Abstract Background: Sedentary behavior (SB) is prevalent in early adolescents and young adults (eAYAs, 12-21 years) during acute lymphoblastic leukemia (ALL) treatment and contributes to cardiometabolic complications. Intervention during therapy can be challenging, but the maintenance phase may be opportune for SB intervention as toxicity from intensive therapy subsides and monthly visits allow for regular study contact. Purpose: To evaluate the feasibility and acceptability of a clinically integrated, multi-component mobile health (mHealth) SB intervention in eAYAs during ALL maintenance phase; and assess effects on SB and health-related quality of life (HRQoL). Methods: This ongoing 12-week, single-arm pilot trial includes a Fitbit with inactivity-triggered prompts, three in-clinic or virtual coaching sessions, and an app-based peer chat group. The intervention is aligned with one 12-week cycle of maintenance therapy, and in-person procedures coincide with monthly clinic visits. Feasibility is defined as ≥70% retention, N=20 enrolled, and Fitbit wear time ≥10 h/day on ≥70% days for ≥50% of sample. Acceptability is evaluated via exit surveys. At baseline and week 12, SB is assessed using the activPAL micro4 device and IPAQ questionnaire, and HRQoL is assessed via validated surveys. Outcome differences were compared by number of maintenance cycles completed at enrollment (≤ 2 [early] vs > 2 [late]). Results: To date, N=20 are enrolled and N=16 have completed the study (median age=16.2 yrs; 69% male; 69% Hispanic; median BMI=23.3kg/m2; 56% in early maintenance). Retention among completers is 94% (N=15) and 38% (N=6) met Fitbit wear time criteria, the majority of whom were in early maintenance (83% [N = 5] vs 14% [N = 1] in late maintenance). Acceptability is high: 93% (N=14) reported the intervention helped reduce SB and 100% would recommend it to peers. A greater proportion of participants in early vs late maintenance strongly agreed the intervention reduced SB (helpful: 88% vs 29%, p = 0.05; recommend: 88% vs 0%; p = 0.001). Overall, device-measured sedentary and sitting time decreased (−10.4 min/day and −26.3 min/day, respectively) and steps increased (+1,993/day) (all p>0.05); self-reported sitting time also decreased (−154 min/day, p=0.002). Participants in early maintenance showed similar trends to those in later cycles. There were no significant changes in HRQoL. Conclusions: Preliminary findings indicate this mHealth SB intervention is feasible, acceptable, and can be clinically integrated during active maintenance therapy for eAYAs with ALL. Participants in early maintenance showed high adherence and engagement, suggesting the feasibility and benefit of SB intervention during active treatment for ALL and potential scalability to other types of cancer. Citation Format: Brittany J. Ivory, Yueh-Yun Chi, Jeannie M. Shin, Britni R. Belcher, David R. Freyer. Evaluation of a clinically integrated mHealth intervention to reduce sedentary time in adolescents and young adults with ALL during maintenance therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3636.

10013 Background: Dinutuximab is a key component of therapy for HRNBL and is widely used in the RR setting. Standard administration requires inpatient infusions of ~10 hours daily. Emerging pediatric and adult data support shorter infusion durations. Evaluating rapid infusion of dinutuximab (RID) with chemotherapy may reduce pain, facilitate outpatient delivery, and decrease healthcare burden. Methods: This prospective, single-institution pilot study enrolled patients from 11/2022-12/2025 following IRB approval. Eligible patients included those ≥1 year old with RR-NBL, adequate organ function, and prior dinutuximab exposure. Patients received chemoimmunotherapy consisting of dinutuximab 17.5 mg/m²/day for 4 days (over 2-4 hours) combined with irinotecan/temozolomide (ITD) or cyclophosphamide/topotecan (CTD) for up to 6 cycles. Outpatient administration was permitted after cycle 1 if tolerated. The primary feasibility endpoint was successful dinutuximab administration over ≤5 hours with ≤1 patient experiencing unacceptable toxicity (UT) during cycle 1 in a 10-patient cohort. Secondary and exploratory endpoints included infusion duration, serial pain scores assessed during and post-infusion, opioid use in morphine milligram equivalents (MME), toxicity, feasibility of outpatient administration, pharmacokinetics (PK) and human anti-chimeric antibody (HACA). Changes in MME were compared using a one-sample t-test. Results: Eleven patients (median age 14 years, range: 3-24) received ITD (n=6) or CTD (n=5). All patients met the primary feasibility endpoint. Median infusion time was 2 hours (range 2-4) across all cycles. One patient (3 years old), enrolled in the early post-transplant period developed UT (grade 3 ventricular dysfunction). The protocol was amended to exclude patients within 6 months of transplant, require dinutuximab tolerance within 2 months, and extend cycle 1 infusion to 4 hours for patients <12 years of age; this patient was replaced per protocol. Across cycles 1-6, mean pain score was 0.4 (SD 0.46), and mean opioid usage was 0.04mg/kg MME (SD 0.07), reflecting a 78% reduction of opioid use in cycle 1 RID compared to the pre-enrollment standard-infusion cycle (p<0.001). Outpatient RID was administered in seven patients without hospital admission; 1 patient was admitted for chemotherapy-related toxicity, 3 patients remained inpatient (social reasons). RID showed expected PK levels; HACA was noted in 1 patient. Most common grade 3 toxicities (27%): increased ALT and hypokalemia; 1 patient (with UT) had grade 4 toxicity (dyspnea, hypocalcemia). Conclusions: RID was feasible and well tolerated, including in the outpatient setting. Pain control was achieved with standard premedication and significantly reduced opioid requirements compared with standard infusion. These data support planned multi-institutional evaluation of RID. Clinical trial information: NCT05421897 .

