The European LeukemiaNet has periodically issued guidelines for the diagnosis and management of acute myeloid leukemia (AML) in adults. These consensus recommendations, most recently updated in 2022, incorporate recent advances in genomic testing, disease detection methods, target identification, and response assessment. Whilst similarities exist between AML in children and adults, pediatric AML is frequently characterized by unique cytogenetic and molecular features, which require distinct genetic and immunophenotypic diagnostics, therapeutic approaches, response assessment criteria, and supportive care strategies. To address these specific needs, an international panel of pediatric hematologist-oncologists, biologists, geneticists, and laboratory medicine scientists convened to develop recommendations for the diagnosis and management of AML in children, adolescents, and young adults (hereafter termed pediatric AML) that are discussed in this special report.

PURPOSE:The Children's Oncology Group phase III clinical trial AAML1831 (ClinicalTrials.gov identifier: NCT04293562) evaluated liposomal daunorubicin and cytarabine (CPX-351) versus standard daunorubicin/cytarabine (DA) induction therapy in children and young adults with newly diagnosed AML. We hypothesized that CPX-351 given during induction 1 and 2 would improve outcomes compared with DA. PATIENTS AND METHODS:Patients (21 years and younger) were randomly assigned to two cycles of DA induction (arm A = DA) or CPX-351 (arm B = CPX-351). All patients also received gemtuzumab ozogamicin in induction 1. Postinduction chemotherapy was according to risk assignment made at the end of induction 1 (EOI1). Those with high-risk (HR) AML received consolidation with allogeneic hematopoietic stem-cell transplantation (HSCT), whereas low-risk (LR) patients received chemotherapy alone. Protocol-specified interim analysis monitored efficacy and futility of CPX-351 induction with respect to the primary end point, event-free survival (EFS) from study entry. Disease-free survival (DFS) was calculated to determine the impact of EOI1 risk assignment. RESULTS:Seven hundred twenty-one eligible patients with FLT3 wild-type AML were randomly assigned to DA (n = 358) or CPX-351 (n = 363). Interim analysis determined that the futility monitoring rule was crossed because of inferior EFS in the CPX-351 arm and the random assignment was stopped. The two-year EFS from study entry was 62.2% for DA versus 51.2% for CPX-351 (P = .011). DFS for patients with HR AML was comparable for both arms. However, DFS was significantly lower and cumulative incidence of relapse (CIR) was higher for LR patients assigned to CPX-351 versus DA (2-year DFS from EOI1: DA: 73.8% v CPX-351 57.5% [P = .001]; 2-year CIR Arm DA: 23.6% v CPX-351: 39.9% [P = .001]). CONCLUSION:CPX-351 was inferior to DA induction in the AAML1831 trial with differential EFS largely driven by events in LR patients.

ABSTRACT:Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric acute myeloid leukemia (AML) that responds to reduced-intensity chemotherapy, as compared with non-DS AML that requires intensive chemotherapy and often stem cell transplant. While most patients with ML-DS have a favorable prognosis, outcomes for those with refractory or relapsed disease are dismal. Children's Oncology Group study AAML1531 introduced the use of measurable residual disease by multiparameter flow cytometry at the end of the first course of induction therapy (EOI-1 MRD) for risk stratification of treatment intensity. Of 280 patients with ML-DS who were enrolled, 41 were classified as high risk (HR) due to positive EOI-1 MRD, and treated with intensified chemotherapy similar to that used for pediatric non-DS AML. Treatment intensification did not improve the 2-year event-free survival compared with patients who were MRD-positive treated with reduced-intensity therapy in the predecessor study AAML0431 (80.5% ± 12.4% vs 76%; P = .247) or overall survival (80.5% ± 12.4% vs 76.2% ± 18.6%; P = .819), but significantly increased the frequency of febrile neutropenia and sepsis events. While stratification of treatment intensity based on MRD was not beneficial, molecular markers of relapse risk proposed by the Japan Children's Cancer Group for ML-DS (alterations of CDKN2A, ZBTB7A, JAK2, TP53) proved prognostic. Relapse risk was 50% in patients who were HR from AAML1531 with any high-risk molecular marker compared with 6.7% in those without. Similar relapse results were obtained in the MRD-negative AAML1531 group, suggesting molecular risk markers can predict outcome and thus be used to stratify therapy in ML-DS. This trial was registered at www.clinicaltrials.gov as #NCT02521493.

