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Poverty-exposed children with cancer are more likely to experience adverse outcomes. Supplemental Nutrition Assistance Program (SNAP) benefits improve food insecurity and child health outcomes, and could be used to mitigate disparities. We conducted a secondary analysis of parent-reported data collected in a frontline pediatric leukemia trial (NCT03020030) to assess SNAP eligibility (proxied by other means-tested program participation) and participation. At diagnosis, 105/287 families (37%) were SNAP-eligible, of whom 53 (50%) were SNAP participants. At 6 months, 104/257 families (41%) were SNAP-eligible, and 59 (57%) were SNAP participants. Interventions to increase benefits participation during childhood cancer treatment represent an immediate opportunity to reduce disparities.
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Bone toxicities are common among paediatric patients treated for acute lymphoblastic leukaemia (ALL) with potentially major negative impact on patients' quality of life. To identify the underlying genetic contributors, we conducted a genome-wide association study (GWAS) and a transcriptome-wide association study (TWAS) in 260 patients of European-descent from the DFCI 05-001 ALL trial, with validation in 101 patients of European-descent from the DFCI 11-001 ALL trial. We identified a significant association between rs844882 on chromosome 20 and bone toxicities in the DFCI 05-001 trial (p = 1.7 × 10-8). In DFCI 11-001 trial, we observed a consistent trend of this variant with fracture. The variant was an eQTL for two nearby genes, CD93 and THBD. In TWAS, genetically predicted ACAD9 expression was associated with an increased risk of bone toxicities, which was confirmed by meta-analysis of the two cohorts (meta-p = 2.4 × 10-6). In addition, a polygenic risk score of heel quantitative ultrasound speed of sound was associated with fracture risk in both cohorts (meta-p = 2.3 × 10-3). Our findings highlight the genetic influence on treatment-related bone toxicities in this patient population. The genes we identified in our study provide new biological insights into the development of bone adverse events related to ALL treatment.
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BACKGROUND: The objective of this study is to assess the concordance and added value of combined comparative genomic hybridization plus single-nucleotide polymorphism microarray (CGH/SNP) analyses in pediatric acute lymphoblastic leukemia (ALL) risk stratification compared to conventional cytogenetic methods. PROCEDURE: This is a retrospective study that included patients aged 1-18 years diagnosed with de novo ALL at Sainte-Justine Hospital between 2016 and 2021. Results from conventional cytogenetic and molecular analyses were collected and compared to those of CGH/SNP. RESULTS: A total of 135 ALL patients were included. Sample failures or non-diagnostic analyses occurred in 17.8% cases with G-banding karyotypes versus 1.5% cases with CGH/SNP. The mean turnaround time for results was significantly faster for CGH/SNP than karyotype with 5.8 versus 10.7 days, respectively. The comparison of ploidy assessment by CGH/SNP and G-banding karyotype showed strong concordance (r = .82, p < .001, r2 = .68). Furthermore, G-banding karyotype did not detect additional clinically relevant aberrations that were missed by the combined analysis of CGH/SNP and fluorescence in situ hybridization. The most common gene alterations detected by CGH/SNP were deletions involving CDKN2A (35.8%), ETV6 (31.3%), CDKN2B (28.4%), PAX5 (20.1%), IKZF1 (12.7%), and copy-neutral loss of heterozygosity (CN-LOH) of 9p (9.0%). Among these, only ETV6 deletion was found to have a significant prognostic impact with superior event-free survival in both univariate and multivariate analyses (adjusted hazard ratio 0.08, 95% confidence interval: 0.01-0.50, p = .02). CONCLUSION: CGH/SNP provided faster, reliable, and highly concordant results than those obtained by conventional cytogenetics. CGH/SNP identified recurrent gene deletions in pediatric ALL, of which ETV6 deletion conferred a favorable prognosis.