10044 Background: Accurate and reproducible response assessment is critical for evaluating efficacy in clinical trials. Central response review is frequently used to reduce inter-site variability but is resource intensive and may delay data availability. Whether centralized review meaningfully alters response endpoints compared with remote source verification of site assessment remains unclear. Methods: We evaluated response assessments from eight NANT phase 1–2 trials conducted between February 2013 and December 2022 in relapsed/refractory high-risk neuroblastoma. Initial investigator-assessed response, remote source-verified response (remote review of radiology/bone marrow [BM] reports), and centrally-reviewed responses (review of radiographic images and BM biopsy slides) were assessed. Each patient’s best overall response (BOR) and individual component responses (BM, MIBG/bone, and soft tissue [ST]) at time of BOR as determined by these three review methods were assessed. Only patients with MIBG-avid disease were included in bone response. Results: Among 244 evaluable patients, concordance between remote source-verified response and central review response exceeded the concordance between initial investigator-assessed response and central review response (BOR: 89% vs 79%, BM: 91% vs 74%, MIBG/bone: 92% vs 83%, ST: 82% vs 74%). Concordance between initial investigator-assessed response and remote source-verified response was 86% for BOR and similar for component response (BM: 83%, MIBG/bone: 91%, ST: 86%). Remote source-verified assessment compared to central review demonstrated higher level of concordance than initial investigator assessment for complete response (CR) (90.0% vs 81.0%), partial response (PR) (85.7% vs 72.7%), minor response (MR) (80.6% vs 71.0%), and stable disease (SD) (92.1% vs 86.7%), indicating improved response classification consistency across all major BOR categories. Overall, the initial investigator-assessed response for CR, PR, and MR agreed with central review 74.0% of the time, while remote source-verified agreed 84.7%. Most discordance reflects relabeling within adjacent categories (e.g., CR vs PR or PR vs MR). A change in response from CR/PR/MR to SD/PD when compared to central review was uncommon: 9.4% for initial investigator-assessed response, and decreased with remote source verification down to 7.1%. A change from CR/PR to MR/SD/PD was more frequent but also improved with remote source verification (from 20% to 11.3%). Conclusions: Remote source verification substantially improves agreement with central review and reduces responder misclassification. These findings demonstrate that structured remote source verification improves response assessment reliability and harmonization with central review, reinforcing its role as an important quality-control mechanism in multicenter trials.

Sedentary behavior (SB) is prevalent among early adolescents and young adults (eAYAs; ages 12–21 years) with acute lymphoblastic leukemia (ALL) and contributes to adverse cardiometabolic and health-related quality-of-life (HRQoL) outcomes. However, SB-focused interventions during active therapy are lacking. This trial aimed to evaluate the feasibility and acceptability of a 10-week, multi-component mobile health (mHealth) intervention among eAYAs receiving maintenance therapy for ALL. This 12-week, single-arm study enrolled 20 eAYAs with ALL receiving maintenance therapy. The 10-week intervention included a wearable activity tracker with inactivity-triggered prompts, individualized coaching sessions, and an app-based peer support group. The intervention was integrated into routine maintenance therapy by aligning the study timeline, visits, and procedures with a single maintenance therapy cycle. Primary endpoints were feasibility (defined by participant retention) and acceptability (via exit surveys and interviews). Secondary endpoints included pre-post intervention changes in device-measured and self-reported SB; exploratory analyses evaluated changes in cardiometabolic biomarkers and HRQoL. Among the 20 participants, there was a 95% retention rate and a high level of intervention acceptability, with 95% reporting the intervention helped reduce SB and 100% recommending it to peers with cancer. Although statistically significant changes in device-measured sedentary time were not detected, there were notable decreases in prolonged sedentary bouts of 1 hour or more (−22.5 min/day, P=.59) and increases in daily steps (+49.5 steps/day, P=.39). Self-reported sitting time significantly decreased (−154 min/day, P=.006). No statistically significant changes were detected in cardiometabolic biomarkers; however, significant improvements were observed in HRQoL domains of physical functioning (+3.1, P=.04) and sleep/rest fatigue (+8.3, P=.05). This novel SB intervention met predetermined feasibility and acceptability criteria and demonstrated potential to reduce SB among eAYAs receiving ALL maintenance therapy, supporting further evaluation in larger trials. ClinicalTrials.gov: NCT06182163.

