China's top 10 achievements in hematology in 2022.

Abstract

In January 2023, the hematology community in China came together for the 3rd Annual Meeting of the Chinese Alliance for Societies of Hematology (CASH). It was also the third time to announce China’s top 10 hematologic achievements of the previous year. Every time, both fundamental and clinical research advances were carefully considered and balanced, and the results were voted on by more than 300 committee members. Even though the first 3 CASH meetings were virtual, they were all well received, with the number of participants reaching more than 1.8 million for the 2023 CASH meeting. With the lifting of travel restrictions in China, the next CASH meeting will be hybrid. We welcome physicians, scientists, and industry representatives from China and the rest of the world to attend the next CASH meeting in 2024. 1. ADENO-ASSOCIATED VIRUS VECTOR GENE THERAPY CLINICAL TRIAL FOR HEMOPHILIA B Two articles from Lei Zhang’s team,1,2 reported that the first liver-tropic adeno-associated virus (AAV) vector gene therapy for hemophilia B in Asia was safe and effective. After 16 months of gene therapy, a hemophilia B patient successfully underwent total knee arthroplasty, which showed the in vivo hemostatic effect of factor IX Padua after gene therapy. In addition, it provided important insights into the treatment of hereditary diseases. A commentary from Blood Science included an extended background for the history of AAV gene therapy for hemophilia B.3 2. UNCOVERING THE EMERGENCE OF HEMATOPOIETIC STEM CELLS IN HUMAN FETAL BONE MARROW AND ITS EVOLUTION IN THE HUMAN LIFESPAN Using single-cell RNA-seq technology, Tao Cheng’s team uncovered the precise time point at which hematopoietic stem cells (HSCs) seeded in human fetal bone marrow (BM), the key niche cells and the ligand–receptor interactions involved in HSC colonization.4 They also delineated the dynamic transcriptional map of HSCs in BM after birth and performed an analysis of the temporal and spatial evolution of human BM HSC development, filling the gap in the development of human BM HSCs, and providing clues and potential strategies for improving the efficiency of clinical transplantation. 3. DEVELOPMENT AND CLINICAL APPLICATION OF NON-VIRAL GENOME-SPECIFIC INTEGRATED CHIMERIC ANTIGEN RECEPTOR-T CELL TECHNOLOGY Recently, chimeric antigen receptor (CAR)-T cell therapy has shown great promise in treating hematological malignancies. However, current CAR-T cell technology still has some limitations. He Huang’s team successfully developed an approach to generate non-viral genome-specific integrated CAR-T cells through CRISPR/Cas9 genome editing.5 The preclinical and clinical studies showed that non-viral PD1-integrated CAR-T cells exhibited high safety and efficacy in treating relapsed/refractory B-cell non-Hodgkin lymphoma. In terms of mechanism, these PD1-integrated CAR-T cells have a high percentage of memory T cells and enhanced anti-tumor immune functions. As a two-in-one approach without using virus, the manufacturing procedure is simplified, with shortened preparation time, reduced production expenses and increased safety and efficacy of the CAR-T cell products. Collectively, this study developed an innovative non-viral genome-specific targeted CAR-T technology, thereby providing a novel strategy to break through the current limitations of CAR-T cell therapy. 4. IDENTIFICATION OF THE IMMUNE-PRONE ERYTHROID PRECURSOR SUBSET DURING HUMAN ONTOGENESIS Human erythroid cell development is sequentially regulated and tightly coordinated during ontogenesis. Beyond the function as inert oxygen carriers, evidence is emerging to suggest that nucleated CD71+ erythroid cells participate in immune responses during development and disease. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. The research from Lihong Shi’s team identified an immune-erythroid subset that emerged as early as the embryonic stage and persisted in adults.6 These immune-erythroid cells possessed dual erythroid and immune regulatory networks and played immunomodulatory roles by actively interacting with various immune cells. Shi’s group also characterized the developmental stage-specific features of these immune-erythroid cells and their immunomodulatory functions. Overall, this analysis provides a valuable data resource and important insights into erythropoiesis, which should help to clarify the immunomodulatory roles of immune-erythroid cells in a variety of diseases. 