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Hibridização Genômica Comparativa , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Feminino , Pré-Escolar , Masculino , Adolescente , Lactente , Estudos Retrospectivos , Hibridização Genômica Comparativa/métodos , Prognóstico , Medição de Risco/métodos , Seguimentos , Taxa de SobrevidaRESUMO
Adolescents and young adult (AYA) patients with acute lymphoblastic leukemia (ALL) face worse outcomes than children. While pediatric-inspired protocols have improved outcomes, the ability of patients to complete these intensive regimens and the reasons for discontinuation are unknown. We analyzed a cohort of 332 AYA patients (aged 15-49 years) and 1159 children (aged 1-14 years) with Ph-negative ALL treated on DFCI consortium protocols. We found that AYA patients completed treatment at lower rates than children (60.8% vs. 89.7%, p < 0.001), primarily due to higher rates of early treatment failure (14.5% vs. 2.4%, p < 0.001). Withdrawal from treatment for toxicity, social/personal, or unknown reasons was uncommon, but higher among AYA patients (9.3% vs 4.7%, p = 0.001). Patients who remained on assigned therapy for one year had favorable overall survival (AYA 5-year OS 88.9%; children 5-year OS 96.4%; p < 0.001). Among patients who continued treatment for 1 year, AYA patients completed asparaginase (defined as receiving 26+ weeks) at lower rates than children (79.1% vs. 89.6%, p < 0.001). Patients who received more weeks of consolidation asparaginase had higher overall and event-free survival. Efforts should focus on identifying patients at risk for early treatment failure and optimizing asparaginase delivery.
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Asparaginase , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Adolescente , Adulto Jovem , Asparaginase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) treated with asparaginase-containing pediatric regimens are commonly overweight or obese. We studied the association of body mass index (BMI) on outcomes of 388 AYAs aged 15 to 50 years treated on Dana-Farber Cancer Institute (DFCI) consortium regimens (2008-2021). BMI was normal in 207 (53.3%) and overweight/obese in 181 (46.7%). Patients who were overweight or obese experienced higher nonrelapse mortality (NRM; 4-year, 11.7% vs 2.8%, P = .006), worse event-free survival (4-year, 63% vs 77%, P = .003), and worse overall survival (OS; 4-year, 64% vs 83%, P = .0001). Because younger (aged 15-29 years) AYAs more frequently had a normal BMI (79% vs 20%, P < .0001), we conducted separate analyses in each BMI group. We found excellent OS among younger and older (30-50 years) AYAs with normal BMI (4-year OS, 83% vs 85%, P = .89). Conversely, in AYAs who were overweight/obese, worse outcomes were seen in older AYAs (4-year OS, 55% vs 73%, P = .023). Regarding toxicity, AYAs who were overweight/obese experienced higher rates of grade 3/4 hepatotoxicity and hyperglycemia (60.7% vs 42.2%, P = .0005, and 36.4% vs 24.4%, P = .014, respectively) but had comparable rates of hypertriglyceridemia (29.5% vs 24.4%, P = .29). In a multivariable analysis, higher BMI was associated with worse OS, hypertriglyceridemia was associated with improved OS, and age was not associated with OS. In conclusion, among AYAs treated on DFCI Consortium ALL regimens, elevated BMI was associated with increased toxicity, increased NRM, and decreased OS. The deleterious effect of elevated BMI was more pronounced in older AYAs.
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Hipertrigliceridemia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Criança , Adolescente , Adulto Jovem , Idoso , Índice de Massa Corporal , Intervalo Livre de Doença , Sobrepeso , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Obesidade/complicaçõesRESUMO
BACKGROUND: Children treated for acute lymphoblastic leukemia (ALL) receive prolonged treatment, resulting in toxicities that affect health-related quality of life (HR-QoL). Longitudinal assessment of HR-QoL allows improved understanding of experiences with ALL. PROCEDURE: Parent-proxy and child self-report HR-QoL over the first year of chemotherapy were evaluated in the context of DFCI Protocol 05-001, a phase 3 therapeutic trial for childhood ALL. HR-QoL was assessed with the Pediatric Quality-of-Life inventory (PedsQL) domains for Pain and Hurt, Procedural Anxiety, Treatment Anxiety, Emotional Functioning, General Fatigue, and Sleep/Rest Fatigue. RESULTS: Total of 281 subjects participated, with 141 contributing at least one child report and 280 at least one parent report. Children with ALL experienced impairment in HR-QoL by both patient and parent report compared to the published PedsQL reference population at each time point on each subscale. Agreement between parent and child assessment of HR-QoL impairment was high, particularly among those for whom HR-QoL was not impaired. During the consolidation phase, which included intensive asparaginase administration, multivariable models demonstrated more impairment in Treatment Anxiety and Procedural Anxiety for children treated with intramuscular asparaginase than intravenous asparaginase, but randomized groups were otherwise similar in HR-QoL. Impairments in fatigue, both General and Sleep/Rest, were evident throughout and worse during intensive asparaginase therapy. CONCLUSIONS: This report examines HR-QoL for children with ALL during treatment longitudinally by parent and patient report across multiple domains. Children with ALL demonstrated substantial impairment in HR-QoL, particularly related to fatigue during intensive consolidation therapy including asparaginase.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Qualidade de Vida , Criança , Humanos , Asparaginase/efeitos adversos , Fadiga/etiologia , Dor , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/psicologia , Qualidade de Vida/psicologiaRESUMO
