In 2024, significant progress was made in the field of pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), bringing new insights and advancements to clinical practice. These studies covered innovations in treatment approaches, evaluations of drug efficacy, and a deeper understanding of the biological characteristics of these diseases. These findings are crucial for advancing precision medicine in pediatric leukemia and improving patient outcomes.

To mark the beginning of the new year, Hematology Frontier invited Dr. Xiaofan Zhu from the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, to review the major breakthroughs and cutting-edge developments in pediatric ALL and AML presented at the 2024 ASH Annual Meeting. Additionally, Zhu summarized the research progress made by their team in 2024, offering valuable insights into clinical practice and future research directions.

Advances in Pediatric ALL Research

Blinatumomab: Expanding Potential in Pediatric ALL

At the 2024 ASH Annual Meeting, two key studies highlighted the potential of blinatumomab in pediatric ALL treatment.

The first study, AALL1731, included newly diagnosed pediatric B-ALL patients classified as standard risk (SR) by the National Cancer Institute (NCI), further stratified into SR-low risk, SR-intermediate risk, and SR-high risk groups. The SR-low-risk group received chemotherapy alone, while the SR-intermediate and SR-high-risk groups were randomly assigned to receive chemotherapy alone or chemotherapy combined with blinatumomab. The results showed that incorporating blinatumomab significantly improved disease-free survival (DFS) in the NCI SR-intermediate and SR-high-risk groups. Additionally, blinatumomab demonstrated good tolerability, with no treatment-related deaths reported.

Another retrospective study analyzed clinical data from newly diagnosed pediatric B-ALL patients who received blinatumomab combined with chemotherapy as frontline treatment. This study included 90 patients who received one or two cycles of blinatumomab in addition to the CCLG-B-ALL-2018 protocol, compared with 212 historical control patients who received the CCLG-B-ALL-2018 regimen alone. The results showed that after one cycle of blinatumomab treatment, the complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate reached 100.0%, while the minimal residual disease (MRD) negativity rate was 94.4%, with multiparameter flow cytometry (MFC) detecting an MRD negativity rate as high as 98.9%. With a median follow-up of 26.8 months, the two-year event-free survival (EFS) rate was 97.8% ± 1.6%, and the two-year overall survival (OS) rate was 98.5%, with a cumulative incidence of relapse (CIR) of only 2.2% ± 1.6%. Moreover, adverse events associated with blinatumomab remained within an acceptable range. These findings suggest that adding blinatumomab to frontline chemotherapy improves remission rates and survival outcomes, particularly for chemotherapy-intolerant or intermediate/high-risk pediatric B-ALL patients.

Additionally, research from Peking University People’s Hospital demonstrated that blinatumomab combined with existing frontline treatment regimens, reduced-intensity chemotherapy, early-phase chemotherapy, and the BCL2 inhibitor venetoclax could benefit pediatric B-ALL patients.

These results reinforce the significance of blinatumomab in pediatric ALL treatment and provide new avenues for optimizing therapeutic strategies. Blinatumomab not only enhances DFS in specific risk groups but also achieves high remission and low relapse rates when combined with chemotherapy, with manageable toxicity. Furthermore, its combination with various existing treatment protocols and targeted inhibitors indicates that blinatumomab will drive pediatric ALL treatment toward greater efficiency, precision, and personalization, potentially improving patient outcomes and quality of life.

CAR-T Therapy: Multi-Target Approaches and Functional Enhancements

In recent years, immunotherapy—particularly CAR-T cell therapy—has yielded remarkable progress in pediatric and adolescent ALL.

A multi-center retrospective study led by Regina Myers from the Children’s Hospital of Philadelphia investigated the incidence, characteristics, and risk factors of cytopenia in pediatric and young adult B-ALL patients treated with 4-1BB-based CAR19 therapy. Among the 379 patients included in the study, 92% achieved complete remission (CR). By day 28 post-treatment, 50% experienced grade 3-4 cytopenia, which decreased to 26% at three months and 17% at six months. Over time, the incidence of severe neutropenia, anemia, and thrombocytopenia declined. Importantly, the presence of cytopenia after CAR-T therapy did not significantly affect relapse-free survival (RFS) or overall survival (OS). This study, the largest to date on cytopenia after CAR19 therapy in pediatric B-ALL, provides new predictive indicators for hematologic toxicity in clinical practice.

