Treatment approaches to childhood T-cell lymphoblastic lymphoma (T-LL) are based on those used for T-cell acute lymphoblastic leukemia (T-ALL), but reports of outcomes with contemporary regimens are limited, as patients with LL are often excluded from ALL clinical trials. In this study, we retrospectively analyzed the characteristics and outcome of a cohort of 23 pediatric patients with T-LL treated between 2006 and 2020 according to Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols. Five-year event-free survival, overall survival, and disease-free survival rates were 78.3% (95% CI: 55.4%-90.3%), 87.0% (95% CI: 64.8%-95.6%), and 90% (95% CI: 65.6%-97.4%), respectively. Morphological marrow disease (defined as 5%-24% blasts) at diagnosis was the only feature associated with adverse prognosis. Treatment based on DFCI ALL protocols is an effective strategy for childhood LL and should be considered at the time of treatment selection.

INTRODUCTION:To provide appropriate interventions for young people with advanced cancer, self-reported questionnaires assessing quality of life (QoL) are crucial. This study aims to develop and test electronic versions of two short self-reported questionnaires (for children aged 8-12 and adolescents aged 13-18). METHODS:We adapted the paper-and-pencil versions of Advance QoL into electronic versions using the REDCap platform. We tested the electronic versions and evaluated their social validity (acceptability, relevance, and satisfaction) through semi-structured cognitive interviews with 20 children (median age 9) and adolescents (median age 15) with cancer. Recruitment and data collection involved two refinement phases, using cognitive interviews to guide adaptations. To analyse responses from the social validity questionnaire, we used the content validity index (CVI), median and range. RESULTS:From the interviews, we identified 22 codes, organised into five themes: (1) content-related elements, such as lack of information regarding a radar chart displayed in the questionnaire; (2) format-related elements, including the unnoticed 24-h time window; (3) technology-related elements, such as the correct date format; (4) positive features (e.g., length, comprehensiveness, user-friendliness); and (5) children-specific elements such as distractibility and attention spans. These insights guided modifications to optimise Advance QoL's electronic use. CVI indices showed high social validity among the participants (children: two out of three CVI indices were ≥ 0.78; adolescents: all three CVI indices were ≥ 0.78). CONCLUSION:Feedback was largely positive. We addressed minor issues using REDCap's features. In its present state, Advance QoL is comprehensible, usable, and considered pertinent by patients. It offers a unique opportunity to collect the self-reported data of a very ill population, thereby providing targets for care.

Hypersensitivity reactions with pegylated Escherichia coli-derived asparaginase formulations are frequent and can complicate delivery of intended therapy for patients with acute lymphoblastic leukemia (ALL). On DFCI 16-001, which enrolled patients aged 1-21 years with newly diagnosed ALL, we piloted pegaspargase rechallenge after Grade 2 hypersensitivity reaction, including premedication and serum asparaginase activity (SAA) assessment. Among those who underwent rechallenge, the rechallenge dose was successfully administered (without reaction and with adequate SAA) in 41.3% of patients. This approach reduces the number of patients requiring switch to alternative asparaginase formulations, which have had limited availability and require frequent dosing.

BACKGROUND:Children treated for acute lymphoblastic leukemia (ALL) are at risk of neurocognitive deficits in attention-concentration, working memory, executive function, and psychomotor speed. OBJECTIVES:This study evaluated longitudinal trajectories and medical/demographic associations with neurocognitive outcomes during treatment of newly diagnosed ALL. METHODS:Patients ages 3-21 treated on DFCI 16-001 (NCT03020030) across eight North American sites (2017-2022) were evaluated using Cogstate across four timepoints from diagnosis through maintenance phase. Linear mixed models estimated trajectories and interactions with clinical factors over time, incorporating random effects for patients and sites. RESULTS:Among 298 patients (median age 7.9 years, 53% male), performance changed significantly over time in varying directions for executive functioning, attention, visual learning, and working memory-accuracy (all p < 0.001). There was a significant interaction overall between age and time for psychomotor function (interaction p = 0.01) and working memory-accuracy (interaction p < 0.001). Older age was associated with worse performance on working memory-speed (β = -0.04) and attention (β = -0.05). Female sex was associated with worse performance on psychomotor function (β = -0.27) and working memory-accuracy (β = -0.50), but better on visual learning (β = 0.47) and working memory-speed (β = 0.30). A greater-than-expected proportion of participants performed below -1.5 SD on tests of attention, executive functioning, and psychomotor functioning at multiple timepoints. CONCLUSIONS:While most patients demonstrated normal neurocognitive functioning, including variable trajectories, a subgroup performed poorly on attention, executive functioning, and psychomotor functioning. Risk factors include older age at diagnosis and female sex, which may provide insight into groups warranting early intervention.