Recognition of aberrant gene isoforms due to DNA events can impact risk stratification and molecular classification of hematolymphoid tumors. In myelodysplastic syndromes, KMT2A partial tandem duplication (PTD) was one of the top adverse predictors in the International Prognostic Scoring System-Molecular study. In B-cell acute lymphoblastic leukemia (B-ALL), ERG isoforms have been proposed as markers of favorable-risk DUX4 rearrangements, whereas deletion-mediated IKZF1 isoforms are associated with adverse prognosis and have been extended to the high-risk IKZF1plus signature defined by codeletions, including PAX5. In this limited study, outlier expression of isoforms as markers of IKZF1 intragenic or 3' deletions, DUX4 rearrangements, or PAX5 intragenic deletions were 92.3% (48/52), 90% (9/10), or 100% (9/9) sensitive, respectively, and 98.7% (368/373), 100% (35/35), or 97.1% (102/105) specific, respectively, by targeted RNA sequencing, and 84.0% (21/25), 85.7% (6/7), or 81.8% (9/11) sensitive, respectively, and 98.2% (109/111), 98.4% (127/129), or 98.7% (78/79) specific, respectively, by total RNA sequencing. Comprehensive split-read analysis identified expressed DNA breakpoints, cryptic splice sites associated with IKZF1 3' deletions, PTD of IKZF1 exon 5 spanning N159Y in B-ALL with mutated IKZF1 N159Y, and truncated KMT2A-PTD isoforms. Outlier isoforms were also effective targeted RNA markers for PAX5 intragenic amplifications (B-ALL), KMT2A-PTD (myeloid malignant cancers), and rare NOTCH1 intragenic deletions (T-cell acute lymphoblastic leukemia). These findings support the use of outlier isoform analysis as a robust strategy for detecting clinically significant DNA events.
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Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Isoformas de Proteínas/genética , Análise de Sequência de RNA , GenômicaRESUMO
BACKGROUND: The outcome of children with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia significantly improved with the combination of imatinib and intensive chemotherapy. We aimed to investigate the efficacy of dasatinib, a second-generation ABL-class inhibitor, with intensive chemotherapy in children with newly diagnosed Ph-positive acute lymphoblastic leukaemia. METHODS: CA180-372/COG AALL1122 was a joint Children's Oncology Group (COG) and European intergroup study of post-induction treatment of Ph-positive acute lymphoblastic leukaemia (EsPhALL) open-label, single-arm, phase 2 study. Eligible patients (aged >1 year to <18 years) with newly diagnosed Ph-positive acute lymphoblastic leukaemia and performance status of at least 60% received EsPhALL chemotherapy plus dasatinib 60 mg/m2 orally once daily from day 15 of induction. Patients with minimal residual disease of at least 0·05% after induction 1B or who were positive for minimal residual disease after the three consolidation blocks were classified as high risk and allocated to receive haematopoietic stem-cell transplantation (HSCT) in first complete remission. The remaining patients were considered standard risk and received chemotherapy plus dasatinib for 2 years. The primary endpoint was the 3-year event-free survival of dasatinib plus chemotherapy compared with external historical controls. The trial was considered positive if one of the following conditions was met: superiority over chemotherapy alone in the AIEOP-BFM 2000 high-risk group; or non-inferiority (with a margin of -5%) or superiority to imatinib plus chemotherapy in the EsPhALL 2010 cohort. All participants who received at least one dose of dasatinib were included in the safety and efficacy analyses. This trial was registered with ClinicalTrials.gov, NCT01460160, and recruitment is closed. FINDINGS: Between March 13, 2012, and May 27, 2014, 109 patients were enrolled at 69 sites (including 51 COG sites in the USA, Canada, and Australia, and 18 EsPhALL sites in Italy and the UK). Three patients were ineligible and did not receive dasatinib. 106 patients were treated and included in analyses (49 [46%] female and 57 [54%] male; 85 [80%] White, 13 [12%] Black or African American, five [5%] Asian, and three [3%] other races; 24 [23%] Hispanic or Latino ethnicity). All 106 treated patients reached complete remission; 87 (82%) were classified as standard risk and 19 (18%) met HSCT criteria and were classified as high risk, but only 15 (14%) received HSCT in first complete remission. The 3-year event-free survival of dasatinib plus chemotherapy was superior to chemotherapy alone (65·5% [90% Clopper-Pearson CI 57·7 to 73·7] vs 49·2% [38·0 to 60·4]; p=0·032), and was non-inferior to imatinib plus chemotherapy (59·1% [51·8 to 66·2], 90% CI of the treatment difference: -3·3 to 17·2), but not superior to imatinib plus chemotherapy (65·5% vs 59·1%; p=0·27). The most frequent grade 3-5 adverse events were febrile neutropenia (n=93) and bacteraemia (n=21). Nine remission deaths occurred, which were due to infections (n=5), transplantation-related (n=2), due to cardiac arrest (n=1), or had an unknown cause (n=1). No dasatinib-related deaths occurred. INTERPRETATION: Dasatinib plus EsPhALL chemotherapy is safe and active in paediatric Ph-positive acute lymphoblastic leukaemia. 3-year event-free survival was similar to that of previous Ph-positive acute lymphoblastic leukaemia trials despite the limited use of HSCT in first complete remission. FUNDING: Bristol Myers Squibb.