TPS10074 Background: CBFA2T3::GLIS2 -rearranged acute myeloid leukemia (AML) is a rare subtype of AML occurring exclusively in very young children and is associated with poor prognosis ( < 15% 5-year event-free survival [EFS]) with best-available multi-agent chemotherapy. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR = 4), which induces cytotoxic and immunologic cell death. CBFA2T3::GLIS2 AML uniquely expresses high cell surface levels of the FRα, suggesting that FRα-targeted therapies may be effective. Preclinical studies have demonstrated that treatment with luvelta can result in leukemia clearance. Preliminary safety and efficacy data from 25 children with relapsed/refractory CBFA2T3::GLIS2 AML treated with luvelta via compassionate use are promising [Williams, et al, BLOOD 2023, 142 (1): 4295]. Methods: This registration-enabling phase 1/2 study (clinicaltrials.gov NCT06679582) will investigate the pharmacokinetics, safety and preliminary efficacy of Luvelta in relapsed or refractory children with CBFA2T3::GLIS2 AML and ≥5% bone marrow (BM) involvement by morphology. The CBFA2T3::GLIS2 fusion will be confirmed at Foundation Medicine by next generation sequencing (NGS). The trial will open in up to 35 centers across US, Europe, Canada and Australia and is actively enrolling. The initial part of the trial will test luvelta monotherapy at 3.5 mg/kg or 4.3 mg/kg administered IV every 2 weeks in a 28-day cycle. Bayesian sequential monitoring is used for safety monitoring. The study committees will review the data to identify the recommended phase 2 dose of luvelta which will then be tested in the second part of the trial. Children who achieve BM morphological complete response (CR) may proceed to allogeneic hematopoietic stem cell transplantation (HSCT) or continue single-agent luvelta for up to 2 years at the investigators’ discretion. Patients without CR after 2 cycles of luvelta monotherapy may add chemotherapy (cytarabine +/- fludarabine or azacytidine) in cycle 3 and beyond. Post-HSCT maintenance therapy with luvelta monotherapy is also allowed for up to 2 years. The primary endpoint is morphologic CR defined as < 5% AML blasts in BM with absolute neutrophil recovery to > 1000 and platelets > 100,000 and absence of extramedullary disease. Secondary endpoints include PK levels and assessment of anti-drug antibody formation, safety, EFS and overall survival. Rates of measurable residual disease-negative CR and FRα antigen levels pre- and post-luvelta will also be explored. Clinical trial information: NCT06679582 .

ABSTRACT INTRODUCTION Vincristine sulfate liposome injection (VSLI), a liposomal formulation of vincristine, may be better tolerated than standard aqueous vincristine and enable dose intensification. PROCEDURES Based on single‐agent tolerability, activity, and FDA approval in adults with acute lymphoblastic leukemia (ALL), we tested the safety and feasibility of VSLI as replacement for standard vincristine in the UK ALL R3 mitoxantrone‐based four‐drug induction (Cohort A), a three‐drug anthracycline‐free induction (Cohort B), and maintenance chemotherapy (Cohort C) in children and young adults with relapsed/refractory B‐cell ALL. RESULTS Among 29 participants with a median age of 12.4 years (range: 1.8–19.6 years), 16 received Cohort A, eight received Cohort B, and five received Cohort C therapy. Dose level 1 (DL1): 1.5 mg/m 2 and dose level 2 (DL2): 2 mg/m 2 of VSLI, each without a dose cap, were tested. Collectively, the median VSLI dose administered was 1.9 mg (range: 0.71–4.06 mg), and 13 (44.8%) received a dose above the standard 2 mg vincristine dose cap. Dose‐limiting toxicities (DLTs) at DL2 were seen in three patients, two in Cohort A and one in Cohort B, prompting further evaluation at DL1 for both cohorts. No DLTs were experienced at DL1. Only DL2 was tested in Cohort C—without DLT. Complete remissions were seen in 14 of 16 (87.5%) participants in Cohort A; three of eight (37.5%) in Cohort B; and one (20%) in Cohort C. VSLI with combination chemotherapy at DL1 was generally well tolerated. CONCLUSION Based on the promising response signal in this heavily pretreated population, further study of VSLI is warranted. (ClinicalTrials.gov NCT02879643)