INTRODUCTION:The clinical course, outcome, risk of malignancy, and causes of mortality in the pediatric dyskeratosis congenita (DC) population have been described in a few studies. METHODS:Data of patients with DC enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) between January 2001 and December 2021 were analyzed. RESULTS:Forty-three patients with DC were diagnosed at a median age of 9 years. The underlying mutated genes included DKC1, PARN, RTEL1, TERC, TERT , and TINF2 . Nine patients developed severe bone marrow failure (BMF). Presence of severe BMF was associated with a higher risk of mortality (HR: 7.5). Patients with DC who were diagnosed at a younger age had lower overall survival. No pediatric patients developed malignancy. Eleven patients received a hematopoietic stem cell transplant. Ten patients died due to organ dysfunction, mostly related to DC. All 5 TINF2 patients died, but no patients died in the TERT, TERC , or RTEL1 groups. CONCLUSIONS:Pediatric patients with DC have a high mortality rate related to BMF and organ dysfunction, but malignancy is uncommon in this age group. Earlier age at diagnosis and presence of severe BMF could be risk factors for mortality. Patients with the TINF2 genotype tend to have a worse outcome than patients with RTEL1, TERC , and TERT .

BACKGROUND:Survivors of childhood acute lymphoblastic leukemia (ALL) frequently exhibit treatment-related neurocognitive impairment, although there is substantial interpatient variability in this outcome. Analysis of biomarkers that reflect the impact of chemotherapy during the two years of treatment for ALL offers the potential to identify children who have subclinical treatment-related neurotoxicity at a time when a protective intervention could prevent the development of persistent impairment. METHODS:We prospectively measured markers indicative of oxidative stress (8-hydroxydeoxyguanosine) and neurodegeneration (total tau) in cerebrospinal fluid (CSF) collected at five timepoints before and during the first year of chemotherapy for ALL among 529 patients enrolled on Dana-Farber Cancer Institute ALL Consortium protocol 16-001 (NCT03020030). RESULTS:CSF 8-hydroxydeoxyguanosine and total tau change significantly over time, with parallel increases emerging during intensive phases of therapy, especially following repeated doses of intrathecal chemotherapy. A concordant increase in both markers was observed in 50% of patients; a concordant decrease was seen in a smaller subset (15%). In multivariable analysis, higher CSF tau was significantly associated with White race and non-Hispanic ethnicity. CONCLUSIONS:Analysis of CSF collected prospectively in a large cohort of children treated for ALL demonstrated significant changes in markers of oxidative stress and neurodegeneration within three months of treatment initiation. IMPACT:The clinical relevance of the putative biomarkers reported here will be validated by testing whether they are predictive of treatment-related cognitive decline. These biomarkers may then serve as surrogate markers for testing the efficacy of protective interventions designed to protect against treatment-induced neurotoxicity and cognitive decline.

