In recent years, the field of hematologic oncology has witnessed remarkable breakthroughs, with acute lymphoblastic leukemia (ALL) emerging as a focal point of progress. Chinese researchers have made significant contributions, driving milestone advancements in both research and clinical practice. To usher in the new year, Hematology Frontier invited Professor Jun Ma from the Harbin Institute of Hematology and Oncology to provide an in-depth review of the key developments in ALL during 2024. This comprehensive analysis aims to guide clinical practice and inspire future research.

Immunotherapy and Cellular Therapy in Adult ALL

The treatment of adult ALL has advanced rapidly, particularly in the fields of immunotherapy and cellular therapy. Globally, the United States and China lead these developments. Historically, adult ALL was characterized by high relapse rates and extremely low cure rates following relapse, leading to dismal five-year survival rates. Treatment options were especially limited for older patients. Over a decade ago, the introduction of bispecific T-cell engagers (BiTEs), such as the CD19/CD3 bispecific antibody, revolutionized treatment by significantly improving outcomes for adult and pediatric relapsed/refractory (R/R) ALL patients and those with minimal residual disease (MRD). These therapies have become essential in bridging patients to allogeneic hematopoietic stem cell transplantation (allo-HSCT), offering high cure rates for transplant-eligible individuals.

In recent years, therapies such as bispecific antibodies and antibody-drug conjugates (ADCs) have been approved in China. Their efficacy has been validated through extensive use, particularly in MRD-positive adult patients, enabling early remission and extending survival, even in elderly populations. At the 2024 ASH Annual Meeting, a study presented promising outcomes for the use of immunotherapies as frontline treatments for ALL. However, due to the limited number of cases observed in newly diagnosed adult patients, larger clinical trials are necessary for further validation.

CAR-T therapy, originally developed for B-cell lymphomas, has expanded its application to B-cell ALL (B-ALL). The first CAR-T therapy approved in China for B-ALL marked its one-year anniversary in 2024, with over 100 patients treated. The therapy demonstrated high remission rates and outcomes comparable to allo-HSCT, reflecting its rapid progress in China and globally.

2024 CSCO Guideline Updates in ALL

At the 2024 CSCO Academic Conference on Hematologic Oncology in February and the CSCO Guidelines Conference in April, significant updates to the CSCO Guidelines for the Diagnosis and Treatment of Malignant Hematologic Diseases (2024) were introduced for ALL. Pre-treatment assessment now includes next-generation sequencing (NGS) as a Level II recommendation to detect gene mutations and copy number variations, enhancing diagnosis, prognosis, and targeted therapy. Prognostic stratification was updated with cytogenetic risk group adjustments based on the 2023 NCCN Guidelines (V4).

For Ph-negative (Ph-) patients achieving MRD negativity after induction therapy, the guidelines added Level I recommendations for conditional use of blinatumomab combined with chemotherapy or as monotherapy for consolidation, reflecting the growing recognition of immunotherapy. For Ph-positive (Ph+) patients aged 65 years and older with MRD-negative or positive status after induction, the guidelines now recommend blinatumomab combined with tyrosine kinase inhibitors (TKIs) for consolidation followed by maintenance therapy.

In the treatment of relapsed/refractory (R/R) ALL, bispecific antibodies and ADCs remain primary strategies. CAR-T therapy has been elevated to a Level I recommendation for Ph-negative R/R B-ALL patients. For Ph-negative R/R T-ALL patients, CAR-T therapy has been newly included as a Level II recommendation. Additionally, for Ph-positive R/R B-ALL patients, blinatumomab and inotuzumab ozogamicin were upgraded from Level II to Level I recommendations. These updates underscore the growing role of immunotherapy and cellular therapy in tailoring treatment to individual patients, offering a pathway to better outcomes.

Key Studies in ALL Research

Significant studies in 2024 shaped the ALL treatment landscape. In July, a team led by Professor Xiaojun Huang published a study in Cancer Letters using high-throughput sequencing to analyze IHG gene rearrangements for MRD detection (NGS-MRD) in 93 adult B-ALL patients, most of whom underwent HLA-haploidentical allo-HSCT. The study showed that NGS-MRD was more accurate than multiparameter flow cytometry (MPFC) in predicting relapse and survival, reinforcing its value in prognosis and treatment planning.

In January, Professor Jianxiang Wang’s team published findings in Haematologica on the IH-2014 regimen, the largest single-center prospective cohort study in China using pediatric-inspired therapy for adult Ph-negative ALL. Results confirmed the regimen’s efficacy and tolerability, particularly for patients under 40. Post-induction MRD levels were identified as reliable predictors of long-term survival and relapse, guiding allo-HSCT decisions during the first remission.

At the 2024 ASH Annual Meeting, Professor Ying Wang presented data on CD19 CAR-T therapy for adult R/R B-ALL. The study reported an 85.4% MRD-negative overall response rate (ORR) after infusion, with high remission rates and low incidence of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These results demonstrate the potential for long-term clinical benefits.

In August, the New England Journal of Medicine published the E1910 study, an international, Phase III randomized trial evaluating blinatumomab combined with consolidation chemotherapy in MRD-negative BCR::ABL1-negative ALL patients. The study showed that blinatumomab significantly improved overall survival, especially in patients under 55 years old, despite an increase in neuropsychiatric adverse events. The findings highlight the importance of blinatumomab in MRD-negative ALL, though longer follow-up is required to confirm survival benefits.

In October, a groundbreaking study by Xiaoming Feng and Jing Pan’s team, published in Nature Medicine, reported on the first clinical application of donor-derived CD5 CAR-T therapy for relapsed/refractory T-ALL. The therapy achieved a 100% complete remission (CR) or CR with incomplete recovery (CRi) rate by Day 30, with reduced relapse risk when followed by allo-HSCT. While donor-derived CAR-T therapy presents a promising strategy, future studies must address infection risks and improve safety to maximize patient outcomes.

Conclusion

In 2024, the integration of immunotherapy, cellular therapy, and precision medicine reshaped the treatment paradigm for ALL. The rapid advancements in clinical research, coupled with updated guidelines, underscore the potential to improve survival rates and offer hope for patients with both newly diagnosed and relapsed/refractory ALL. The strides made in ALL treatment over the past year lay a solid foundation for continued innovation in this evolving field.