Introduction HCT is an established curative treatment for CAYA with high-risk/relapsed B-ALL. Use of TBI, vs non-TBI conditioning, has been associated with better LFS but also with significant late effects. We hypothesized that CAYA with pre-HCT negative NGS-MRD receiving non-TBI conditioning could achieve outcomes comparable to patients receiving TBI. Objectives/Methods PTCTC conducted a phase II prospective trial at 45 centers in North America (NCT03509961; 2018-25) to evaluate outcomes of myeloablative non-TBI conditioning for allogeneic HCT in B-ALL patients at lower risk for relapse defined by absence of pre-HCT NGS-MRD (Clonoseq™) of B-cell receptor rearrangements. Prior blinatumomab (BLIN), inotuzumab (INO), or CAR-T therapies were allowed. All graft sources were permitted. GVHD prophylaxis was according to graft source and institutional standards. Results 51 patients in CR1 (49%) or CR2 (51%) received HCT on the study treatment arm. Median age at diagnosis and HCT were 11.9 and 13.5 years, respectively. Pre-HCT, 65%, 8%, and 33% of patients received BLIN, INO, or CAR-T, respectively. 86% of patients received the preferred study non-TBI regimen (busulfan, fludarabine, thiotepa). Donors included matched sibs 37%, mismatched related/haplo 35%, matched unrelated 20%, or unrelated cord blood 8%. Donor graft sources were 71% bone marrow and 21% peripheral blood stem cells.At a median follow-up of 2.3 (range: 0.2-6.0) years, the 2-year OS and EFS were 82.1% and 76.3%, respectively. Age at HCT (≤10 vs >10yrs) and prior BLIN were associated with decreased EFS (HR= 1 vs 0.2, p=0.0080) and (HR=3.7 vs 1, p=0.047), respectively. Acute GVHD occurred in 20 patients (39%, with 15 (75%) grade 1-2 and 5 (25%) grade 3-4). Chronic GVHD occurred in 13 patients (25%; 11 (85%) requiring systemic immunosuppressive treatment).When compared to the observational cohort of the study, age (at diagnosis and HCT) was also associated with EFS and OS, and NGS-MRD positivity was significantly associated with poor outcomes for all endpoints. No differences were noted in relapse, RFS, or OS in patients receiving TBI vs. non-TBI regimens (see Figures). Conclusions Younger age at diagnosis and HCT and prior BLIN therapy were associated with inferior outcomes. NGS-MRD positivity was significantly associated with poor outcomes for all endpoints.OS in our treatment cohort is comparable to published CIBMTR results in B-ALL where patients predominantly received TBI-based conditioning. Our results show that pre-HCT NGS-MRD can be used to allow the choice of myeloablative non-TBI conditioning for CAYA undergoing allogeneic HCT with outcomes similar to TBI-based approaches. Additional analyses to be reported at the meeting include assessment of clinical factors that impact post-HCT outcomes (e.g. GVHD, cytogenetics, and post-HCT BM and PB NGS-MRD) in both our treatment (n=51) and observational (n=151) cohorts.

Background:Atypical teratoid rhabdoid tumor (ATRT) is a rare pediatric central nervous system tumor with little data on the efficacy of upfront treatment strategies. This study reports prognostic factors and survival of children with newly diagnosed ATRT at high-volume centers treated as per the Children's Oncology Group trial ACNS0333. Methods:Data were collected retrospectively from 13 institutions. Included subjects were children with newly diagnosed ATRT, treated as per ACNS0333, a single-arm phase III trial of intensive chemotherapy and radiation therapy (RT). Data were analyzed to assess the prognostication of clinical variables and estimates of event-free survival (EFS) and overall survival (OS). Results:Eighty subjects were included, with a median age at diagnosis of 18 months, 70% had localized disease, and 53% underwent complete tumor resection at the time of diagnosis. Fifty patients (63%) completed all therapy phases, while 12 patients (15%) experienced progression during treatment. Fifty-three patients (66%) received post-induction consolidation with high-dose chemotherapy and stem cell rescue (HDC/SCR), and 55 (69%) received RT. The 4-year EFS and OS for the entire cohort were 49% and 53%, respectively. Patients completing all therapy phases had superior outcomes (4-year EFS: 63%; OS: 67%). Absence of disease post-induction correlated with improved outcomes (4-year EFS: 64%; OS: 70%), and patients with primary spinal cord tumors had poor outcomes despite intensive therapy. Conclusions:Children with ATRT treated as per ACNS0333 with multi-modal therapy, including HDC/SCR and RT, have improved survival compared to those treated without RT and is higher than previously reported on study.