Introduction: Current protocols treating acute lymphoblastic leukemia (ALL) in children, adolescents, and young adults utilize bone marrow (BM) measurable (minimal) residual disease (MRD) to assess early treatment response and risk stratify post-induction therapy. Measuring MRD in peripheral blood (PB) may provide a less invasive way to quantitate leukemia burden facilitating more frequent and nuanced assessment of disease status and may provide additional insight on tumor biology. Methods: Next-generation sequencing of immunoglobulin and T-cell receptor loci by the clonoSEQ Assay (Adaptive Biotechnologies Corporation, Seattle, USA) was used to evaluate paired BM and PB samples from participants enrolled on a front line ALL clinical trial DFCI 16-001 (NCT03020030). Participants were selected by having paired samples available. Participants on 16-001 were stratified into initial risk groups by age, presenting white blood cell count, immunophenotype, CNS status, and adverse leukemia biology. MRD was evaluated at End-induction IA, 4 weeks after starting therapy (TP1, 138 pairs after QC) and if the TP1 result was greater than 100 per million cells (10^-4) MRD was evaluated again at end-induction IB, 10 weeks after the start of treatment (TP2, 42 pairs after QC). MRD was assessed in patients classified as very high risk at a third timepoint approximately 19 weeks after the start of therapy (TP3, 26 pairs after QC). BM MRD value by clonoSEQ if available determined final risk group; PB MRD was not used for clinical decision-making. Scatterplots were created and Spearman correlation coefficients were calculated to assess correlation between BM and PB MRD. Results: This analysis includes 213 paired BM and PB samples from 149 participants with median age at diagnosis 6.1 years (1-19.7), 54% male, 74% White, 77% Non-Hispanic, and 87% with B-cell immunophenotype. In this cohort, 50% were categorized as initial low risk, 29% initial high risk, and 21% initial very high risk. Of the 213 paired samples, 7 PB samples failed quality control (QC) leaving 206 for the correlation analysis. BM and PB MRD were highly correlated across all samples (R=0.78, p<2.2x10-16) and at each time point including TP1 (R=0.79, p<2.2x10-16), TP2 (R=0.71, p=1.7x10-7), and TP3 (R=.83, p=1.2x10-7). BM and PB MRD were highly correlated for both B-ALL (N=184, R=0.76, p<2.2x10-16) and T-ALL samples (N=29, R=0.88, p=6.1x10-10). Concordance was similar to the whole cohort for B-ALL samples at TP1(R=0.76, p<2.2x10-16), TP2 (R=0.7, p=3.2x10-6), and TP3 (R=0.89, p=8.9X10-9). For 44 paired samples with protocol defined high BM MRD (more than 100 per million cells for TP1, more than 1000 per million cells for TP2 or TP3), correlation with PB was also strong (R=0.50, p=5.0x10-4) however there is a discordance rate of 50% with 22 having a PB value below the protocol cut-off value. Using the whole cohort, samples with BM count in the range that may have effected management on 16-001 between 100 and 3000 per million cells were not correlated with PB (R=0.056, p=0.76). In subgroup analysis by initial risk group (low, high, and very high) and favorable tumor biology (presence of double trisomies 4 and 10 or ETV6::RUNX1) correlation remained strong. Conclusions: In this analysis, BM and PB MRD during treatment for pediatric ALL were highly correlated, particularly at high and low levels of detectable BM disease, across protocol defined risk groups, immunophenotype, and with favorable leukemia biology. At moderate levels of BM detectable disease, correlation with PB detectable disease was less strong limiting immediate direct replacement of BM sampling with PB. PB represents a desirable sample for assessing MRD allowing more frequent and less invasive evaluation of ALL disease status particularly for children, allowing for less painful modality to monitor disease status and less exposure to sedation/anesthesia. High correlation between BM and PB suggests that PB may represent a valuable adjunct for patient monitoring. With regard to specific levels for risk stratification, more work is needed. Correlation of PB MRD with ALL outcomes including event free and overall survival in the future will be essential in determining utility of PB MRD assessments.

Although typically curative, treatment for pediatric acute lymphoblastic leukemia (ALL) is associated with neurotoxicity and leads to chemotherapy-related cognitive impairment (CRCI) in 40–70

Purpose Limited data are available on the cardiorespiratory and muscle fitness of children with acute lymphoblastic leukemia (ALL) during chemotherapy. This pilot study evaluated the safety of testing the cardiorespiratory and muscle fitness of two children with ALL at different risk levels in early chem treatment. Methods Two girls with low- and high-risk B-cell ALL (DFCI-16-001) took part in two test sessions: T1 (induction, consolidation 1A/C) and T2 (consolidation 2). Each testing session included a maximal oxygen uptake ( V ˙ O 2 max) exercise test, muscular strength tests, physical activity and quality of life questionnaires, and a semi-structured interview. The parents agreed to these assessments at the start of chemotherapy treatment. Results The participants experienced no significant adverse effects from undertaking the cardiorespiratory and muscular tests, and there was no impact on their chemotherapy treatment schedule. At their post-test interview, both participants reported that thigh pain and fatigue were the most difficult part of the V ˙ O 2 max exercise test. Regarding physical performance outcomes, both participants exhibited low scores compared to their gender, weight- and age-predicted V ˙ O 2 max and on most strength test values. Conclusion The physical tests were safely and successfully conducted with these two participants during early chemotherapy.

