The use of chimeric antigen receptor T cells (CAR-Ts) is effective in the treatment of hematological malignancies. It has been reported that HBV is reactivated after CAR-T immunotherapy for refractory/relapsed hematological malignant B-cell tumors. However, there is little literature on donor-derived CAR-T therapy combined with allogeneic hematopoietic stem cell transplantation in hepatitis B patients with acute T-lymphocytic leukemia. We report the case of one patient with hepatitis B associated with relapsed/refractory acute T-lymphocytic leukemia (T-ALL) treated with donor-derived CD7 CAR-T therapy and allogeneic hematopoietic stem cell transplantation. During treatment, the copy number of hepatitis B virus continuously decreased, and AST, ALT, DBIL and TBIL remained within the controllable ranges. CD7-negative MRD recurred 4.5 months after transplantation, and the flow cytometry results became negative after immunosuppressive reduction. Seven months after transplantation, the patient had complete remission, and the copy number of hepatitis B virus decreased to below 102. This is the first study on the safety and effectiveness of donor-derived CD7 CAR-T therapy bridging to allogeneic hematopoietic stem cell transplantation in a patient with relapsed/refractory acute T-lymphocytic leukemia and hepatitis B.

Refer to the original:https://doi.org/10.3389/fimmu.2022.931452

T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous hematological malignancy that accounts for 25% to 50% of all cases in both children and adults. The genetic diversity of T-ALL itself limits the development of targeted therapy and immunotherapy in this field to some extent, so the clinical treatment of T-ALL is faced with many difficulties, and the prognosis of patients with relapsed/refractory T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma (R/R T-ALL/LBL) is even less ideal.

Recently, the team led by Director Zhihui Li in Director Tong Wu’s team at Beijing GoBroad Boren Hospital has published a paper in the journal Transplantation and Cellular Therapy which, focusing on the dilemma of diagnosis and treatment of R/R T-ALL/LBL, investigated the long-term outcomes in R/R T-ALL/LBL patients treated with CD7 CAR-T bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT) at Beijing Boren Hospital, and demonstrated that this combination strategy could improve long-term disease-free survival (DFS) in this patient population.

Compared with B-cell blood tumors, the CAR-T therapy of T-cell blood tumors is quite challenging. Previously, the teams of Director Tong Wu and Director Zhihui Li explored CD7 CAR-T bridging allo-HSCT in the treatment of T-cell blood tumors and their research results have been presented on many international academic occasions such as the American Society of Hematology (ASH) Annual Meeting and the European Hematology Association (EHA) Annual Meeting. They have shared the valuable experience of the Boren’s physician teams in the field of CAR-T for T-cell blood tumors with global peers for consecutive years.

 

Study Abstract

The study retrospectively analyzed 90 patients with R/R T-ALL (n=40) or T-LBL (n=50) treated at Beijing GoBroad Boren Hospital from February 2018 to January 2023. The median age was 14 (range: 2-65) years old.

All patients had received chemotherapy prior to transplantation, and the median number of lines of pre-transplantation treatment was 4 (range: 1-7). Thirty-two (35.6%) patients were sensitive to chemotherapy and achieved CR before transplant (CR group), and 58 (64.4%) cases were resistant to chemotherapy and in non-remission (NR) pre-HSCT. Forty-one of 58 patients in NR received CD7 CAR-T before allo-HSCT (CAR-T group) and the rest 17 patients in NR underwent salvaged transplant (NR group).

After a median follow-up of 25.5 (95% CI: 19.6-32) months, the overall survival (OS) and DFS in the CAR-T group were similar to those in the CR group and superior to those in the NR group. The 2-year OS was 54.4%, 69.9%, and 35.3%, and the 2-year DFS was 51.0%, 61.1%, and 17.6%, respectively. After 1 year, the cumulative recurrence rate in the CAR-T and CR groups was significantly lower than that in the NR group (31.67% and 29.0% vs. 70.5%). In addition, the treatment-related mortality was 17.29%, 9.8%, and 11.76%, respectively (p=0.65).

Prior to transplantation, somatic and germline gene mutations in T-ALL/LBL patients were detected by NGS in this study, and the results showed that TP53 and MED12 mutations were significantly associated with high recurrence and mortality after transplantation.