Ixazomib (MLN 9708) is an oral proteasome inhibitor, preclinically more potent than bortezomib, that is currently US Food and Drug Administration-approved for the treatment of multiple myeloma. We conducted a phase 1/2 study to estimate the maximum tolerated dose, recommended phase 2 dose (RP2D), and early efficacy of ixazomib when combined with chemotherapy in pediatric patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Patients aged ≤21 years with R/R ALL/LL (including Down syndrome) were eligible. Ixazomib was combined with up to 3 different 28-day blocks of well-established, relapsed ALL chemotherapy. Ixazomib was tested at 2 dose levels (DL; DL1: 1.6 mg/m2 per dose; DL2: 2 mg/m2 per dose) using a 3+3 design. Dose-limiting toxicities (DLTs) during block 1 were used to make DL escalation decisions. Twenty-four patients enrolled, all with ALL (10 in phase 1, 14 in phase 2). The most common categories of grade ≥3 attributable adverse events were gastrointestinal disorders (n = 12) and febrile neutropenia (n = 9). Two patients experienced a DLT (both treated at DL2 in phase 2), however, DL2 was determined to be the RP2D. The complete response rate for evaluable patients was 67%; 64% (9/14) of whom were also flow minimal residual disease negative. The half-life was consistent across DLs and was comparable with that previously reported in adults. Oral capsule and liquid formulations were determined to be palatable. Ixazomib can be combined with chemotherapy with an acceptable safety profile and an encouraging early efficacy signal in pediatric R/R ALL. This trial was registered at www.clinicaltrials.gov as NCT03817320.

10033 Background: Patients with relapsed/refractory (RR) high-risk neuroblastoma (HR-NB) have poor survival. Tumor response may be an early predictive endpoint, though response may not reflect long term survival. We evaluated the association between NANT Response Criteria (NANTRC) v1.2/2.0 with event-free survival (EFS) and overall survival (OS) in patients with RR-NB treated on contemporary NANT Phase 1/2 trials. Methods: Patients enrolled on 8 NANT trials from 2013 to 2022 were included. For patients enrolled on more than one trial, the first trial data was included. NANTRC were utilized to grade individual response components (soft tissue [ST], bone/MIBG, bone marrow [BM]) and overall response (complete [CR], partial [PR], minor [MR] response, stable disease [SD], or progressive disease [PD]). Patient/tumor characteristics, prior therapy and relapse, and disease at enrollment were analyzed for association with best overall response (BOR). Component and BOR were analyzed for association with EFS and OS from trial treatment initiation. EFS and OS were compared with the log-rank test and estimated by the Kaplan-Meier methods. Results: Among 244 patients, 3-year OS was 52% (95% confidence interval [CI] 46-58%), and EFS was 22% (95% CI 14-32%). OS differed significantly by best overall response (p<0.001), driven primarily by inferior outcomes of patients with PD. The 3-year OS was 16% (95% CI 9-29%) for patients with PD. Patients achieving objective response (CR/PR/MR) had an OS of 63% (95% CI 55-74%) and EFS 25% (95% CI 15-43%), while those achieving disease control (CR/PR/MR/SD) had very similar OS of 63% (95% CI 57-71%) and EFS 29% (95% CI 20-43%). Among patients with response of CR, PR, MR, or SD, OS and EFS were not significantly different. For individual components, a similar impact on OS was seen for PD vs no PD (all p<0.001), with BOR of PD in MIBG/bone and ST having OS <10%. Patients lacking either BM or bone/MIBG involvement (but not ST) at baseline and remained not involved in those components demonstrated superior OS (both p<0.001). Patients with BOR of PD had shorter time from diagnosis to first progression (median of 1.4 vs 1.8 years, p=0.035), and higher incidence of MYCN -amplified disease (46% vs. 14%, p<0.001) and prior history of progression (95% vs 73%, p<0.001). Conclusions: In RR-HRNB treated on contemporary NANT trials, BOR of PD is associated with inferior OS. Patients achieving disease control (CR/PR/MR/SD) experienced comparable outcomes regardless of response achieved. These findings support disease-control as a clinically meaningful efficacy endpoint for early-phase neuroblastoma trials. 3-year survival by component response. Component Response N OS % (95% CI) EFS* % (95% CI) BM Non-PD 100 47 (38, 58) 17 (7, 38) PD 18 29 (14, 61) - Bone/MIBG Non-PD 180 59 (52, 66) 22 (13, 35) PD 30 7 (2, 26) - ST Non-PD 142 61 (53, 70) 28 (18, 44) PD 35 9 (3, 25) - *EFS censored at time of new therapy.