BACKGROUND:This study describes neurocognitive functioning during the first month of induction chemotherapy for childhood acute lymphoblastic leukemia (ALL) and associations with age, sex, risk of relapse, maternal education, household material hardship (HMH), and oxidative stress. METHODS:Patients treated on protocol 16-001 (NCT03020030) across eight North American sites (2017-2022) consented for optional testing using Cogstate at six timepoints throughout treatment. The baseline data presented were collected within the first month after diagnosis. RESULTS:Among 406 eligible patients, 330 (81%) consented (53% males, mean age = 8.8 years, SD = 4.7). Over 63% of participants performed within normal limits for their age range. Additionally, no relationship was observed at baseline between neurocognition and maternal education, HMH, or oxidative stress. In contrast, a linear relationship was observed between older age and weaker psychomotor speed (p < 0.0001), attention (p < 0.0001), and working memory (p = 0.019). Males also demonstrated faster psychomotor speed (p = 0.0027), while females demonstrated stronger visual learning (p = 0.011). Furthermore, having a higher risk of relapse was associated with slower psychomotor speed (p = 0.006) and weaker attention (p = 0.033). CONCLUSIONS:Our findings indicate that most ALL patients in this study who were assessed at baseline did not display cognitive impairments, except for a small subset of participants who were below age expectations across domains. These baseline findings also identify subgroups based upon age, sex, and ALL risk classification that begin medical treatment with neurocognitive delays, warranting monitoring to elucidate whether exposure to therapy further impacts these domains. Additionally, the lack of impact on neurocognitive functioning at baseline of maternal education, HMH, and/or oxidative stress enables subsequent assessments to effectively identify the potential emergence of deficits as a result of exposure to medical treatment.

Background: L-asparaginase (ASP) is a universal component of acute lymphoblastic leukemia (ALL) therapy. Although highly effective, it can cause severe toxicities that may interrupt, delay, or require cessation of therapy. A serum asparaginase activity (SAA) of 0.1 IU/mL is associated with therapeutic effect; however, for several weeks after a dose of pegylated E.coli asparaginase formulations (pegaspargase or calaspargase), SAA levels exceed this threshold. With standard dosing, SAA varies between patients, with some achieving higher sustained levels than others. Some prior studies suggest that higher SAA levels may increase toxicity risk, but findings are inconsistent. Calaspargase is a relatively new formulation now standardly used in frontline therapy for childhood ALL. Whether higher SAA levels increase the risk of ASP-associated toxicities among patients receiving calaspargase has not been previously investigated. The Dana-Farber Cancer Institute (DFCI) ALL Consortium protocol 11-001 was a randomized Phase III trial comparing the efficacy and toxicity of calaspargase, given every 3-weeks x 10 doses to pegaspargase, given every 2-weeks x 15 doses during post-induction multiagent therapy. We evaluated whether higher nadir SAA levels (NSAA) obtained prior to each dose were associated with ASP-associated toxicities among patients receiving calaspargase. Methods: DFCI 11-001 enrolled patients 1 – 21 years with newly diagnosed ALL and lymphoblastic lymphoma. For the present analysis, patients who received post-induction calaspargase and had SAA levels available for evaluation were included. Patients assigned to the calaspargase arm received this formulation at a dose of 2500 IU/m2 every 3-weeks during Consolidation II therapy; NSAA levels were obtained 3-weeks after each dose. Using individual patient-level data, a mixed linear model was used to estimate the effect of week 4 SAA (collected prior to the 2nd dose) on all subsequent SAA levels collected through Consolidation II. Models indicated that NSAA levels collected prior to the 2nd dose of calaspargase using > 75th percentile cutoff highly predicted all subsequent NSAA levels; therefore, patients with high NSAA prior to 2nd dose (defined as being > 75th percentile) were considered to have high NSAA for this analysis. ASP-associated toxicity was defined as a composite endpoint, and patients were grouped as having no toxicities or ≥1 of the following: pancreatitis (mild, moderate, severe), thromboembolic event, or ≥ grade 3 hyperbilirubinemia as defined by CTCAE v 4.0. High NSAA level after 1st dose of calaspargase was evaluated as a predictive factor for composite toxicity. Additional analyses were performed to assess if patient or disease-related factors contributed to elevated SAA levels. Results: Between 2012 and 2015, N=239 patients were enrolled on DFCI 11-001, and 119 were randomized to the calaspargase arm; N=75 of these patients were included in the present analysis. The median NSAA prior to 2nd dose of calasparagase was 0.585 IU/mL, and the range was 0.025- 0.993 IU/mL. NSAA obtained prior to the 2nd dose was at or above the 75th percentile in N=19 patients (considered high NSAA) and was below the 75th percentile in N=56. There was no association between high NSAA levels and any of the following: age (p=0.53), sex (p=0.78), body mass index [BMI] (p>0.99), body surface area [BSA] (p=0.14), leukemia immunophenotype (p>0.99) or final risk group (p>0.99). There was no significant difference in the likelihood of toxicity for patients with high NSAA levels. Specifically, 37% (N=7) of patients with high NSAA levels developed at least 1 ASP-associated toxicity, vs. 29% (N=16)of patients with NSAA levels <75th percentile (p=0.57). Similarly, there was no association between ASP-associated toxicity and age (p=0.51), sex (p=0.29), BMI (p=0.21), BSA (p=0.5), or leukemia immunophenotype (p=0.85). Conclusions: Among patients receiving calaspargase for ALL, we found no association between high NSAA levels and ASP-related toxicity; NSAA levels were also not associated with demographic or disease characteristics. These results suggest that decreasing SAA via dose reduction or capping calaspargase doses may not reduce the rate of ASP-related toxicity. While our findings warrant further exploration to determine the utility of NSAA level as a predictor of toxicity risk, other potential risk factors for, and interventions to prevent, ASP-related toxicities should also be examined.