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Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Masculino , Feminino , Mesilato de Imatinib/uso terapêutico , Dasatinibe/efeitos adversos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do TratamentoAssuntos
Neoplasias Hematológicas , Fatores de Transcrição , Criança , Humanos , Proteínas de Ligação a DNA/genética , Éxons , Neoplasias Hematológicas/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas c-ets/genética , Fatores de Transcrição/genética , Translocação Genética , Variante 6 da Proteína do Fator de Translocação ETSRESUMO
BACKGROUND: Parent psychological distress during childhood cancer treatment has short- and long-term implications for parent, child, and family well-being. Identifying targetable predictors of parental distress is essential to inform interventions. We investigated the association between household material hardship (HMH), a modifiable poverty-exposure defined as housing, food, or utility insecurity, and severe psychological distress among parents of children aged 1-17 years with acute lymphoblastic leukemia (ALL) enrolled on the multicenter Dana-Farber ALL Consortium Trial 16-001. METHODS: This was a secondary analysis of parent-reported data. Parents completed an HMH survey within 32 days of clinical trial enrollment (T0) and again at 6 months into therapy (T1). The primary exposure was HMH at T0 and primary outcome was severe parental distress at T0 and T1, defined as a score greater than or equal to 13 on the Kessler-6 Psychological Distress Scale. Multivariable models were adjusted for ALL risk group and single parent status. RESULTS: Among 375 evaluable parents, one-third (32%; n = 120/375) reported HMH at T0. In multivariable analyses, T0 HMH was associated with over twice the odds of severe psychological distress at T0 and T1 HMH was associated with over 5 times the odds of severe distress at T1. CONCLUSIONS: Despite uniform clinical trial treatment of their children at well-resourced pediatric centers, HMH-exposed parents-compared with unexposed parents-experienced statistically significantly increased odds of severe psychological distress at the time of their child's leukemia diagnosis, which worsened 6 months into therapy. These data identify a high-risk parental population who may benefit from early psychosocial and HMH-targeted interventions to mitigate disparities in well-being.
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Pobreza , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Inquéritos e Questionários , Pais/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Fatores de Risco , Estresse Psicológico/epidemiologia , Estresse Psicológico/etiologia , Estresse Psicológico/diagnósticoRESUMO
Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.
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Antineoplásicos , Pancreatite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Camundongos , Asparaginase/efeitos adversos , Retinoides/efeitos adversos , Vitamina A/uso terapêutico , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Análise de Sistemas , Antineoplásicos/efeitos adversosRESUMO
INTRODUCTION: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, has a relatively favorable long-term prognosis. Yet the complexity of treatment and the emotionality of the diagnosis leave families feeling unprepared for many aspects of therapy. This qualitative study aimed to identify desired elements and format of a communication resource to support patients and families facing a diagnosis of ALL. METHODS: Semi-structured interviews of 12 parents of children receiving ALL treatment, 10 parents of survivors of ALL, and eight adolescent and young adult (AYA) survivors of ALL were conducted between February and June 2021. The interviews focused on communication experiences throughout treatment and identified domains to be addressed in a resource in development. RESULTS: All participants supported the development of an interactive, electronic health (eHealth) resource to help navigate ALL treatment. They felt a website would be helpful in addressing information gaps and mitigating pervasive feelings of overwhelm. Participants specifically sought: (a) information resources to address feelings of cognitive overload; (b) practical tips to help navigate logistical challenges; (c) clear depictions of treatment choices and trajectories to facilitate decision-making; and (d) additional psychosocial resources and support. Two overarching themes that families felt should be interwoven throughout the eHealth resource were connections with other patients/families and extra support at transitions between phases of treatment. CONCLUSIONS: A new diagnosis of ALL and its treatment are extremely overwhelming. Patients and families unanimously supported an eHealth resource to provide additional information and connect them with emotional support, starting at diagnosis and extending throughout treatment.