5. KEY MECHANISMS OF DISSEMINATED INTRAVASCULAR COAGULATION INDUCED BY HEATSTROKE The high mortality rate from heatstroke is due to the progression of heatstroke-induced disseminated intravascular coagulation (DIC), and in most patients, organ damage cannot be stopped by cooling treatments. If global warming continues, heatstroke may become a more prominent cause of mortality, but the pathogenesis of DIC remains largely unknown. The research by Ben Lu’s team showed that Z-DNA binding protein 1 (ZBP1), a Z-nucleic acid receptor, mediates heatstroke-induced DIC by triggering RIPK3-dependent programmed cell death.7 This finding overturns previous academic views and achieves a major theoretical breakthrough, shedding new light on the pathophysiology of heatstroke-induced DIC. It also indicates the link between temperature stress response, programmed cell death and DIC and organ dysfunction, providing important drug targets and therapeutic directions for the prevention and treatment of major diseases. 6. INNOVATIVE TREATMENT STRATEGIES OF CAR-T CELL THERAPY FOR TREATMENT OF B-CELL MALIGNANCIES CAR-T cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Recently, a number of articles and research highlights have been published in Blood Science focusing on CAR-T cell therapy.8 The research from Kailin Xu’s team described clinical results in the treatment of relapsed/refractory multiple myeloma and central-nervous-system B-cell acute lymphoblastic leukemia using CAR-T cell therapy, providing innovative insights into this form of therapy with promising therapeutic potential for B-cell malignancies.9,10 7. THE METABOLIC REGULATION OF HEMATOPOIETIC STEM CELLS FOR EXPANSION AND REJUVENATION Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation. However, the mechanism remains incompletely understood. The research from Meng Zhao’s team unveiled novel GCN2-Src-AKT and Sphk2-HIF1α-PDK3 axes as checkpoints in the control of HSC metabolic fitness, providing new strategies for HSC expansion and rejuvenation.11,12 8. ELUCIDATING CHEMO-RESISTANCE IN MINIMAL RESIDUAL DISEASE IN CHILDHOOD LEUKEMIA The rapid advancement of single-cell RNA technology has created a powerful tool and an unprecedented opportunity to uncover the heterogeneous cell populations and chemo-resistance mechanism in minimal residual disease (MRD) of childhood leukemia. The research from Tao Cheng’s team provides insights into the transcriptomic characteristics of childhood leukemia MRD cells and proposes that hypoxia signaling pathway activation might serve as a valuable therapeutic target for childhood MRD.13 9. BUSULFAN PLUS CYCLOPHOSPHAMIDE VERSUS TOTAL BODY IRRADIATION PLUS CYCLOPHOSPHAMIDE FOR ADULT ACUTE B LYMPHOBLASTIC LEUKEMIA The study from Qifa Liu’s team showed that for adult B-cell acute lymphoblastic leukemia patients in first complete remission and undergoing human leukocyte antigen-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT), the efficacy and safety of busulfan plus cyclophosphamide (BuCy) was not inferior to that of total body irradiation (TBI) plus cyclophosphamide.14 This study suggested that the BuCy regimen may be considered the standard for the care of these populations undergoing allo-HSCT, especially in some HSCT centers that cannot offer the TBI regimen. 10. CLINICAL STUDY OF CILTACABTAGENE AUTOLEUCEL, AN ANTI-B-CELL MATURATION ANTIGEN CHIMERIC CAR-T CELL THERAPY, IN THE TREATMENT OF RELAPSED/REFRACTORY MULTIPLE MYELOMA Although novel therapeutic agents have markedly improved the overall survival of myeloma patients, multiple myeloma (MM) is as yet considered incurable. Limited availability of these therapeutic agents and high unmet clinical need remains. This pivotal phase II, open-label study, conducted across 8 sites in China from Sai-juan Chen’s team, enrolled adult patients with relapsed/refractory multiple myeloma (RRMM) who had received at least 3 lines of prior therapy, including a proteasome inhibitor and immunomodulatory drug.15 The studies demonstrated a positive risk-benefit profile for ciltacabtagene autoleucel in this RRMM patient population exposed to multiple lines of treatment; the studies also offer a promising treatment option. It is expected to achieve longer progression-free survival and overall survival, or even the chance of being cured.