Linear regression between CSF 8OHdG and CSF tau at each of five timepoints.

Importance There are conflicting data on the association of overweight or obesity with clinical outcomes in childhood acute lymphoblastic leukemia (ALL). The duration of exposure to overweight or obesity may be a better indicator of the risk of poorer outcomes. Objective To determine the association of the duration of overweight or obesity with treatment-related toxic effects, minimal residual disease, relapse, and survival in childhood ALL. Design, Setting, and Participants In this prospective cohort study, fluctuations in z scores of body mass index (BMI) for age from diagnosis to the end of treatment (EOT) were examined in 794 children registered on a Dana Farber Cancer Institute ALL Consortium protocol from May 31, 2005, to December 15, 2011. Height and weight were abstracted from the medical record for classification of BMI z scores at diagnosis through EOT and into survivorship. Data were analyzed from July 1 to 31, 2024. Main Outcomes and Measures The duration of overweight or obesity was defined as having overweight or obesity at 2 or more time points and compared with having overweight or obesity at no more than 1 time point. Kaplan-Meier survival curves were generated to examine association of overweight or obesity with overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse. Results Among the 794 patients included in the analysis, the mean age at diagnosis was 6.7 (range, 1.0-17.9) years, with 441 (55.5%) being male, 136 (17.1%) Hispanic, and 553 (69.6%) non-Hispanic. The prevalence of overweight or obesity increased from 234 of 793 (29.5%) at diagnosis to 346 of 715 (48.4%) by EOT. Having overweight or obesity at baseline or developing overweight or obesity during induction was not associated with treatment-related toxic effects or higher minimal residual disease. Children with overweight or obesity at 2 or more time points experienced inferior OS (3-year OS, 93.8% vs 98.0%; P = .01), increased relapse (3-year relapse rate, 10.5% vs 5.8%; P = .02), and lower EFS (3-year EFS, 89.0% vs 93.7%; P = .02), compared with children with overweight or obesity at no more than 1 time point. Multivariable Cox proportional hazards regression models revealed an association between increased risk of death (hazard ratio [HR], 3.49; 95% CI, 1.28-9.51; P = .01) and relapse (HR, 1.92; 95% CI, 1.07-3.46; P = .03) among children with overweight or obesity at 2 or more time points. Conclusions and Relevance In this prospective cohort study of children with ALL, longer duration of overweight or obesity was associated with lower OS and EFS and higher rates of relapse, underscoring the need for interventions targeting overweight or obesity during treatment of children with ALL.