Importance:Therapeutic responses in acute myeloid leukemia (AML) demonstrate considerable variability both across and within established risk stratifications and age groups. Moreover, significant racial disparities persist, with Black patients experiencing inferior survival outcomes compared with their White counterparts. Objective:To validate the association of the previously reported 10 single nucleotide variant (SNV)-based ara-C pharmacogenomics score (ACS10) with survival outcomes in a large cohort of pediatric AML patients; to evaluate whether ACS10 remains relevant in an adolescent and young adult (AYA) population of patients with AML treated with similar intensive induction chemotherapy protocols; and to assess the association of ACS10 with race and treatment outcomes in both cohorts. Design, Setting, and Participants:This cohort study included patients from the Children's Oncology Group's AAML1031 trial, a multicenter, open-label randomized clinical trial that enrolled pediatric patients with newly diagnosed, treatment-naive primary AML from June 2011 to July 2017 (aged 0 to 29.5 years) and from the Alliance for Clinical Trials in Oncology frontline protocols, which included AYA patients from 9 different trials that enrolled patients with newly diagnosed AML from 1992 to 2010. Data were analyzed from September 2022 to March 2025. Exposures:Patients in the AAML1031 trial were randomized to 2 arms, standard chemotherapy alone or standard chemotherapy with the addition of bortezomib. Patients in the Alliance for Clinical Trials in Oncology cohorts were treated with similar intensive induction chemotherapy protocols. Main Outcomes and Measures:ACS10 scores were evaluated for association with outcomes according to race, treatment arm, and hematopoietic stem cell transplant (HSCT) status. Results:The study included 1086 patients with AML. There were 717 patients from the pediatric AML cohort (median [range] age, 9.6 [0.04-29.2 years]; 379 [53%] male; 33 [5%] Asian, 84 [12%] Black, and 522 [73%] White) and 369 AYA patients with AML from the Alliance for Clinical Trials in Oncology group (median [range] age, 30 [17-39] years; 196 [53%] male; 7 [2%] Asian, 32 [9%] Black, and 288 [78%] White). Within the standard treatment arm of AAML1031, patients in the low ACS10 group had significantly worse event-free survival (EFS) compared with those in the high ACS10 group (all patients: hazard ratio [HR], 1.42; 95% CI, 1.05-1.95; P = .02; non-HSCT cohort: HR, 1.48; 95% CI, 1.06-2.07; P = .02). The ACS10 score remained significantly associated with EFS in multivariable analysis after adjusting for age, race, risk group and white blood cell count, within the standard treatment arm (HR, 1.44; 95% CI, 1.03-2.02; P = .03). In the Alliance for Clinical Trials in Oncology AYA non-HSCT cohort, the low ACS10 score group had significantly inferior overall survival (OS) and a higher point estimate for EFS compared with patients with a high ACS10 score (OS: HR, 1.50; 95% CI, 1.05-2.14; P = .03; EFS: HR, 1.32; 95% CI, 0.95-1.83; P = .10). A higher number of early deaths was observed in the low ACS10 group compared with the high ACS10 group, but the difference was not statistically significant (death within 30 days of treatment initiation: 6 of 112 [5%] vs 2 of 257 [1%]; P = .07). Across both cohorts, a low ACS10 score was significantly more abundant in Black patients compared with White patients (eg, in Alliance for Clinical Trials in Oncology cohort, 27 of 32 Black patients [84%] had low ACS10 scores compared with 64 of 288 White patients [22%]; P < .001) and inferior survival was observed in Black patients (eg, OS of Black compared with White patients in AAML1031 cohort: HR, 1.47; 95% CI, 1.02-2.13; P = .04). In the AAML1031 cohort, there were no significant differences in EFS or OS between Black and White patients receiving augmented treatment, suggesting that the addition of bortezomib was associated with benefit for Black patients. Conclusions and Relevance:In this study of 717 pediatric and 369 AYA patients with AML, the ACS10 score was associated with EFS in pediatric and AYA patients when treated with a standard induction regimen. There was a higher abundance of low ACS10 scores in Black patients, and Black patients treated with augmented therapy (ie, the addition of bortezomib) seemed to have improved outcomes. Integrating the ACS10 score into a prospective clinical trial to personalize induction therapy based on an individual's genetic profile has the potential to improve treatment outcomes.

PURPOSE:Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML. METHODS:We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group. RESULTS:Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P < .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss. CONCLUSION:HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.