Meanwhile, researchers at Bambino Gesù Children’s Hospital in Italy conducted a study on CD7.PEBL-CAR-T therapy for relapsed/refractory (r/r) T-ALL patients. The study enrolled nine patients who received a median dose of 1 (0.5-3) ×10⁵/kg. Before treatment, the median percentage of CD7+ blast cells in bone marrow (BM) was 12.1% (range: 0.1-70%), with two patients having BM/extramedullary disease. All patients successfully generated CAR-T cells, with a median total cell count of 1.75 (0.05-3) ×10⁶/kg and a peak expansion of 365.10 ± 112.41 cells/μL. During treatment, seven patients experienced grade 1 cytokine release syndrome (CRS), and one had grade 2 CRS, with no cases of immune effector cell-associated neurotoxicity syndrome (ICANS). However, all nine patients developed grade 4 neutropenia, nine had grade 3-4 thrombocytopenia, four had grade 1-2 anemia, and five had grade 3 anemia. These findings suggest that CD7.PEBL-CAR-T is a promising option for inducing remission in advanced r/r T-ALL, although the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a post-CAR-T consolidation strategy remains to be determined.

Additionally, a study from Shanghai Children’s Medical Center evaluated CD19/CD22 CAR-T therapy in 318 pediatric r/r B-ALL patients, assessing clinical responses, side effects, and CAR-T expansion and persistence. The CR+CRi rate was 99.1%, with MRD negativity in all cases. Among 267 patients with isolated or combined hematologic relapse, the 12-month EFS and OS rates were 72.4% and 91.4%, respectively. Patients who underwent consolidation transplantation post-CAR-T therapy had better EFS, though OS was not significantly improved. These results suggest that CD19/CD22 CAR-T therapy is a safe and effective approach for achieving durable remission in pediatric r/r B-ALL, with bicistronic CAR-T therapy offering superior persistence compared to tandem dual-target designs.

Overall, CAR-T therapy is evolving toward more precise efficacy assessments, toxicity management, and optimized cell design to provide better outcomes for pediatric leukemia patients.

Advances in Targeted and Precision Therapies

A phase I study from Bambino Gesù Children’s Hospital in Italy found that combining BCL2 and BCL-XL/BCL2 inhibitors (venetoclax and navitoclax) with conventional chemotherapy could overcome drug resistance in r/r leukemia patients. This combination holds great potential for inducing complete remission in heavily pretreated and refractory pediatric and adolescent B-ALL or T-ALL patients, offering a bridge to long-term remission strategies.

Meanwhile, a study from the Institute of Hematology & Blood Diseases Hospital in China explored the safety, efficacy, and pharmacokinetics of olverembatinib alone or combined with lisaftoclax in pediatric and adolescent patients with r/r Ph+ ALL. The results demonstrated that olverembatinib plus lisaftoclax was well tolerated and exhibited strong and sustained antileukemic activity in this population.

Genomic Insights into Pediatric T-ALL

The University of Münster in Germany analyzed copy number variations (CNVs) and targeted sequencing data from pediatric and adult T-ALL/T-LBL patients. The study revealed age-related differences in CNV accumulation, distinct gene mutation patterns between pediatric and adult cases, and early clonal evolution with CNV emergence preceding subclonal mutations.

Additionally, researchers at the Children’s Hospital of Philadelphia conducted transcriptomic analysis on 203 pediatric T-LBL patients from the Children’s Oncology Group (COG), uncovering key molecular distinctions between T-LBL and T-ALL, including differences in drug responses, genetic alterations, and prognostic relevance. These findings enhance the understanding of pediatric T-LBL and highlight the necessity of genomic profiling for different subgroups.

Advances in Pediatric AML Research

Notable Efficacy of Gemtuzumab Ozogamicin (GO)

Gemtuzumab ozogamicin (GO), a key targeted therapy in pediatric acute myeloid leukemia (AML), has demonstrated significant efficacy in multiple clinical trials in recent years.

In the Myechild 01 trial, all newly diagnosed pediatric AML patients received an induction regimen based on mitoxantrone and cytarabine (MA) during the first treatment cycle, and were then randomized to receive either one or three doses of GO. Risk stratification was performed based on cytogenetic/molecular characteristics, treatment response, and minimal residual disease (MRD) levels. Among the 515 patients randomized to receive GO, 16 did not receive the treatment. Of the total cohort, 179 patients (35%) underwent hematopoietic stem cell transplantation (HSCT). The two-year event-free survival (EFS) rate was 70% (95% CI: 66-74%), and the overall survival (OS) rate was 88% (95% CI: 85-91%). 94% of patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) within one or two treatment cycles, while the two-year cumulative incidence of relapse (CIR) was 25%. A total of 79 patients died, with only 11 deaths (2%) occurring during the first remission period. Grade 3 or higher severe adverse events (sAEs) occurred in 59% of patients at least once. These findings indicate that combining GO with MA induction therapy, followed by risk-adapted treatment, yields promising outcomes.

