Editor's Note: TP53-abnormal B-ALL is widely recognized as one of the highest-risk and most refractory subtypes of B-ALL. Not only is it highly resistant to conventional chemotherapy, but it is also particularly prone to antigen escape and early relapse following immunotherapy, posing major challenges in clinical management. During the 2026 Cross-Strait Hematology Academic Conference, Oncology Frontier – Hematology Frontier invited Professor Xiaowen Tang from the First Affiliated Hospital of Soochow University to provide a systematic interpretation of the tumor biological characteristics and high-risk factors of TP53-abnormal B-ALL. Professor Tang also discussed strategies for optimizing CAR-T therapy through lymphodepletion regimen optimization and multi-target design, as well as the comprehensive management pathway involving bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT), and looked ahead to future breakthroughs in precision risk stratification, relapse prediction, and integrated treatment.

Oncology Frontier – Hematology Frontier: Traditional salvage therapies for TP53-abnormal B-ALL are associated with poor outcomes and high relapse rates, and this subtype is widely recognized as an extremely high-risk disease. Could you discuss the unique biological characteristics of TP53-abnormal tumors that fundamentally contribute to the failure of chemotherapy and targeted therapies? When CAR-T therapy is selected as a salvage treatment, what baseline risk factors in patients with TP53 abnormalities require particular attention?

Professor Xiaowen Tang: TP53 is a key tumor suppressor gene that plays an important role in DNA damage repair, maintenance of genomic stability, regulation of apoptosis and cellular senescence, antitumor immunity, and tumor suppression. It is therefore often referred to as the “guardian of the genome.”

The efficacy of conventional cytotoxic chemotherapy is highly dependent on intact TP53 function to induce tumor-cell apoptosis. Once TP53 function is lost, tumor cells become significantly less sensitive to chemotherapy. Conventional chemotherapy may not only fail to achieve an effective response but may also select for more drug-resistant clones, resulting in low response rates, high levels of measurable residual disease (MRD), and a significantly increased risk of relapse.

Therefore, tumors with TP53 abnormalities require more specialized treatment strategies, with immunotherapy representing one of the important approaches. At present, TP53-abnormal B-ALL is clinically regarded as one of the highest-risk and most refractory subtypes.

Oncology Frontier – Hematology Frontier: CAR-T therapy offers an opportunity for deep remission in patients with TP53-positive high-risk B-ALL. However, compared with patients with TP53 wild-type disease, these patients continue to face a higher risk of early relapse following CAR-T therapy. Based on your clinical experience, what optimization strategies involving CAR-T itself or combination therapies can currently be adopted to overcome immune escape associated with TP53 deficiency and prolong remission? Following remission with CAR-T therapy, would you recommend bridging to allogeneic hematopoietic stem cell transplantation?

Professor Xiaowen Tang: TP53-abnormal tumors are not only resistant to conventional chemotherapy but are also highly prone to immune escape during immunotherapy. Existing literature has shown that whether patients receive a CD19 bispecific antibody, such as blinatumomab, or CD19 single-target CAR-T-cell therapy, they are highly susceptible to CD19-negative relapse. Therefore, relying solely on CD19 single-target CAR-T therapy often provides only a transient remission and makes it difficult to maintain long-term disease control.

To address these challenges, our team has conducted the following explorations and optimization strategies:

First, we added the hypomethylating agent decitabine (DAC) to the FC lymphodepletion regimen before CAR-T-cell infusion. Research from Professor Weidong Han’s team in China has also demonstrated that decitabine combined with CAR-T therapy can significantly improve treatment efficacy. The underlying mechanism is that decitabine can upregulate CD19 expression on the surface of tumor cells and improve the immunosuppressive tumor microenvironment, thereby enhancing CAR-T-cell expansion and persistence in vivo and ultimately improving overall treatment efficacy.

Second, with regard to target selection, given the high relapse rate following single-target CD19 therapy, we conducted a post hoc analysis based on three prospective clinical studies carried out at our center. The results showed that, compared with single-target therapy, CD19/CD22 dual-target CAR-T-cell therapy significantly increased the complete remission (CR) rate and MRD-negative CR rate, significantly improved 3-year overall survival (OS) and leukemia-free survival (LFS), and reduced the 3-year cumulative incidence of relapse (CIR). These findings suggest that the dual-target strategy can effectively overcome antigen escape and reduce the risk of relapse.

In addition, for patients with high-risk TP53-abnormal B-ALL who are particularly prone to treatment resistance and immune escape, once remission is achieved through immunotherapy, including bispecific antibodies or CAR-T therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) should be performed as soon as possible as a consolidation strategy, in order to maintain the efficacy of immunotherapy and prevent subsequent CD19-negative relapse.