BACKGROUND:Venetoclax is a potent, oral BCL-2 inhibitor approved as combination therapy for the treatment of adults with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. This study evaluated the safety and preliminary efficacy of venetoclax alone or combined with chemotherapy in paediatric and adolescent/young adult patients with relapsed/refractory AML. PROCEDURE:In this phase 1, open-label, two-part, multicentre study, paediatric and adolescent/young adult patients (<25 years of age) with relapsed/refractory AML were treated with venetoclax alone or in combination with hypomethylating agents or cytarabine. The study is registered with ClinicalTrials.gov, NCT03236857. RESULTS:A total of 37 patients received treatment with either venetoclax as a monotherapy (n = 3) or in combination with decitabine (n = 5), azacitidine (n = 19), low-dose cytarabine (n = 1) or high-dose cytarabine (HDAC; n = 9). Febrile neutropenia (57%), hypokalaemia (38%), and thrombocytopenia (35% [thrombocytopenia, 19%; platelet count decreased, 16%]) were the most common grade 3/4 treatment-emergent adverse events. Across all venetoclax combinations, the overall response rate (ORR) was 24% (9/37), and the median duration of response was 2.6 months (95% CI, 0.5-7.9). Among the combinations, ORR was 44% with venetoclax plus HDAC and 21% with venetoclax plus azacitidine. In biomarker-evaluable patients, responses to venetoclax plus chemotherapy were observed in patients harbouring mutations across a range of functional classifications and heterogeneous BH3 family member dependencies. CONCLUSIONS:Venetoclax alone or combined with chemotherapy was well tolerated in paediatric and adolescent/young adult patients with relapsed/refractory AML, with promising, although transient, responses with venetoclax plus HDAC or azacitidine.

BACKGROUND:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and although many patients respond to induction therapy, those who relapse or have refractory disease face a poor prognosis. Venetoclax has promising preclinical and clinical activity in ALL. Here, we report the safety and preliminary efficacy of venetoclax combined with chemotherapy in pediatric and adolescent/young adult patients with relapsed/refractory ALL. PROCEDURE:This phase 1, open-label, two-part, multicenter study evaluated venetoclax combined with chemotherapy in pediatric and adolescent/young adult patients (<25 years of age) with relapsed/refractory ALL. The study is registered with ClinicalTrials.gov, NCT03236857. RESULTS:Thirty-one patients were treated and received venetoclax monotherapy (n = 1), venetoclax plus dexamethasone and/or vincristine and/or pegasparaginase (VXL; n = 20) or venetoclax plus cytarabine and/or etoposide and/or pegasparaginase (n = 10). Patients were heavily pretreated, with a median of 3 prior lines of therapy. The most common grade 3/4 treatment-emergent adverse event was febrile neutropenia (55%). One fatal adverse event possibly related to venetoclax occurred. The overall response rate of treated patients was 42%, with all responding patients achieving complete remission/complete remission with incomplete marrow recovery. In biomarker-evaluable patients, responses to venetoclax plus VXL-based or cytarabine-based chemotherapy were observed in patients harboring a range of genetic alterations and heterogeneous BH3 family member dependencies. CONCLUSIONS:Venetoclax plus VXL-based or cytarabine-based chemotherapy was overall well tolerated, with promising preliminary efficacy.