Background: Obesity adversely impacts disease response and survival for children, adolescents, and adults with acute lymphoblastic leukemia (ALL). We previously demonstrated that patients undergoing induction chemotherapy experience profound changes in body composition within these first 28 days, gaining significant fat mass and losing muscle mass (“sarcopenic obesity”). Changes in weight, and related anthropometrics such as body mass index (BMI), thus may not accurately reflect changes in body composition. This discrepancy has important implications for research and clinical assessments of sarcopenia, cachexia, malnutrition, and metabolic health during therapy. Dual-energy X-ray absorptiometry (DXA) is the ‘gold standard’ imaging modality for body composition assessment. However, serial imaging requires repeated radiation exposure and is logistically challenging to integrate into clinical practice. Therefore, we investigated whether anthropomorphic measures could be used as accurate surrogates for DXA to facilitate conduct of future research trials and integration of body composition assessment into clinical practice. Patients & Methods: The T2020-003 IDEAL2 randomized phase 2 trial (NCT05082519) conducted via the Therapeutic Advances in Childhood Leukemia/Lymphoma consortium is assessing a diet, exercise, and sedentary behavior intervention during induction chemotherapy in youths 7-25 years old to reduce gain in fat mass (FM) and obesity-induced chemoresistance versus standard of care. DXA scans are performed within the first 4 days of therapy when possible and again at end of induction (EOI). Patients are concurrently measured for height, weight, and waist circumference. A planned analysis tested for correlations between FM, body fat percentage (BF%), and lean mass (LM) by DXA with available anthropometric calculations validated in general populations, including: BMI, BMI z-score, relative fat mass (RFM), body roundness index (BRI), a body shape index (ABSI), waist to height ratio (WHtR), and the conicity index (C-Index). Pearson correlation coefficients and associated 95% confidence intervals (CI) were calculated to assess linear correlation. Measurements where the lower bound of the 95% CI was ≥0.9, 0.70-0.89, or 0.4-0.69 were considered to be very strongly (“directly”), strongly, or moderately correlated, respectively. Results: As of July 1, 2025, 45 of 82 (55%) enrolled subjects had DXA scans performed at diagnosis, and 30 (37%) had DXA scans performed at both diagnosis and EOI. Amongst the 45 patients with DXA scans at diagnosis, median age was 15.8 years (range 8.3-21.1), majority were male (80%), and most were of Hispanic or Latino ethnicity by self report (80%). At diagnosis, FM was most directly correlated with BMI (r=0.98 [95% CI 0.963-0.989]) and strongly correlated with BMI Z-score (r=0.85 [0.737-0.916]), BRI (r=0.92 [0.857-0.956]), and WHtR (r=0.91 [0.837-0.949]). BF% was strongly correlated with BMI Z-score, RFM, BRI, and WHtR, but not with BMI. In contrast, no measures strongly or directly correlated with change in FM or BF% during induction. Change in FM was only moderately correlated with BMI (r=0.70 [0.453-0.846]), RFM (r=0.74 [0.491-0.875]), BRI (r=0.74 [0.497-0.877]), WHtR (r=0.76 [0.523, 0.885]). No measure was directly or strongly correlated with LM at diagnosis or change in LM during induction. Conclusion: DXA scans are challenging to obtain urgently at the start of ALL therapy, and <50% of our IDEAL2 study cohort was able to be scanned at both diagnosis and EOI. Multiple anthropometric calculations show excellent correlation to FM and BF% as surrogates of adiposity at diagnosis, but none were sufficiently correlated to estimate change in body composition by EOI. Similarly, anthropometric measurements were not adequate for assessment of LM at diagnosis or change over induction. Future research trials and clinical assessments may rely on anthropometrics as a measure of body fat at diagnosis, but clinical or research assessments focused on treatment-induced changes in body composition, or on assessments of lean mass at any timepoint, will continue to require direct radiographic assessments.

Supplemental Figure 2 shows overall 5-year survival curves by subsequent malignant neoplasm (SMN) type from SMN diagnosis among those with primary adolescent and young adult (AYA) (a) female breast cancer, (b) cervical/uterine cancer, (c) Hodgkin lymphoma who were diagnosed between 1998 and 2020 (California Cancer Registry Data). Shaded areas represent 95% confidence intervals.