The COG AAML1831 Phase III randomized trial investigated the efficacy of GO within standard therapy versus GO combined with CPX-351 (liposomal cytarabine and daunorubicin) in pediatric de novo AML patients. A total of 721 eligible patients without FLT3 mutations were randomized into Group A (n=358) and Group B (n=363). MRD levels at the end of induction 1 (EOI1) were comparable in both groups (23% in both A and B), and there was no significant difference in selective treatment discontinuation rates (A: 9%, B: 11%). The two-year EFS rate was significantly higher in Group A (60.9%, 95% CI: 54.3-66.8%) compared to Group B (51.2%, 95% CI: 44.7-57.4%; P=0.019). However, OS did not differ significantly between the two groups [A: 75.5% (95% CI: 69.3-80.5%); B: 74.5% (95% CI: 68.4-79.6%); P=0.782]. Patients in Group B had significantly lower EFS and higher relapse rates (P<0.05), indicating that GO combined with CPX-351 significantly improves EFS in pediatric AML.

Oral Combination Therapy: The Role of Revumenib

A study conducted at The University of Texas MD Anderson Cancer Center included relapsed/refractory (r/r) AML or mixed-phenotype acute leukemia (MPAL) patients aged 12 years and older, who received an all-oral combination regimen consisting of Revumenib, venetoclax, and the hypomethylating agent ASTX727. The results showed a remarkable overall response rate (ORR) of 88% (23/26), with a CR/CRh rate of 58%—including a complete remission (CR) rate of 46% and a CR with partial hematologic recovery (CRh) rate of 12%. These findings suggest that the all-oral SAVE regimen could achieve high remission rates in r/r AML patients carrying KMT2A rearrangements (KMT2Ar), NPM1 mutations (NPM1mut), or NUP98 rearrangements (NUP98r).

Dr. Xiaofan Zhu’s Reflections on 2024 and Outlook for 2025

Dr. Xiaofan Zhu reflected on the remarkable progress made in pediatric hematologic malignancies throughout 2024, particularly highlighting the significant breakthroughs presented at the ASH Annual Meeting. Pediatric ALL remains the most common hematologic malignancy in children, and research in this area has been extensive, yielding substantial advancements. One of the most notable developments has been the shift in immunotherapy from a salvage treatment to a frontline approach. This transition represents a major milestone that could redefine the treatment landscape for B-cell acute lymphoblastic leukemia (B-ALL), offering a path to reduced toxicity while enhancing efficacy. Additionally, important studies have been conducted on bone marrow failure syndromes such as aplastic anemia, contributing to a deeper understanding of disease management and treatment optimization.

The field of pediatric non-malignant hematologic disorders has also seen considerable progress. Efforts have been focused on reducing treatment-related toxicity while refining prognostic stratification to ensure more tailored treatment approaches. These advancements provide new strategies for improving patient outcomes and guiding future clinical decision-making.

Throughout 2024, Zhu’s team actively participated in major academic conferences, including the 14th International Society of Pediatric Oncology (SIOP) Asia Congress, the 85th Annual Meeting of the Japanese Society of Hematology (JSH), the 29th Congress of the European Hematology Association (EHA), and the ASH Annual Meeting. At the EHA Annual Meeting, the team had three studies selected in the pediatric leukemia field, focusing on predicting relapse risk and optimizing treatment strategies for relapsed/refractory pediatric ALL patients. In the bone marrow failure field, two studies explored the correlation between telomere length and treatment response in non-severe aplastic anemia patients and examined the clinical characteristics and prognosis of Shwachman-Diamond syndrome following progression to MDS or AML. The team’s contributions to the pediatric MDS field included two studies that revealed the genomic landscape of advanced-stage pediatric MDS and provided key insights into chemotherapy bridging strategies before transplantation.

During the ASH Annual Meeting, the team submitted 28 studies covering pediatric acute leukemia, bone marrow failure syndromes, hematopoietic stem cell transplantation, and other critical areas in pediatric hematology. More than half of these studies were accepted for presentation, marking a significant achievement for the team. While none were selected for oral presentations, Zhu emphasized that this serves as motivation to continue striving for groundbreaking research in pediatric hematologic oncology.