Introduction: Survival in childhood AML has plateaued and new therapeutic strategies are essential. CPX-351 (Vyxeos) is a liposomal preparation of cytarabine and daunorubicin with superior pharmacokinetic properties when compared to free drug. The Children's Oncology Group (COG) Phase III clinical trial AAML1831 tested the hypothesis that CPX-351 given during Inductions 1 and 2 would improve treatment outcomes and reduce long-term toxicities compared to a standard chemotherapy. Methods: COG AAML1831 randomized patients (pts) <22 years of age with de novo AML to 2 different induction regimens. Pts with FLT3 mutations were offered enrollment onto gilteritinib-containing regimens and are not included in this analysis. Arm A patients received cytarabine, daunorubicin and gemtuzumab ozogamicin (DA+GO) during Induction 1 and DA during Induction 2. Patients on Arm B received, during Induction 1, CPX-351 on days 1, 3 and 5 and GO on day 6; the CPX-351 dosing was repeated in Induction 2. Centralized risk stratification occurred after Induction 1 and was based on cytomolecular findings and end of induction 1 (EOI 1) minimal residual disease (MRD) >0.05% by central multidimensional flow cytometry. Pts were designated as low risk 1 (LR1; favorable genetics and MRD negative), low risk 2(LR2; pts not in LR1 or HR), or high risk (HR; MRD+ without favorable genetics or any high risk genetics) and received 4 (LR1) versus 5 (LR2) cycles of chemotherapy or 2-3 cycles followed by hematopoietic stem cell transplant (HSCT; HR). Results: A total of 721 eligible pts without FLT3 mutations were randomized to Arm A (n=358) or Arm B (n=363). Age, race, ethnicity and sex were similar for the 2 arms; distribution of risk-defining cytomolecular features were also comparable, with exception of higher rates of inv(16)(p13.1q22.1) (Arm A: 10% vs Arm B: 6%; p=0.03) but not t(16;16)(p13.1;q22) CBFB-MYH11 AML. Pts on Arm A were also more likely to be CNS negative at time of initial assessment (Arm A: 86%; Arm B: 79%; p=0.026). EOI 1 MRD was comparable (Arm A: 23%; Arm B: 23%) and elective withdrawal rates at EOI1 did not differ significantly between the 2 arms (Arm A: 9%; Arm B: 11%). However, Induction 2 treatment toxicities [grade 3 infection (Arm A: 7.4%; Arm B: 27.2%), grade 3 sepsis (Arm A: 3.5%; Arm B: 5.1%)] and median cycle length (Arm A: 35 days; Arm B: 44 days) were higher in Arm B though this did not translate into higher Induction 2 treatment related mortality. Protocol-specified interim analyses using data available on 12/31/23 were performed to monitor efficacy and futility of event-free survival (EFS) for Arm A and Arm B patients without FLT3 mutations. Closure of this randomization was recommended given the futility monitoring rule was crossed. Using a 6/30/24 data cutoff, 2-year EFS from study entry for Arm A was 60.9% (95% CI: 54.3-66.8%) vs. 51.2% (95% CI: 44.7-57.4%) for Arm B (p=0.019) though overall survival (OS) was not significantly different [Arm A: 75.5% (95% CI-69.3-80.5%); Arm B: 74.5% (95% CI - 68.4-79.6%]; p=0.782]. Outcomes for HR patients were comparable for both arms whereas EFS was significantly lower and relapse rates (RR) higher for LR patients on Arm B [2-yr EFS from EOI1: Arm A: 71.9% vs. Arm B 57.8% (p=0.006); 2-year RR Arm A: 16.1% vs. Arm B: 25.4%, p=0.018). EFS from EOI1 in the LR1 patients was particularly impacted (Arm A: 78.3%; Arm B: 62.6%, p=0.029) while LR2 EFS from EOI is Arm A: 67.2 % vs. Arm B: 54.6% (p=0.079); most events reported for either group were relapse. Conclusion The primary randomization of the Phase III study COG AAML1831, a comparison between standard induction therapy and CPX-351, was terminated early because the futility boundary was crossed. The difference in EFS observed was driven mainly by events in LR pts, particularly those that received 4 cycles of chemotherapy (LR1). Further analysis is underway to determine additional factors that may have contributed to the inferior outcomes observed for pts enrolled on Arm B.

Aberrant expression of HOX and MEIS1 family genes, as seen in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutated leukemias leads to arrested differentiation and leukemia development. HOX family genes are essential gatekeepers of physiologic hematopoiesis, and their expression is regulated by the interaction between KMT2A and menin. Menin inhibitors block this interaction, downregulate the abnormal expression of MEIS1 and other transcription factors and thereby release the differentiation block. Menin inhibitors show significant clinical efficacy against KMT2A-rearranged and NPM1-mutated acute leukemias, with promising potential to address unmet needs in various pediatric leukemia subtypes. In this collaborative initiative, pediatric and adult hematologists/oncologists, and stem cell transplant physicians have united their expertise to explore the potential of menin inhibitors in pediatric leukemia treatment internationally. Our efforts aim to provide a comprehensive clinical overview of menin inhibitors, integrating preclinical evidence and insights from ongoing global clinical trials. Additionally, we propose future international, inclusive, and efficient clinical trial designs, integrating pediatric populations in adult trials, to ensure broad access to this promising therapy for all children and adolescents with menin-dependent leukemias.