Following transplantation, patients should continue to receive regular consolidation and maintenance therapy, including immunotherapies such as monoclonal antibodies and bispecific antibodies, or maintenance therapy with hypomethylating agents. In the future, treatment of TP53-abnormal B-ALL will inevitably depend on an integrated therapeutic approach to further improve long-term survival.

Oncology Frontier – Hematology Frontier: At present, prospective clinical studies investigating CAR-T optimization strategies specifically for TP53-abnormal B-ALL remain relatively limited. Considering the current state of diagnosis and treatment in China, what major barriers in CAR-T clinical research and clinical management of this subtype still urgently need to be overcome? In the future, in which directions can we further optimize the treatment pathway and improve long-term outcomes for patients with high-risk TP53-abnormal B-ALL?

Professor Xiaowen Tang: The therapeutic challenges associated with TP53-abnormal ALL are now widely recognized. The management of these patients should be optimized in the following areas:

First, establish a comprehensive, longitudinal management and precision risk-stratification system. Clinicians need to fully recognize the high-risk prognostic characteristics of this disease at the time of initial diagnosis and identify high-risk patients as early as possible. In the future, there is an urgent need to establish unified diagnostic criteria and clinical pathways for TP53 abnormalities nationwide and implement precise risk-stratified management. Particular attention should be paid to identifying patients with “multi-hit” TP53 abnormalities to guide individualized treatment.

Second, develop diversified combination treatment strategies. Given the complex mechanisms underlying relapse in these patients, in addition to primary and secondary treatment resistance, tumor antigen escape can readily occur during immunotherapy. Future treatment regimens should therefore deeply integrate multiple immunotherapeutic approaches, including novel monoclonal antibodies, bispecific antibodies, and CAR-T-cell therapies. Through multimodal combination strategies, the goal is to improve response rates, particularly MRD-negative CR rates, thereby creating favorable conditions for subsequent hematopoietic stem cell transplantation.

Third, improve relapse prediction and early-warning systems. There is currently a lack of precise tools for predicting relapse in clinical practice. In the future, more advanced detection technologies should be introduced, including dynamic monitoring of TP53 mutations and loss of heterozygosity (LOH), combined with next-generation sequencing (NGS) and other approaches to comprehensively assess the depth of molecular response following treatment. This would enable early identification of patients at risk of relapse and timely intervention.

Overall, future breakthroughs in this highest-risk subtype will mainly focus on several areas. First, establish dedicated precision risk-stratification and treatment standards for TP53-abnormal disease. Second, develop multi-target and bispecific CAR-T-cell therapies to effectively overcome antigen escape during immunotherapy. Third, establish a seamless bridging strategy between CAR-T therapy and hematopoietic stem cell transplantation while strengthening maintenance treatment following transplantation or CAR-T therapy to comprehensively prevent relapse. Fourth, promote the integrated application of novel drugs and technologies. Through comprehensive, integrated management, we aim to substantially improve long-term survival in these patients with refractory disease.

Expert Profile

Professor Xiaowen Tang

The First Affiliated Hospital of Soochow University

  • Deputy Director of the Department of Hematology; Chief Physician and Professor; Doctoral Supervisor and Postdoctoral Co-Supervisor
  • Research focuses: Clinical and basic research on hematopoietic stem cell transplantation and cellular immunotherapy
  • National Committee Member, Hematology Branch of the Chinese Medical Doctor Association
  • Deputy Head, Hematopoietic Stem Cell Transplantation Group, Hematology Branch of the Chinese Medical Association
  • Council Member, Cross-Strait Medicine and Health Exchange Association; Deputy Director of the Hematology Professional Committee
  • Chair, Hematology Branch of the Jiangsu Medical Association
  • Chair-Elect, Hematology Physicians Branch of the Jiangsu Medical Doctor Association
  • Chair, Hematopoietic Stem Cell Transplantation and Immunotherapy Branch of the Jiangsu Association of Research Hospitals
  • Deputy Director, Hematology Professional Committee of the Jiangsu Association of Integrated Traditional Chinese and Western Medicine
  • Head, Leukemia Group, Hematology Branch of the Jiangsu Medical Association
  • Key Medical Talent under the Jiangsu Provincial “Revitalizing Health through Science and Education” and “Strengthening Health through Science and Education” Programs
  • Jiangsu Provincial “333 High-Level Talent,” “Six Talent Peaks” Talent, and Gusu Leading Talent
  • Visiting Scholar at the University Hospital of Nantes, France; MD Anderson Cancer Center, USA; and Fred Hutchinson Cancer Research Center, USA
  • Editorial Board Member, Chinese Journal of Hematology
  • Editorial Board Member, International Journal of Blood Transfusion and Hematology
  • Editorial Board Member, Chinese Journal of Organ Transplantation
  • Invited Reviewer for journals including JHO, Annals of Hematology, and BMT
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