Introduction: Over 90% of children with acute lymphoblastic leukemia (ALL) will survive their cancer in the context of >2 years of multi-agent chemotherapy. This intensive treatment paradigm may lead to significant treatment-related financial toxicity for families— an outcome highly relevant to long-term child and family well-being. The magnitude and trajectories of financial toxicity are unknown in pediatric oncology, and necessary to inform optimal screening and intervention strategies for children with cancer and their families. Development of new household material hardship ([HMH], housing, food, or utility insecurity) or income loss during cancer treatment are concrete, targetable metrics of financial toxicity. We present results from Dana-Farber Cancer Institute (DFCI) ALL Consortium Trial 16-001, the first pediatric oncology clinical trial to systematically collect longitudinal HMH and household income data as an embedded correlative trial aim. Methods: DFCI 16-001 (NCT03020030) enrolled children ages 1-<22 years with de novoB- or T-cell ALL at 8 US and Canadian centers from 2017-2021. Participants <18 years were eligible to opt-in to the correlative HMH study at time of initial trial consent. Parents/guardians of participants completed surveys within 32-days of trial enrollment and longitudinally at 6-, 12-, and 24-months. Financial toxicity was the primary endpoint of interest for this secondary analysis, defined by two variables: (1) development of any new HMH domain (food, housing, or utility insecurity) at 6-24 months as compared to baseline and (2) catastrophic income loss defined as ≥25% annual household income loss at 6-24 months compared to baseline. Cumulative incidence of new HMH and catastrophic income loss in the presence of competing risks of coming off study (off-protocol therapy, death, relapse) were estimated using the Aalen-Johansen method. A subcohort analysis was conducted among participants who reported no HMH at baseline. Multivariable competing risk models evaluated the association of patient, household, and disease characteristics with risk of developing new HMH. Results: Among 422 participants (15% Hispanic and 7% non-Hispanic Black, 23% single-parent household, 40% annual household income <200% federal poverty level) with evaluable baseline survey data, 115 (27%) reported HMH at baseline. The cumulative incidence of any new HMH was 19.3% (95% CI: 15.9-23.5) at 6-months, 27.7% (95% CI: 23.8-32.4) at 12-months, and 30.0% (95% CI: 25.9-34.7) at 24-months. The cumulative incidence of catastrophic income loss was 20.3% (95% CI: 16.7-24.7) at 6-months, 28.6% (95% CI: 24.5-33.5) at 12-months, and 31.5% (95% CI: 27.2-36.5) at 24-months. Among the subcohort of 307 families with no baseline HMH, the cumulative incidences of any new HMH or catastrophic income loss at 24-months were 24.3% (95% CI: 19.9-29.6) and 27.9% (95% CI: 23.1-33.7), respectively. In multivariable modeling, children who identified as non-Hispanic Black (RR 3.5, 95% CI: 1.7-7.3), lived in a single-parent household (RR 2.1, 95% CI: 1.3-3.2), preferred a non-dominant language (i.e. non-English for US participants and non-English/French for Canadian participants, RR 2.1, 95% CI: 1.2-3.6), or had baseline household income <200% federal poverty level (RR 1.8, 95% CI: 1.1-2.9) were more likely to develop new HMH during treatment. Conclusion: Nearly a third of families of children receiving chemotherapy for ALL develop catastrophic financial toxicity during therapy including new unmet basic needs such as food insecurity, or ≥25% income loss. A majority experience this financial toxicity by 6-months into treatment, identifying a key inflection point for potential intervention. Importantly, nearly 1 in 4 families who had no HMH at the time of their child's diagnosis developed HMH during therapy. These findings stress the clinical importance of longitudinal financial screening over the course of cancer treatment, given the high prevalence of new material needs that arise and the potential to address these needs with family-centered interventions. Future work will assess the impact of early financial toxicity on clinical outcomes in this population and focus on the development of interventions to mitigate the profound financial toxicity impacting families during leukemia care.