Background and Significance: Aberrant expression of HOX family and MEIS1 genes, commonly found in KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant acute leukemias, leads to arrested differentiation and leukemia development. HOX family genes are crucial regulators of normal hematopoiesis, and their expression is controlled by the KMT2A-menin interaction. Robust preclinical activity of ziftomenib, a potent and orally bioavailable inhibitor of this interaction, against these high-risk leukemia subtypes has been demonstrated. Initial data from the KOMET-001 phase 1/2 clinical trial (NCT04067336) reported 35% complete remission rates in adults with relapsed/refractory NPM1-m acute myeloid leukemia (AML) treated with ziftomenib monotherapy (Fathi EHA 2023 abstract #LB2713). Given the high-risk nature and prevalence of these leukemias in pediatric patients, we designed a phase 1 clinical trial to assess the safety and determine the recommended phase 2 dose (RP2D) of ziftomenib in combination with chemotherapy for children with relapsed/refractory acute leukemias. Study Design and Methods: ITCC-101/APAL2020K (NCT06376162) is an international multicenter phase 1 clinical trial investigating ziftomenib administered orally once daily with fludarabine 30 mg/m2 and cytarabine 2000 mg/m2 administered intravenously once daily on days 1-5 (FLA regimen) in pediatric patients 0 to 21 years of age with first or greater relapsed/treatment-refractory KMT2A-rearranged, NUP98-rearranged, or NPM1-mutant AML, acute lymphoblastic leukemia (ALL), mixed phenotype acute leukemia (MPAL), or acute undifferentiated leukemia (AUL). In cycle 1, ziftomenib therapy will start on day 8 to investigate the potential to mitigate risk of differentiation syndrome and will be continued for 28-42 days. Subsequent therapy may continue in 28-day cycles with ziftomenib given as monotherapy or in combination with FLA chemotherapy at investigators' discretion depending upon response and safety data. Patients must have performance status ≥50%, adequate end-of-organ function, and sufficient wash-out of prior anti-cancer therapies. Exclusion criteria include isolated CNS relapse and symptomatic CNS3, known bone marrow failure syndromes, juvenile myelomonocytic leukemia or acute promyelocytic leukemia, uncontrolled infection, and concomitant proton pump inhibitor use. The study will employ a rolling six design in its primary objective to explore the safety and pharmacokinetics (PK) of ziftomenib with FLA chemotherapy and to identify the recommended phase 2 dose of ziftomenib in cohorts of patients with AML or with ALL/MPAL/AUL. Given potential for differential ziftomenib metabolism and PK in youngest children, participants <2 years old (stratum B) may enroll following establishment of safe ziftomenib/FLA dosing in at least three children 2 years of age (stratum A). Secondary and exploratory objectives include investigation of ziftomenib pharmacodynamics and preliminary assessment of clinical efficacy within a phase 1 trial, including estimation of remission induction with flow cytometric and molecular measurable residual disease assessments, rates of subsequent allogeneic hematopoietic stem cell transplantation (HSCT), and 2-year event-free and overall survival. The study will also assess the feasibility of single-agent ziftomenib post-transplant ‘maintenance’ therapy for relevant patients and as continuation therapy for those in ziftomenib/FLA-induced remission who do not proceed to HSCT. Up to 32 participants will be enrolled. Conclusion: The overarching goal of the APAL2020K/ITCC-101 phase 1 trial is to develop a safe and effective therapeutic regimen of ziftomenib in combination with multi-agent chemotherapy for children, adolescents, and young adults with high-risk genetic subtypes of acute leukemias targetable by menin inhibition. If successful, this precision medicine approach could significantly improve clinical outcomes for this challenging pediatric patient population with persistent unmet medical need.

Despite improved outcomes in newly diagnosed pediatric AML, relapsed disease remains a therapeutic challenge. Factors contributing to slow progress in improving outcomes include inherent challenges in pediatric clinical trial accrual and the scarcity of novel targeted/immunotherapy agents available for pediatric development. This paradigm is changing, however, as international collaboration grows in parallel with the development of promising targeted agents. In this review, we discuss the therapeutic landscape of relapsed pediatric AML, including conventional chemotherapy, targeted therapies, and the challenges of drug approvals in this patient population. We highlight current efforts to improve communication among academia, industry, and regulatory authorities and discuss the importance of international collaboration to improve access to new therapies. Among the therapeutic options, we highlight the approach to second hematopoietic stem cell transplant (HSCT) and discuss which patients are most likely to benefit from this potentially curative intervention. Importantly, we acknowledge the challenges in providing these high-risk interventions to our patients and their families and the importance of shared communication and decision making when considering early-phase clinical trials and second HSCT.

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children 's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome pro filing and/or karyotyping were performed to identify leukemia -associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identi fied with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10 , 13 (10.2%) with PICALM::MLLT10 , and 10 (7.9%) X::MLLT10 : (2 each of DDX3X and TEC ), with 6 partners ( DDX3Y, CEP164, SCN2B, TREH, NAP1L1 , and XPO1 ) observed in single patients. Patients with MLLT10 (n = 127) demonstrated adverse outcomes, with 5 -year event -free survival (EFS) of 18.6% vs 49% in patients without MLLT10 (n = 1953, P < .001), inferior 5 -year overall survival (OS) of 38.2% vs 65.7% ( P <= .001), and a higher relapse risk of 76% vs 38.6% ( P < .001). Patients with KMT2A::MLLT10 had an EFS from study entry of 19.5% vs 12.7% ( P = .628), and an OS from study entry of 40.4% vs 27.6% ( P = .361) in those with other MLLT10 fusion partners. Patients with PICALM::MLLT10 had an EFS of 9.2% vs 20% in other MLLT10 - without PICALM ( X::MLLT10 ; P = .788). Patients with PICALM::MLLT10 and X::MLLT10 fusions exhibit a DNA hypermethylation signature resembling NUP98::NSD1 fusions, whereas patients with KMT2A::MLLT10 bear aberrations primarily affecting distal regulatory elements. Regardless of the fusion partner, patients with AML harboring MLLT10 fusions exhibit very high -risk features and should be prioritized for alternative therapeutic interventions.