However, multivariate analysis showed that MED12 mutation did not affect OS (p=0.49) or DFS (p=0.394).

 

 

Study Conclusion

This retrospective study demonstrated that CD7 CAR-T bridging allo-HSCT significantly improved long-term DFS in patients with chemotherapy-resistant T-ALL/LBL, and achieved safety and efficacy comparable to those in the CR group. CD7 CAR-T (p=0.037), TBI conditioning (p=0.002), and cGVHD (p=0.004) were independent protective factors for OS, while aGVHD (p=0.034) and TP53 mutation (p=0.002) were independent risk factors for OS. CD7 CAR-T (p=0.005) and TBI conditioning (p=0.024) were protective factors for DFS, while TP53 mutation (p=0.02) was a risk factor for DFS. At the same time, the study also revealed the overview of somatic and germline gene mutations in R/R T-ALL/LBL patients, and preliminarily identified the gene mutation factors affecting the transplant outcome.

With the rapid advancement of precision genomics, the role of genetic predisposition genes in the diagnosis and treatment of hematologic malignancies has become increasingly evident. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), germline genetic variants not only influence disease susceptibility and immune status, but also profoundly affect post-transplant immune reconstitution, complication risks, and long-term survival outcomes. Consequently, incorporating genetic predisposition genes into systematic pre-transplant evaluation has emerged as a critical strategy for improving both the safety and efficacy of transplantation.

Professor Zhihui Li from the hematopoietic stem cell transplantation team at GoBroad Healthcare Group provides an in-depth interpretation of the clinical value of genetic predisposition genes in guiding transplant decision-making.

Patients with Homozygous IEI Mutations: Superior Survival Outcomes with Unrelated Donors

Studies have shown that patients harboring homozygous mutations in genes associated with inborn errors of immunity (IEI) achieve significantly better survival outcomes when transplanted with unrelated donors compared with related donors. The underlying reason lies in the familial aggregation of IEI-associated mutations. Related donors are more likely to carry the same homozygous or heterozygous pathogenic variants, resulting in donor-derived hematopoietic and immune cells with latent functional defects.

After transplantation, these hidden immune deficiencies may impair effective immune reconstitution, increasing the risk of severe infections and non-relapse-related mortality. In contrast, the likelihood that an unrelated donor carries the same homozygous IEI mutation is extremely low. Such donors typically possess intact immune function, facilitating robust and stable immune reconstitution, thereby reducing transplant-related complications and improving long-term survival.

Pre-Transplant Genetic Testing: From an “Optional Tool” to a Foundational Component

Based on these findings, testing for genetic predisposition genes should be considered a fundamental component of pre-transplant evaluation. For patients with hematologic malignancies who are candidates for allo-HSCT, systematic screening of genes related to hematopoiesis and immune function is recommended, with particular attention to IEI-associated genes and variants linked to cellular and humoral immunodeficiencies.

Genetic testing results not only support comprehensive risk assessment, but also directly inform donor selection and transplant strategy development, enabling more rational and evidence-based clinical decisions.

Genetics-Guided Donor Selection and Risk-Stratified Management

In donor selection, patients carrying homozygous IEI-related mutations should preferentially receive grafts from unrelated donors to minimize potential genetic and immunologic risks. For patients with pathogenic germline variants affecting cellular or humoral immunity, priority should be given to donors with intact immune function who do not harbor the same high-risk variants, regardless of whether the donor is related or unrelated.

At the same time, these patients should be classified as a high-risk transplant population and managed accordingly after transplantation. Risk-stratified post-transplant care should include intensified dynamic monitoring of immune reconstitution, enhanced infection prevention and early intervention strategies, and the use of immunologic supportive therapies when necessary, in order to reduce transplant-related complications.

Toward Personalized Transplantation: Genetics-Driven Optimization of Clinical Decision-Making

Overall, genetic predisposition information introduces a new dimension to decision-making in allogeneic hematopoietic stem cell transplantation. From donor selection to post-transplant management, individualized strategies based on germline genetic risk can enable safer and more precise transplantation.

Looking ahead, the systematic integration of genetic assessment into the transplant workflow has the potential to further improve transplant success rates and deliver greater long-term survival benefits for patients.