Background With intensified, multiagent chemotherapy protocols, outcomes for childhood T-cell acute lymphoblastic leukemia (T-ALL) have improved with most patients (pts) achieving long term cure. However, identification of prognostic variables that can be used to assign risk-adapted therapy has lagged behind that for B-ALL. Here we present results of the T-ALL cohort enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 16-001. Methods DFCI 16-001 enrolled children with ALL ages 1 to 21 years from Mar 2017 to Sept 2022. Pts with T-ALL were classified as initial high-risk (HR) and received multiagent induction chemotherapy, including doxorubicin and dexamethasone. Pts with adverse biology (KMT2A-R, low hypodiploidy, IKZF1 deletion) were upstaged to very high risk (VHR); those with Ph+ ALL were removed from protocol during induction. Induction Failure (IF) was defined as M3 marrow at end of the first month of treatment (TP1), or M2/M3 marrow approximately 10 weeks after starting therapy (TP2). For pts achieving complete remission (CR), Final Risk Group was assigned as follows: 1) Final Intermediate Risk (IR): Absence of adverse biology and low TP1 MRD (<10-4); 2) Final HR: Absence of adverse biology, high TP1 MRD but low TP2 MRD (<10-3); 3) Final VHR: Adverse biology regardless of MRD or high TP2 MRD (>10-3). Pts assigned to Final VHR received 2 intensified Consolidation cycles, including nelarabine, high-dose cytarabine, and etoposide. MRD was assessed using next generation sequencing (NGS) by ClonoSEQ (Adaptive, Seattle WA). Early T-cell precursor (ETP) and near-ETP status was centrally determined by flow cytometry, but was not used to assign risk group. Cranial radiation (18 Gy) was administered to pts with CNS3 status. Protocol therapy continued until 24 months from date of CR. Overall survival (OS) and event-free survival (EFS) were estimated with the Kaplan-Meier method and compared between groups with a log-rank test. Results Eighty-six pts with T-ALL enrolled; 77 pts were classified as Initial HR and 9 as Initial VHR based on biology (all with KMT2A-R). Twelve pts were identified as ETP-ALL and 6 as near-ETP. Eight pts were classified as CNS3 at diagnosis. Of the 83 pts evaluable for induction events, 76 (91.6%) achieved CR; 4 HR and 3 VHR pts were classified as having IF and removed from protocol therapy. There were no induction deaths. Of the 76 pts who achieved CR, 33 (38%) were assigned to Final IR, 24 (28%) to Final HR, and 19 (22%) to Final VHR. Of the pts achieving CR, 3 relapses have been observed (2 isolated CNS relapses, 1 marrow-involved relapse). With a median follow up of 4.9 yrs, 4-yr EFS and OS for the T-ALL cohort was 84.8% and 91.5%, respectively. The 4-yr EFS was 96.3% for Final IR/HR pts (Final IR:93.4%; Final HR:100%), and 79% for Final VHR pts (p=0.024). There was no significant difference in outcome by MRD at TP1, however, pts with high TP2 MRD (n=13) had a significantly worse outcome than those who achieved low MRD either at TP1 or TP2 (n=62), 4-yr EFS 69.2% vs 95%, (p=0.0032). Pts with ETP/near-ETP ALL (n=18) had a 4-yr EFS of 66.7% compared with 88.9% for non-ETP ALL (p=0.034), largely due to IF events (n=4); 2 pts with ETP/near-ETP experienced SMN; there were no relapses in this group. The 4-yr OS for ETP/near-ETP was 93.8%, compared with 90.5% for non-ETP. Pts with KMT2A-R (n=9) had an inferior 4-yr EFS of 55.6%. On a univariate Cox model for EFS, significant predictors of adverse outcome were high TP2 MRD (HR 6.36, p=0.035), KMT2A-r (HR 4.07, p=0.018) and ETP or near-ETP status (HR 2.93, p=0.047); age, presenting white blood cell count, CNS status and TP1 MRD were not significant. Conclusions Overall outcomes for pts with T-ALL enrolled on DFCI 16-001 were favorable, and comparable to prior DFCI Consortium trials despite omission of cranial radiation for all but CNS3 pts. Pts with absence of adverse biology who achieved low MRD at either TP1 or TP2 had an excellent 4-yr EFS of 96.3%, comparable to the most favorable B-ALL subtypes, supporting future studies to investigate treatment de-intensification for this pt subset. Pts with ETP/near-ETP experienced high rates of IF, but OS remained comparable to non-ETP T-ALL pts. Novel treatment strategies are needed for VHR T-ALL pts, including those with high TP2 MRD and/or KMT2A-rearrangements.