IntroductionAnthracyclines are effective in treating acute myeloid leukemia (AML) but limited by cardiotoxicity. CPX-351, a liposomal daunorubicin and cytarabine, may provide therapeutic benefit with less cardiotoxicity. Acute changes in left ventricular systolic function and cardiac biomarkers were evaluated after a cycle of CPX-351 in children with relapsed AML treated on the phase 1/2 Children's Oncology Group study, AAML1421.MethodsSubjects received 135 units/m2/dose of CPX-351 on days 1, 3, and 5 as cycle 1. Echocardiograms were performed and centrally quantitated at baseline and at the end of cycle 1 (day 29 +/− 1 week). High sensitivity troponin (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were measured at baseline and serially through the end of cycle 1 (days 5, 8, 15, 22 and 29). Differences between baseline and post-CPX-351 echo/biomarker measures were analyzed using Wilcoxon signed rank tests. Linear regression was used to model post-CPX-351 left ventricular ejection fraction (LVEF) with cTnT/NT-proBNP at each time point, controlling for baseline LVEF. Cancer therapy related cardiac dysfunction (CTRCD) was defined as a decline in LVEF of ≥10%–<50%.ResultsTwenty-five of 38 heavily anthracycline pre-treated (median 348 mg/m2 daunorubicin equivalents) subjects enrolled on AAML1421 were included in the cardiac analyses. At baseline, centrally quantitated LVEF was <50% in 8 of 25 subjects (32%) with a median LVEF of 53.8% [48.0, 56.9]. Following CPX-351, LVEF declined significantly (ΔLVEF −3.3% [−7.8, 0]) and 6 of 25 subjects (24%) experienced CTRCD. Amongst all subjects, hs-cTnT was modestly increased at end of cycle 1 compared to baseline [baseline hs-cTnT 7.2 (3, 10.6); ΔcTnT 1.80 (0, 6.1), p = 0.03]. NT-proBNP remained stably elevated without significant change. No significant associations were seen between NT-proBNP or cTnT levels and post-CPX-351 LVEF.DiscussionIn this single arm study of anthracycline pre-treated children exposed to CPX-351, baseline abnormalities in cardiovascular function were prevalent. Following CPX-351, LVEF decreased, cTnT increased, and NT-proBNP did not change. Longer follow-up is needed to determine whether these changes result in clinically meaningful long-term decrements in cardiac function. An ongoing randomized trial of CPX-351 compared to standard anthracyclines in anthracycline naïve patients will provide further insight into the cardiac effects of CPX-351 (ClinicalTrials.gov; NCT04293562).