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Neoplasias , Pais , Criança , Adolescente , Adulto Jovem , Humanos , Pais/psicologia , Comunicação , Pesquisa Qualitativa , Neoplasias/terapia , Neoplasias/psicologia , AconselhamentoRESUMO
PURPOSE: Neurocognitive impairment is frequently observed among survivors of childhood acute lymphoblastic leukemia (ALL) within the domains of attention, working memory, processing speed, executive functioning, and learning and memory. However, few studies have characterized the trajectory of treatment-induced changes in neurocognitive function beginning in the first months of treatment, to test whether early changes predict impairment among survivors. If correct, we hypothesize that those children who are most susceptible to early impairment would be ideal subjects for clinical trials testing interventions designed to protect against treatment-related neurocognitive decline. METHODS: In this pilot study, we prospectively assessed neurocognitive functioning (attention, working memory, executive function, visual learning, and processing speed), using the Cogstate computerized battery at six time points during the 2 years of chemotherapy treatment and 1-year post-treatment (Dana-Farber Cancer Institute ALL Consortium protocol 11-001; NCT01574274). RESULTS: Forty-three patients with ALL consented to serial neurocognitive testing. Of the 31 participants who remained on study through the final time point, 1 year after completion of chemotherapy, 28 (90%) completed at least five of six planned Cogstate testing time points. Performance and completion checks indicated a high tolerability (≥ 88%) for all subtests. One year after completion of treatment, 10 of 29 patients (34%) exhibited neurocognitive function more than 2 standard deviations below age-matched norms on one or more Cogstate subtests. CONCLUSIONS: Serial collection of neurocognitive data (within a month of diagnosis with ALL, during therapy, and 1-year post-treatment) is feasible and can be informative for evaluating treatment-related neurocognitive impairment.
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Função Executiva , Leucemia , Criança , Humanos , Estudos de Viabilidade , Memória de Curto Prazo , Testes Neuropsicológicos , Projetos Piloto , Estudos ProspectivosRESUMO
Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (<18 years). After a median of 1 (range, 1-3) cycle of treatment, 24 patients (55%) achieved complete remission, 62% (18/29) with combination therapy and 40% (6/15) with monotherapy (P = .21). Most responders (21, 88%) pursued allogeneic stem cell transplant (alloSCT). Overall survival (OS) was 12.8 months (95% confidence interval, 6.93-not reached) in the entire cohort and was higher in the combination therapy than in the monotherapy group (24-month OS, 53% vs 8%; P = .003). The rate of neurotoxicity was similar between groups (27% vs 17%; P = .46) and grade 3/4 anemia and thrombocytopenia were more frequent in the combination group (76% vs 20%; P < .001% and 66% vs 27%; P = .014, respectively). In a multivariate analysis, nelarabine combination therapy and alloSCT post nelarabine were associated with improved OS (hazard ratio, 0.41; P = .04 and hazard ratio, 0.25; P = .008, respectively). In conclusion, compared with monotherapy, nelarabine combination therapy was well tolerated and associated with improved survival in pediatric and adult patients with R/R T-ALL/LBL.
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Linfoma , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adulto , Humanos , Criança , Adulto Jovem , Estudos Retrospectivos , Linfócitos T/patologiaRESUMO
AALL1931, a phase 2/3 study conducted in collaboration with the Children's Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli-derived asparaginases. Each dose of a pegylated E coli-derived asparaginase remaining in patients' treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.