Subspecialty pediatrics have lagged behind primary care pediatrics in recognizing adverse social determinants of health (SDOH) as salient to outcomes, key drivers of inequity, and worthy of systematic investigation.1 A population frequently hospitalized with chronic illness with well-defined inequities is children with cancer. More than 1 in 5 pediatric oncology families report low-income, and at least 1 household material hardship (HMH; food, housing, or utility insecurity) at diagnosis.2 Identifying whether children from marginalized racial/ethnic groups are disproportionately exposed to poverty, a modifiable SDOH, can inform intervention opportunities for children with chronic illness to mitigate disparities.3 We leveraged parent-reported poverty data collected as a prospective aim of a clinical trial for children with newly diagnosed acute lymphoblastic leukemia (ALL) to characterize modifiable poverty exposures by race/ethnicity.The Dana Farber Cancer Institute ALL Consortium phase III randomized clinical trial 16-001 (NCT03020030) enrolled children aged 1 to 21 years with de novo ALL from 2016 to 2022 at 8 US and Canadian centers. It included an embedded prospective cohort study evaluating parent-reported SDOH via survey within 32 days of enrollment.4,5 The study was approved by enrolling sites' institutional review boards.Child's parent-reported race and ethnicity were collected using US and Canadian federal reporting guidelines and combined to reflect populations per best practice (Supplemental Table 1). HMH was defined as at least 1 of 3 resource insecurities (housing, food, or utilities) using a standardized instrument,5 and additionally examined as ordinal number of unmet resource needs (0–3). Low income was defined as annual household income <200% US Federal Poverty Level for subject year of enrollment.6 To allow comparison across the trial cohort, Canadian to US dollar conversion was calculated via the July 2022 exchange rate of 1 CAD to 0.7765 USD.7 Comparisons were made using the χ2 test or Fisher exact test, as appropriate. Analyses were performed using SAS, version 9.The analytic cohort included 375 subjects, including 247 (66%) treated at US sites and 128 (34%) at Canadian sites. Parent-reported race/ethnicity and poverty exposures are displayed in Supplemental Table 2.One hundred and twenty (32%) families reported HMH at diagnosis, including 47% (n = 17) of Black families (P < .001) and 68% (n = 45) of Hispanic families (P < .001) vs 19% (n = 46) of non-Hispanic White (NHW) families (Fig 1). Housing insecurity was present in 33% (n = 12) of Black families (P < .001) and 47% (n = 31) of Hispanic families (P < .001) vs 11% (n = 26) of NHW families. Many Black and Hispanic families reported more than 1 resource insecurity; specifically, 8% (n = 3) of Black families (P = .10) and 14% (n = 9) of Hispanic families (P = .001) vs 3% (n = 6) of NHW families reported 3 HMH domains.Among 336 (89%) families with available income data, 131 (39%) reported low income, including 52% (14/27) of Black families and 74% (40/54) of Hispanic families vs 27% (62/226) of NHW families (P = .009 and <.001, respectively).Overall, among 179 families who reported any poverty exposures, 40% (n = 72) reported both low-income and HMH poverty exposures (Fig 2).In a subspecialty pediatric patient cohort, we demonstrate that Black and Hispanic children with ALL experience high frequencies of modifiable poverty exposures at diagnosis. Implications of these poverty exposures include differential health care access and inferior disease outcomes—including higher rates of relapse and death.2 These data identify actionable risk exposures disproportionately experienced by marginalized children with complex chronic illness. They provide immediate opportunities for subspecialist and hospital-based pediatric providers to address disparities rooted in systemic racism.In this cohort, HMH and income poverty distinguished overlapping but nonidentical populations (Fig 2),8 identifying opportunities for exposure-specific (income vs resource poverty) interventions. For example, children living in low-income households may benefit from guaranteed income pilots or interventions to increase means-tested governmental program participation,9 whereas those facing resource insecurities absent low income may require direct resource provision—such as food or transportation vouchers—during cancer treatment.10 Cancer-specific interventions targeting both are currently in development (NCT03638453).Our data are limited by a geographically restricted cohort, with underrepresentation of racial/ethnic identities. Merging of US and Canadian racial/ethnic groups risks misclassification. Replication of these data using larger, more diverse cohorts is ongoing in the Children's Oncology Group (NCT03914625, NCT03126916).These data identify marked inequities in modifiable SDOH experienced by marginalized populations within a paradigmatic subspecialty population requiring frequent hospitalization. They provide immediate targets for interventions aimed at addressing racial/ethnic outcome disparities applicable to pediatric populations with complex chronic illness.