Abstract Introduction: Outcomes for children with de novo hematologic malignancies have improved significantly over the past 50 years. However, overall survival (OS) following relapsed or refractory (r/r) disease remains poor, with 5-year OS ranging from 20% to 66%. Clinical trials are crucial for developing novel therapeutic strategies to improve outcomes for this subset of patients. Methods: The Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium develops and conducts clinical trials for pediatric hematologic malignancies. TACL maintains an electronic Screening Log to capture data on the frequency of clinical trial enrollment among patients with r/r hematologic malignancies. Each TACL member site logs all occurrences of r/r disease requiring a therapeutic attempt in an electronic database on a monthly basis. We analyzed the TACL Screening Log to assess enrollment rates in therapeutic trials for r/r events from January 1, 2021, to December 31, 2023, to identify barriers to trial participation. We also queried ClinicalTrials.gov to compile a list of clinical trials enrolling pediatric patients with r/r hematologic malignancies for at least 6 months during this period to correlate the number of available trials with observed enrollment trends. Results: A total of 895 unique patients from 33 pediatric academic institutions across the United States and Australia were screened for enrollment on therapeutic trials with 1115 total screens. The rate of enrollment on a clinical trial at time of r/r disease was 15% (132/895). Similar enrollment rates were observed for children (13%) and for adolescents and young adults (AYA) aged ≥15 years (11%). No differences in enrollment rates were noted based on sex, race or ethnicity. Patients with Down Syndrome (DS) demonstrated a much lower rate of trial enrollment (3% vs. 15% for those without DS). Of the 1115 screening entries, enrollment was lower among patients with r/r Ph+ ALL (6%, 2/35), Hodgkin lymphoma (HL) (0%, 0/33) or non-Hodgkin lymphomas (NHL) (0%, 0/52) in comparison with B-lymphoblastic leukemia (B-ALL; 13%, 79/605), T-lymphoblastic leukemia (T-ALL; 11%, 7/65) and acute myeloid leukemia (AML;16%, 49/315). Among patients with leukemia, those with isolated extramedullary disease also had a particularly low rate of enrollment (2%, 2/112) compared to those with bone marrow involvement (14%, 116/806). Enrollment increased with the number of prior treatment attempts but decreased with increasing number of prior bone marrow transplants. Reported barriers to enrollment included unavailability of suitable trial (47%), preference for non-trial therapies (25%), restrictive eligibility criteria (23%), and social or geographic factors (2%). Our search of ClinicalTrials.gov identified 123 relevant clinical trials for r/r pediatric hematologic malignancies: 56 trials for r/r B-ALL/NHL, 32 for r/r T-ALL/NHL, 41 for r/r AML, 42 for r/r NHL and 19 for r/r HL. Of these, 39 (32%) were single institution trials while 36 (29%) were open at more than 20 institutions. 10 (24%) of the NHL trials were Molecular Analysis for Therapy Choice (MATCH) trials testing small molecule inhibitors for tumors (including lymphomas) with rare, genetic lesions. Various immunotherapies were investigated in 66 (54%) of the trials. 17 trials (14%) were primarily designed for adults, with lower age limit of 12 years.Conclusions: We found that 15% of children with r/r hematologic malignancies enrolled on a trial, consistent with previous studies but significantly lower than the estimated 42% enrollment rate for those with de novo disease. The historical disparity in trial participation between younger children and the AYA population appears to have narrowed within large pediatric medical centers, likely due to increased engagement efforts. Certain patient groups with r/r hematologic malignancies including those with DS, Ph+ ALL and isolated extramedullary involvement of leukemia show low rates of clinical trial enrollment due to lack of relevant trial options. No patients with r/r lymphoma enrolled on study despite a significant number of available trials, suggesting problems with access or restrictive eligibility criteria for this particular group. Identification of these enrollment barriers and gaps will facilitate efforts to improve clinical trial availability and participation, ultimately leading to new therapeutic developments and improved outcomes for this patient population with unmet need.

Philadelphia-like (Ph-like) B-cell Acute Lymphoblastic Leukemia (B-ALL) is a subset of high-risk (HR) ALL, constituting 5-15% of pediatric and adult non-Down Syndrome (DS) B-ALL, and is associated with poor survival. Approximately half of Ph-like B-ALL cases exhibit cytokine receptor-like factor 2 overexpression (CRLF2+). Through a series of consecutive trials studying body composition in ALL, we found a strong association between CRLF2+ B-ALL and obesity. CRLF2+ B-ALL was more prevalent in those presenting with obesity, and the odds of being CRLF2+ increased by 13% for every kilogram of fat mass present at diagnosis (Mittelman et al, Blood, 2021). We also previously reported for HR B-ALL that obesity is associated with chemotherapy resistance (as evidenced by minimal residual disease [MRD]) and a poorer prognosis, with a 30-50% increased risk for poorer event free survival (EFS) and overall survival (OS). However, the impact of obesity on outcomes specifically in patients with Ph-like B-ALL is unknown. Given the poor prognosis of Ph-like B-ALL, the association of a common subtype of Ph-like B-ALL with obesity, and the sustained high prevalence of childhood obesity, this is a critical knowledge gap addressed by this study. We conducted a retrospective study of patients treated for non-DS Ph-like B-ALL from 2006 – 2024, with earlier cases diagnosed retroactively. Data included diagnosis (Ph-like subtype), age, sex, self-reported ethnicity, body mass index (BMI), treatment protocol, and clinical outcomes (MRD, EFS, OS). An event was defined as refractory disease, relapse, or death for EFS, and death for OS. Obesity was defined as BMI ≥95th percentile for age and sex for patients aged 19 years and younger, and a BMI of ≥30 kg/m2 for patients over 20 years old. End of induction (EOI) MRD was evaluated in those with available MRD as a binary endpoint (<0.01% versus ≥0.01%). Survival was estimated using the Kaplan-Meier method, and 95% confidence intervals (CIs) were calculated using Greenwood's method. Cox regression was used to associate EFS and OS with potentially prognostic variables (Ph-like subtype, central nervous system (CNS) 1 or 2 versus CNS 3). A chi-square test was used to compare MRD persistence in patients with and without obesity. Survival time was measured from the time of diagnosis until time of event or last follow-up. All statistical analyses were two-sided, with a Type I error rate of 0.05 used to determine significance. This study was exempted per the Institutional Review Board (IRB). Of 80 patients with Ph-like ALL, 66 patients (83%) were included (excluded for DS-ALL [n=8], insufficient treatment/outcome data [n=6]). Of the 66, 47 (71%) were male, 54 (82%) were of Hispanic/Latinx ethnicity, and 40 (61%) had obesity. Ages ranged from 2 to 20 years (median: 16.2 years). The majority of cases were CRLF2+ (either IgH:CRLF2 or P2RY8:CRLF2 fusions, n=57/66, 87%), with the remainder harboring ABL-class fusions, PDGFRB fusions, CSF1R-fusions, or JAK2 mutations. Twelve (18%) patients received a targeted therapy (tyrosine kinase inhibitor or JAK inhibitor). There was no significant difference in MRD persistence in those with versus without obesity (65% vs 63%, p=0.88). On the multivariable EFS analysis, we found evidence for increased risk of an event among patients presenting with versus without obesity (hazard ratio [HR] 2.03; 95% CI 0.942-4.395, p=0.071). In patients who achieved EOI MRD negativity, those with obesity had a significantly lower EFS (p=0.014) than those without obesity (3-year EFS: 59% [95% CI: 31.3-87.3%] versus 100%); however, patients with persistent EOI MRD had poorer EFS regardless of obesity (39% vs 34%, p=0.81). There was no statistically significant difference for OS in patients with versus without obesity overall and regardless of MRD status. Obesity negatively impacted EFS in pediatric patients with Ph-like ALL, predominantly in those with EOI MRD negativity, leading to poor outcomes in this group with expected favorable prognoses. Obesity did not impact OS, indicating that salvage therapies remained successful in achieving sustained remissions for those with obesity failed by frontline treatment, though increased morbidity associated with relapse therapy must be considered. These findings add to the growing literature implicating obesity as a poor prognostic factor in higher risk acute leukemias. Further studies will explore obesity's impact on molecular drivers of Ph-like ALL.

