Professor Yonghong Zhang presented her team's profound insights and clinical experience on topics including the clinical value of germline susceptibility gene research and the optimization of precision therapy under molecular stratification. Her perspective offers important guidance for the future development of pediatric hematologic oncology.

Q1: In your view, what are the critical challenges currently facing pediatric hematologic oncology research? What novel approaches and methodologies are emerging?

Prof. Zhang: Refined precision therapy guided by molecular stratification represents a cutting-edge direction in hematologic oncology. The central question is how molecular subtyping can optimize individualized therapeutic strategies. Notably, while targeted and immunotherapies have already been widely incorporated into frontline regimens for adult hematologic malignancies, their application in pediatrics remains constrained by relatively lagging clinical trial progress.

With the rapid advancement of molecular biology technologies, the clinical potential of immunotherapy and targeted therapy in children is becoming increasingly evident. Treatment decisions informed by precise molecular profiling may enable rational reductions in chemotherapy dosage, thereby improving long-term quality of life and creating opportunities to explore innovative combinatorial regimens. Drawing upon an expanding body of clinical data from China, we are optimistic that targeted therapies will ultimately be incorporated into first-line pediatric protocols, benefiting a broader population of children.

Special clinical challenges arise in children with congenital anomalies complicated by hematologic malignancies, particularly in cases with T-cell or lymphocyte dysfunction. For example, lymphoma patients harboring mutations in hemophagocytic syndrome-related genes (e.g., PRF1, UNC13D) often present with hemophagocytosis, high relapse rates, and even coexistence of multiple lymphoma subtypes. Similarly, children with mismatch repair deficiencies exhibit profound intolerance to chemotherapy, heightened rates of treatment-related complications, and an increased risk of secondary malignancies. Addressing these challenges will depend heavily on the advancement of germline susceptibility gene research, which now enables clinicians to more accurately identify heritable predispositions and tailor individualized treatment strategies accordingly.

Q2: In refractory/relapsed pediatric lymphoma, which germline susceptibility genes has your team identified as being particularly significant? How do these mutations affect therapeutic response and prognosis?

Prof. Zhang: In clinical practice, certain children present with atypical pathological features and heterogeneous clinical manifestations at diagnosis. This is especially prominent in refractory and relapsed lymphoma cases, where it is essential to investigate underlying disorders, particularly immunodeficiency-related genetic predispositions.

Recent data from Beijing GoBroad Boren Hospital indicate that approximately 12% of refractory/relapsed lymphoma patients harbor pathogenic germline variants, with hemophagocytic syndrome-related mutations—especially UNC13D defects—being of particular importance. Such mutations impair lymphocyte antiviral and antitumor functions, markedly increasing the risk of relapse and the coexistence of multiple lymphoma subtypes. For instance, a child initially diagnosed with Burkitt lymphoma may subsequently develop Hodgkin lymphoma or NK/T-cell lymphoma following Epstein–Barr virus reinfection, reflecting the malignant transformation induced by defective lymphocytes in virus-infected B or T cells.

Accurate identification of germline susceptibility variants is therefore pivotal in guiding therapeutic strategies. Patients with mismatch repair deficiencies or germline TP53 mutations demonstrate poor tolerance to chemotherapy, higher rates of treatment-related complications, and significantly elevated risks of secondary cancers. Our team has observed cases of sequential occurrence of glioma and lymphoma, highlighting the necessity for dynamic surveillance systems.

Given these observations, individualized treatment strategies are imperative: once hematologic remission is achieved, early allogeneic hematopoietic stem cell transplantation should be considered to restore normal immune function. With ongoing advances in molecular biology, deeper investigation of germline susceptibility genes will support the development of precise prognostic models and individualized interventions. Early genetic risk screening combined with targeted and immunotherapeutic approaches is expected to substantially improve long-term survival and cure rates in these high-risk pediatric populations.

Q3: Looking ahead, what research directions in germline susceptibility gene studies for pediatric hematologic malignancies merit further exploration? What areas will your team prioritize?

Prof. Zhang: The management of pediatric lymphomas has entered the era of precision medicine. Earlier refinements based on pathological classification and risk-adapted stratification have significantly improved therapeutic outcomes. Current data indicate cure rates exceeding 90% for pediatric Hodgkin lymphoma and over 80% for non-Hodgkin lymphoma. Against this backdrop of high cure rates, research priorities are shifting toward the management of treatment-related toxicities—for example, reducing anthracycline exposure to mitigate cardiovascular toxicity and restricting radiotherapy indications to minimize long-term adverse effects.

At present, targeted and immunotherapies are primarily employed in second- or later-line settings. Our next research objective is to systematically refine treatment regimens for Chinese children across lymphoma subtypes, with the goal of integrating targeted therapies into frontline protocols. This strategy aims to reduce long-term toxicities while simultaneously enhancing long-term survival and quality of life.