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Antineoplásicos , Hipersensibilidade a Drogas , Erwinia , Hipersensibilidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Asparaginase/efeitos adversos , Escherichia coli , Hipersensibilidade a Drogas/etiologia , Antineoplásicos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
PURPOSE: We aimed to study prognostic factors and efficacy of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission of patients with noninfant childhood acute lymphoblastic leukemia (ALL) with 11q23/KMT2A rearrangements treated with chemotherapy regimens between 1995 and 2010. PATIENTS AND METHODS: Data were retrospectively retrieved from 629 patients with 11q23/KMT2A-rearranged ALL from 17 members of the Ponte-di-Legno Childhood ALL Working Group. Clinical and biologic characteristics, early response assessed by minimal residual disease at the end of induction (EOI) therapy, and allo-HSCT were analyzed for their impact on outcomes. RESULTS: A specific 11q23/KMT2A translocation partner gene was identified in 84.3% of patients, with the most frequent translocations being t(4;11)(q21;q23) (n = 273; 51.5%), t(11;19)(q23;p13.3) (n = 106; 20.0%), t(9;11)(p21_22;q23) (n = 76; 14.3%), t(6;11)(q27;q23) (n = 20; 3.8%), and t(10;11)(p12;q23) (n = 14; 2.6%); 41 patients (7.7%) had less frequently identified translocation partner genes. Patient characteristics and early response varied among subgroups, indicating large biologic heterogeneity and diversity in therapy sensitivity among 11q23/KMT2A-rearranged ALL. The EOI remission rate was 93.2%, and the 5-year event-free survival (EFS) for the entire cohort was 69.1% ± 1.9%, with a range from 41.7% ± 17.3% for patients with t(9;11)-positive T-ALL (n = 9) and 64.8% ± 3.0% for patients with t(4;11)-positive B-ALL (n = 266) to 91.2% ± 4.9% for patients with t(11;19)-positive T-ALL (n = 34). Low EOI minimal residual disease was associated with favorable EFS, and induction failure was particularly predictive of nonresponse to further therapy and relapse and poor EFS. In addition, EFS was not improved by allo-HSCT compared with chemotherapy only in patients with both t(4;11)-positive B-ALL (n = 64 v 51; P = .10) and 11q23/KMT2A-rearranged T-ALL (n = 16 v 10; P = .69). CONCLUSION: Compared with historical data, prognosis of patients with noninfant 11q23/KMT2A-rearranged ALL has improved, but allo-HSCT failed to affect outcome. Targeted therapies are needed to reduce relapse and treatment-related mortality rates.
Assuntos
Produtos Biológicos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Recidiva , Estudos Retrospectivos , Translocação Genética , Cromossomos Humanos Par 11RESUMO
Background: Oral chemotherapy nonadherence is a challenge in clinical oncology. During therapy for acute lymphoblastic leukemia (ALL), poor adherence to 6-mercaptopurine (6MP) increases relapse risk. Clinically significant nonadherence is reported in 30% of children treated for ALL on Children's Oncology Group (COG) trials. Whether nonadherence rates vary across regimens with different treatment schedules and modes of administration is unknown. Methods: We conducted an exploratory, cross-sectional survey study on parents of children (1-18 years) receiving continuation therapy on, or as per Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001. Treatment required weekly visits to the clinic and 14 days of oral 6MP every 3 weeks. Survey assessed self-reported sociodemographics, medication-taking, chemotherapy comprehension, and 6MP adherence; adherence survey items were developed from published surveys. Patients were grouped as nonadherent if they endorsed missing one 6MP dose during the last cycle, or more than one dose during prior cycles, for nonmedical reasons. Results: Sixty-two families completed the surveys, all of whom had evaluable adherence data. In total, 25% of patients met the study definition of nonadherence. Twenty-three percent reported that it was "not easy" to follow administration guidelines around the dairy intake and 57% requested more teaching and educational resources. Conclusion: Self-reported nonadherence to oral 6MP in the DFCI ALL Consortium is high, with rates similar to those observed in the COG. This suggests that the additional contact during weekly infusions on the DFCI is insufficient to address barriers affecting oral chemotherapy adherence.
Assuntos
Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Mercaptopurina/uso terapêutico , Estudos Transversais , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Administração Oral , RecidivaRESUMO
Social determinants of health (SDoH) are associated with stark disparities in cancer outcomes, but systematic SDoH data collection is virtually absent from oncology clinical trials. Trial-based SDoH data are essential to ensure representation of marginalized populations, contextualize outcome disparities, and identify health-equity intervention opportunities. We report the feasibility of a pediatric oncology multicenter therapeutic trial-embedded SDoH investigation. Among 448 trial participants, 392 (87.5%) opted-in to the embedded SDoH study; 375 (95.7%) completed baseline surveys, with high longitudinal response rates (88.9-93.1%) over 24 months. Trial-embedded SDoH data collection is feasible and acceptable and must be consistently included within future oncology trials.