BACKGROUND:Cisplatin is used to treat solid tumors but causes irreversible hearing loss. Pedmark, a formulation of sodium thiosulfate (STS), is approved to prevent cisplatin-induced hearing loss (CIHL). Prior to approval, non-Pedmark formulations of STS pentahydrate (STS-P) were prescribed off-label for otoprotection and continue to be used in the absence of data. PROCEDURE:This multicenter retrospective study examined tolerability, toxicity, and hearing outcomes of STS-P used off-label for otoprotection. Exploratory analyses compared toxicity and hearing data in patients receiving STS-P versus the pre-Pedmark investigational formulation (STS-inv) tested in trials. RESULTS:Fifty-nine patients received STS-P (16 or 20 g/m2). Infusion-related reactions (IRR) occurred in 14% (8/59), more commonly in patients receiving 20 g/m2. No severe adverse events occurred. One patient (2%) discontinued STS-P for IRR. The prevalence of CIHL (International Society of Paediatric Oncology [SIOP] Grade ≥2) at the end of therapy and at the most recent hearing assessment was 30% at both timepoints (12/40 and 8/27, respectively). In exploratory analyses comparing STS-P with STS-inv (n = 14), there was no difference in tolerance or toxicity. In multivariable analysis, a lower risk for CIHL at the end of therapy was found for age ≥5 years, higher dosing of 20 g/m2, and received STS-inv (odds ratio 0.02, 95% confidence interval: 0.0003-0.691, p < 0.01). No difference was present at the most recent exam. CONCLUSIONS:STS-P off-label for otoprotection following cisplatin was tolerable in a real-world setting across age groups and cancer types. Formal testing in larger studies of different STS formulations is needed to explore possible differences in toxicity and CIHL prevention.