Background . Myeloid leukemia of Down syndrome (ML-DS) is a distinct form of pediatric AML that is treated with DS-specific reduced intensity chemotherapy with a resulting favorable prognosis (5-year EFS 89.9%). In contrast, non-responders and patients with relapsed ML-DS have a dismal outcome. The aim of Children's Oncology Group (COG) study AAML1531 was introduce risk stratification of chemotherapy intensity for patients with ML-DS based on measurable residual disease by multi-parameter flow cytometry at the end of the first course of induction (EOI-1 MRD), which is used to risk stratify treatment intensity for non-DS pediatric AML patients and was prognostic in the preceding ML-DS trial, AAML0431. Methods . AAML1531 enrolled 280 patients with ML-DS between November 2015 and April 2022. All patients received the same first course of induction therapy (Induction I): daunorubicin, cytarabine, 6-thioguanine (DAT). Those with EOI-1 MRD <0.05% were classified as Standard Risk (SR, Arm A) and treated with reduced-intensity chemotherapy based on the historical control, AAML0431, but with elimination of the second induction course of AAML0431 therapy, which consisted of high-dose cytarabine/asparaginase, to reduce infectious events. Patients with EOI-1 MRD >0.05% were classified as High Risk (HR, Arm B) and had their subsequent treatment intensified to a level consistent with that of pediatric non-DS AML (Induction II: mitoxantrone/high-dose cytarabine; Intensification I: cytarabine/etoposide; Intensification II: high-dose cytarabine/asparaginase) with the aim of reducing the number of relapse events. Cytogenetic results were centrally reviewed and MRD was measured by multidimensional flow cytometry in a reference laboratory (Hematologics, Inc., Seattle, WA). Results.We previously reported outcomes for the SR group (n=114) (Hitzler et al. Blood 2021). We now report outcomes of patients in the ML-DS HR group (n=41). Efficacy: Intensification of chemotherapy for EOI-1 MRD-positive patients did not significantly improve the 2-year EFS compared to that of the AAML0431 EOI-1 MRD-positive cohort (AAML1531: 80.5 + 12.4% vs. AAML0431: 76%, p=0.247). OS also did not differ significantly (AAML1531: 80.5 + 12.4% vs. AAML0431: 76.2 + 18.6%, p=0.819). There were 7 relapses and 1 death as first event. Of the 7 patients with relapse, 6 did not survive (2-year-OS 14.3 + 26.5% after relapse). Adverse events: Febrile neutropenia (FN) occurred in 25.4% of all AAML1531 patients during the common Induction I phase. During intensified post-induction therapy on the HR arm, the course-specific proportions of FN were 31.7% of 41 patients (Induction II), 27.5% of 40 patients (Intensification I) and 26.3% of 38 patients (Intensification II). The corresponding proportions on the reduced-intensity SR arm were significantly lower than on the HR arm: 3.7% of 108 patients (Induction II, p<0.001), 6.9% of 101 patients (Induction III, no corresponding HR course), 6.1% of 98 patients (Intensification I, p=0.001) and 8.6% of 93 patients (Intensification II, p=0.008). Sepsis grade 3 or greater was reported in 9.8% of 41 patients (Induction II, p=0.005) treated on HR arm compared to none treated on the SR (Ind II, n=108), and in 3.3% in the common Induction phase (Induction I). Conclusions. Intensification of chemotherapy for patients with ML-DS with positive EOI-1 MRD neither improved EFS nor OS and resulted in more FN and a greater number of sepsis events. While EOI-1 flow cytometric MRD detected ML-DS patients whose outcomes were poorer than those without MRD (Taub et al. Blood 2017), intensification of chemotherapy was not beneficial to the MRD-positive group. Overall, results of AAML1531 demonstrate that stratification of treatment intensity according to flow cytometric EOI-1 MRD did not did not improve outcomes for patients with ML-DS. Alternative approaches such as mutational profiling of ML-DS blasts should be evaluated with regard to prognostication, risk stratification and identification of targets for novel agents to improve the overall outcome for this disease.

169 Background: Outcomes for children and adolescents/young adults (AYAs) with acute myeloid leukemia (AML) remain suboptimal and are decidedly poor for patients with subtypes defined by high-risk features, including canonical genetic alterations and relapsed/refractory presentation. Due to their rarity, these subtypes are difficult to study within the existing clinical trials paradigm. Data sharing efforts aim to increase our understanding of rare cancer subtypes by pooling data from multiple sources. The INTERnational Acute myeloid leukemia ConsorTium (INTERACT) was established to pool and share data on pediatric and AYA patients with AML. Methods: In 2019, a data dictionary was created through an iterative, consensus-driven process that analyzed pre-existing clinical trials case report forms as the initial basis. By developing this standardized representation for data on patients with AML, data could be harmonized and integrated. A memorandum of understanding was signed in 2021, formally establishing INTERACT. An executive committee was convened to establish scientific priorities, facilitate ongoing data dictionary work, usher agreements with data contributors and review data requests submitted by investigators. In January 2024, the initial set of AML data was released on the Pediatric Cancer Data Commons (PCDC) data portal. Results: As of April 2024, the data dictionary includes 157 standardized data elements that were used to harmonize clinical data on 3,413 patients who participated in seven clinical trials conducted by four pediatric oncology cooperative groups across the United States, Europe, and Asia. Elements in the data dictionary include demographics, initial disease characteristics, genetic alterations, and survival status. Aggregate data can be freely explored using the publicly-available PCDC data portal (portal.pedscommons.org) and investigators seeking line-level access to data may submit a project request to the INTERACT executive committee for consideration. Conclusions: International collaborative data-sharing efforts will advance our understanding of pediatric and AYA AML by reducing barriers that constrain our study of AML to smaller cohorts of data. We hope that an early outcome of data sharing will be to increase our understanding of optimal treatments for patients with relapsed/refractory disease. Future goals of INTERACT include identifying data from additional studies to include, establishing relationships with new data contributors, and establishing working groups to advance the consortium’s scientific and clinical trials goals.