, there were 31 patients with aGvHD, among whom eight had grade I aGvHD, and 23 had grade II–IV aGvHD. Thus, the reduced incidence of grade II–IV aGvHD in CAR-T group was evident (21.6% [8/37] vs. 51.1% [23/45], P = 0.01).
During the follow-up, patients in CAR-T group had a lower risk of positive alteration of MFC-MRD (27.0% [10/37] vs. 48.9% [22/45], P = 0.04). The 2-year mPFS probabilities were 0.744 in CAR-T group (95% confidence interval [CI]: 0.612–0.904) and 0.435 in control group (95% CI: 0.302–0.627, P for KM curve = 0.02), respectively [Figure 1A]. However, when it comes to fusion genes or high-risk gene mutations, patients in both groups had comparable gPFS probabilities (P = 0.19) [Figure 1B].
Figure 1.
The Kaplan–Meier curves for disease progression of R/R B-ALL patients after HSCT. (A) The mPFS in CAR-T group and control group. (B) The gPFS in CAR-T group and control group. (C) The DFS in CAR-T group and control group. (D) The OS in CAR-T group and control group. CAR-T: Chimeric antigen receptor T; CI: Confidence interval; DFS: Disease-free survival; gPFS: Gene-progression-free survival; HSCT: Hematopoietic stem cell transplantation; MFC-MRD: Multiparameter flow cytometry-minimal residual disease; mPFS: MFC-MRD-progression-free survival; OS: Overall survival; R/R B-ALL: Relapsed/refractory B-cell acute lymphoblastic leukemia.
Regarding B-ALL relapse, there were seven patients in CAR-T group and 19 in control group who experienced B-ALL relapse post-HSCT (18.9% [7/37] vs. 42.2% [19/45], P = 0.02). The KM curve described a significant difference in DFS probabilities in CAR-T group and control group (P = 0.01). The 2-year DFS probabilities in CAR-T and control group were 0.825 (95% CI: 0.707–0.963) and 0.537 (95% CI: 0.399–0.723), respectively [Figure 1C]. The statistical significance existed in cumulative incidence of relapse through Fine-Gray test (P = 0.01) when the TRM was considered as a risk factor in relapse investigation [Supplementary Figure 3, http://links.lww.com/CM9/B621].
To further evaluate the effect of bridging CAR-T on the prognosis of HSCT, we merged the patients in both groups to perform univariate and multivariate analyses adjusted with confounding factors. In this adjusted model, CAR-T group was the only pre-HSCT predictor for less incidence of relapse (Hazard ratio [HR] = 0.369, P = 0.02) [Supplementary Table 2, http://links.lww.com/CM9/B621].
After transplantation, 16 patients died during the follow-up. Eight recipients died due to transplantation-related severe infection (three in CAR-T group and five in control group) and one recipient in control group died due to severe aGvHD with liver failure. Another patient in control group died of intracranial hemorrhage and brain herniation. Six recipients died from relapse after HSCT (two in CAR-T group and four in control group). The 2-year OS probabilities showed an statistically insignificant difference (P = 0.17) [Figure 1D].
In conclusion, our retrospective cohort study of consecutive patients proved that bridging CAR-T cells was an excellent novel therapy to improve the poor prognosis of the children and young adult R/R B-ALL patients after allo-HSCT. The treatment reduced the incidence of platelet engraftment failure, grade II-IV aGvHD, positive alteration of MFC-MRD, and the R/R B-ALL relapse. For more rigorous confirmation, a prospective RCT is anticipated in our further study.
Funding
This study was supported by grants from the National Natural Science Foundation of China (Nos. 82070184 and 82270228) and sponsored by Beijing Nova Program (No. 20220484235), Peking University People's Hospital Research and Development Funds (No. RDL2021-01).
Conflicts of interest
None.
Supplementary Material
Footnotes
Xiangyu Zhao and Haotian Wu contributed equally to this work.
How to cite this article: Zhao XY, Wu HT, Cheng YF, Xu ZL, Chen YH, Chang YJ, Wang Y, Zhang XH, Xu LP, Huang XJ. Bridging chimeric antigen receptor T-cell before transplantation improves prognosis of relapsed/refractory B-cell acute lymphoblastic leukemia. Chin Med J 2023;136:2011–2013. doi: 10.1097/CM9.0000000000002764
References
- 1.Sun W, Huang X. Role of allogeneic haematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukaemia in the era of immunotherapy. Chin Med J 2022;135: 890–900. doi: 10.1097/cm9.0000000000001898. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Hu GH Zhao XY Zuo YX Chang YJ Suo P Wu J, et al. Unmanipulated haploidentical hematopoietic stem cell transplantation is an excellent option for children and young adult relapsed/refractory Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia after CAR-T-cell therapy. Leukemia 2021;35: 3092–3100. doi: 10.1038/s41375-021-01236-y. [DOI] [PubMed] [Google Scholar]
- 3.Mei H Chen F Han Y Hou M Huang H Huang X, et al. Chinese expert consensus on the management of chimeric antigen receptor T cell therapy-associated coagulopathy. Chin Med J 2022;135: 1639–1641. doi: 10.1097/cm9.0000000000002288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Xu Q Xu H Xue L Wang M Pan G Zhang X, et al. CD19-targeted chimeric antigen receptor-modified T cells induce remission in patients with relapsed acute B lymphoblastic leukemia after umbilical cord blood transplantation. Chin Med J 2021;135: 98–100. doi: 10.1097/cm9.0000000000001491. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Zhao YL Liu DY Sun RJ Zhang JP Zhou JR Wei ZJ, et al. 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. Front Immunol 2021;12: 605766. doi: 10.3389/fimmu.2021.605766. [DOI] [PMC free article] [PubMed] [Google Scholar]