Introduction: HCT is an established curative treatment for children, adolescents, and young adults (CAYA) with high-risk/relapsed B-ALL. Inclusion of TBI in HCT conditioning has been shown to be superior to non-TBI approaches for B-ALL, but is associated with significant late effects. Based upon retrospective data showing low rates of relapse, we hypothesized that patients with negative pre-HCT MRD by next-generation-sequencing of IgH B-cell receptor rearrangements (NGS-MRD) could achieve 2-year EFS exceeding 75% with a non-TBI regimen, an outcome comparable to those receiving TBI-based regimens. Methods: The Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) conducted a phase II prospective trial at 45 Centers in North America (ONC1701 EndRAD: NCT03509961) between 2018 and 2025 to evaluate outcomes of myeloablative non-TBI conditioning regimens for allogeneic HCT in B-ALL patients at lower risk for relapse defined by absence of NGS-MRD (Clonoseq) of B-cell receptor rearrangements (BCR) just prior to HCT. Eligibility criteria included age >/= 1 year to <31 years, first or second complete remission status (CR1/CR2), and no isolated or combined CNS disease at relapse. Prior blinatumomab, inotuzumab ozogamicin, or CAR-T treatments were allowed. All graft sources were permitted. Mismatched related/haploidentical grafts received post-transplant cyclophosphamide or TCRαβ/CD19 depletion according to institutional preference. All patients received myeloablative non-TBI conditioning. Graft-versus-host disease (GVHD) prophylaxis was according to graft source and institutional standards. Results: Fifty-one patients (51% males) in CR1 (49%) or CR2 (51%) status received HCT. Median age (range) at initial diagnosis and HCT were 11.9 (1.2-28.1) and 13.5 (2.3-32.5) years, respectively. Of patients enrolled, 33% were White/Non-Hispanic, 37% Hispanic, 12% Black or African American, and 18% other. Prior to HCT, 28 patients (55%) received blinatumomab, 1 (2%) received inotuzumab, while 11 (21%) received CAR-T, 7 (14%) received 2 prior immunotherapies, and 4 (8%) had no prior immunotherapy.Forty-four patients (86%) received the preferred study non-TBI conditioning regimen (busulfan, fludarabine, thiotepa); 2 comparable allowed regimens were received: fludarabine, melphalan, and thiotepa by 3 patients (6%) and melphalan, fludarabine, clofarabine, and thiotepa by 4 patients (8%). Donors included HLA matched siblings (41%), mismatched related/haploidentical (33%), matched unrelated (18%), or unrelated cord blood (8%). Related and unrelated donor graft sources were 71% bone marrow and 21% peripheral blood stem cells. Transplant-related mortality in the first 100 days post-HCT was low at 2%. At a median follow up of 2.3 (range: 0.2-6.0) years, the 2-year OS and EFS (alive/relapse-free) were 82% (95% CI: 67.1%, 90.6%) and 76.3% (95% CI: 61.1%, 86.1%), respectively. Five patients (10%) who were pre-HCT NGS-MRD negative by BCR had detectable T-cell receptor sequences (BCR-/TCR+); all 5 are alive and relapse-free. Non-relapse mortality (NRM) was 12% (6 patients, 0.1-2.9 years from HCT to NRM) and occurred predominantly in older children (4 (67%) >/=14 yrs old). Relapses occurred in 6 children, with 4 (67%) undergoing HCT in CR2. Four of the six relapses occurred after matched sibling donor HCT. Acute GVHD occurred in 20 patients (39%, with 15 (75%) grade 1-2 and 5 (25%) grade 3-4). Chronic GVHD occurred in 13 patients (25%) (11 (85%) requiring systemic immunosuppressive treatment). Conclusions: The primary endpoint of our study was met with the 2-year EFS exceeding 75% following non-TBI conditioning and allogeneic HCT in pre-HCT NGS-MRD negative B-ALL. OS in our cohort is comparable to published Center for International Blood & Marrow Transplant Research (CIBMTR) results in B-ALL where patients receive TBI-based conditioning. Our results show that pre-HCT NGS-MRD can be used to allow the choice of myeloablative non-TBI preparative regimens for CAYA undergoing allogeneic HCT that may result in decreased late effects. Additional analyses to be reported at the meeting will more fully investigate factors that impact post-HCT outcomes, including baseline cytogenetics/genomics and post-HCT bone marrow and peripheral blood NGS-MRD, along with planned comparisons to an observational cohort (n=146) enrolled on the trial including infants and older patients treated non-TBI approaches and older children treated with TBI-based regimens.

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)

Supplementary Fig. 5 Progression-free survival in NAC treated and observation patients

Supplemental Table 2 shows treatments received by subsequent malignant neoplasm status.

Supplementary Fig. 2 Cumulative incidence of SIOP Grade ≥2 hearing loss

BACKGROUND:Survivors of adolescent and young adult (AYA, ages 15-39 years at diagnosis) cancer are at increased risk for subsequent malignant neoplasms (SMN), of which lung cancer is the most lethal. Factors contributing to lung SMN development and outcomes are not well characterized. METHODS:Survivors of AYA cancer diagnosed between 1998 and 2020 were identified in the California Cancer Registry (n = 251,632). Pearson's χ2 and Fisher's exact tests were used to determine associations between sociodemographic and cancer characteristics and SMN status. Multivariable Cox proportional hazard regression, adjusting for age, time from primary diagnosis, race/ethnicity, insurance, primary cancer site, stage, and treatment, evaluated associations between these characteristics and the incidence and mortality of lung cancer as first SMN. RESULTS:A total of 675 (0.7%) survivors were diagnosed with lung SMN, of whom 487 (72.1%) died. The median time from primary diagnosis to lung SMN was 13.0 years (IQR 4.0-20.0 years). Nearly half (46.5%) of survivors with lung SMN had metastatic disease. Non-Hispanic Black survivors were more likely than non-Hispanic White survivors to develop lung SMN [adjusted HR (aHR) = 1.47; 95% confidence interval (95% CI), 1.13-1.91] but were not more likely to die from lung SMN (aHR = 0.84; 95% CI, 0.56-1.27). Primary cancer treatment with both chemotherapy and radiation was associated with a greater likelihood of lung SMN (aHR = 1.41; 95% CI, 1.11-1.80) compared with receiving neither. CONCLUSIONS:Lung SMN has a long latency and high mortality among survivors of AYA cancer. IMPACT:More research is needed on lung cancer prevention, education, and early detection, particularly among survivors at higher risk.

Supplemental Table 3 shows vital status and cause of death by subsequent malignant neoplasm status.