Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia: Results from the Phase 2/3 AALL1931 Study
Maese, Luke D; Loh, Mignon L; Choi, Mi Rim; Lin, Tong; Aoki, Etsuko; Zanette, Michelle; Agarwal, Shirali; Iannone, Robert; Silverman, Jeffrey A; Silverman, Lewis B; Raetz, Elizabeth A; Rau, Rachel E
AALL1931 (NCT04145531), 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 E. coli-derived asparaginases. Each dose of a pegylated E. coli-derived asparaginase remaining in patients' treatment plan was substituted by six doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three dosing regimens were evaluated: Cohort 1a, 25 mg/m2 MWF; Cohort 1b, 37.5 mg/m2 MWF; Cohort 1c, 25/25/50 mg/m2 MWF. The primary and key secondary efficacy outcomes were the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours as well as at 48 hours during the first treatment course, respectively. 167 patients were enrolled: Cohort 1a (n=33), 1b (n=83), and 1c (n=51). Mean SAA levels (IU/mL) at 72-hr were 0.16 for Cohort 1a, 0.33 for Cohort 1b, and 0.47 for Cohort 1c; and 0.45, 0.88, and 0.66 at 48-hr, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72-hr and 48-hr 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 (TRAEs) occurred in 86/167 (51%) patients; TRAEs leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Study results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with those of other asparaginases.
Racial and ethnic disparities in childhood and young adult acute lymphocytic leukaemia: secondary analyses of eight Children's Oncology Group cohort trials
Gupta, Sumit; Dai, Yunfeng; Chen, Zhiguo; Winestone, Lena E; Teachey, David T; Bona, Kira; Aplenc, Richard; Rabin, Karen R; Zweidler-McKay, Patrick; Carroll, Andrew J; Heerema, Nyla A; Gastier-Foster, Julie; Borowitz, Michael J; Wood, Brent L; Maloney, Kelly W; Mattano, Leonard A; Larsen, Eric C; Angiolillo, Anne L; Burke, Michael J; Salzer, Wanda L; Winter, Stuart S; Brown, Patrick A; Guest, Erin M; Dunsmore, Kimberley P; Kairalla, John A; Winick, Naomi J; Carroll, William L; Raetz, Elizabeth A; Hunger, Stephen P; Loh, Mignon L; Devidas, Meenakshi
BACKGROUND:Previous studies have identified racial and ethnic disparities in childhood acute lymphocytic leukaemia survival. We aimed to establish whether disparities persist in contemporaneous cohorts and, if present, are attributable to differences in leukaemia biology or insurance status. METHODS:Patients with newly diagnosed acute lymphocytic leukaemia in inpatient and outpatient centres in the USA, Canada, Australia, and New Zealand, aged 0-30 years, who had race or ethnicity data available, enrolled on eight completed Children's Oncology Group trials (NCT00103285, NCT00075725, NCT00408005, NCT01190930, NCT02883049, NCT02112916, NCT02828358, and NCT00557193) were included in this secondary analysis. Race and ethnicity were categorised as non-Hispanic White, Hispanic, non-Hispanic Black, non-Hispanic Asian, and non-Hispanic other. Event-free survival and overall survival were compared across race and ethnicity groups. The relative contribution of clinical and biological disease prognosticators and insurance status was examined through multivariable regression models, both among the entire cohort and among those with B-cell lineage versus T-cell lineage disease. FINDINGS/RESULTS:Between Jan 1, 2004, and Dec 31, 2019, 24 979 eligible children, adolescents, and young adults with acute lymphocytic leukaemia were enrolled, of which 21 152 had race or ethnicity data available. 11 849 (56·0%) were male and 9303 (44·0%) were female. Non-Hispanic White patients comprised the largest racial or ethnic group (13 872 [65·6%]), followed by Hispanic patients (4354 [20·6%]), non-Hispanic Black patients (1517 [7·2%]), non-Hispanic Asian (n=1071 [5·1%]), and non-Hispanic other (n=338 [1·6%]). 5-year event-free survival was 87·4% (95% CI 86·7-88·0%) among non-Hispanic White patients compared with 82·8% (81·4-84·1%; hazard ratio [HR] 1·37, 95% CI 1·26-1·49; p<0·0001) among Hispanic patients and 81·8% (79·3-84·0; HR 1·45, 1·28-1·65; p<0·0001) among non-Hispanic Black patients. Non-hispanic Asian patients had a 5-year event-free survival of 88·1% (95% CI 85·5-90·3%) and non-Hispanic other patients had a survival of 82·8% (76·4-87·6%). Inferior event-free survival among Hispanic patients was substantially attenuated by disease prognosticators and insurance status (HR decreased from 1·37 [1·26-1·49; p<0·0001] to 1·11 [1·00-1·22; p=0·045]). The increased risk among non-Hispanic Black patients was minimally attenuated (HR 1·45 [1·28-1·65; p<0·0001] to 1·32 [1·14-1·52; p<0·0001]). 5-year overall survival was 93·6% (91·5-95·1%) in non-Hispanic Asian patients, 93·3% (92·8-93·7%) in non-Hispanic White patients, 89·9% (88·7-90·9%) in Hispanic, 89·7% (87·6-91·4%) in non-Hispanic Black patients, 88·9% (83·2-92·7%) in non-Hispanic other patients. Disparities in overall survival were wider than event-free survival (eg, among non-Hispanic other patients, the HR for event-free survival was 1·43 [1·10-1·85] compared with 1·74 [1·27-2·40] for overall survival). Disparities were restricted to patients with B-cell acute lymphocytic leukaemia, no differences in event-free survival or overall survival were seen in the T-cell acute lymphocytic leukaemia group. INTERPRETATION/CONCLUSIONS:Substantial disparities in outcome for B-cell acute lymphocytic leukaemia persist by race and ethnicity, but are not observed in T-cell acute lymphocytic leukaemia. Future studies of relapsed patients, access to and quality of care, and other potential aspects of structural racism are warranted to inform interventions aimed at dismantling racial and ethnic disparities. FUNDING/BACKGROUND:National Cancer Institute and St Baldrick's Foundation.
Central Nervous System Status is Prognostic in T-Cell Acute Lymphoblastic Leukemia: A Children's Oncology Group Report
Gossai, Nathan; Devidas, Meenakshi; Chen, Zhiguo; Wood, Brent L; Zweidler-McKay, Patrick A; Rabin, Karen R; Loh, Mignon L; Raetz, Elizabeth A; Winick, Naomi J; Burke, Michael J; Carroll, Andrew J; Esiashvili, Natia; Heerema, Nyla A; Carroll, William L; Hunger, Stephen P; Dunsmore, Kimberly P; Winter, Stuart Sheldon; Teachey, David T
To determine the prognostic significance of central nervous system (CNS) leukemic involvement in newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL), outcomes on consecutive, phase 3 Children's Oncology Group (COG) clinical trials were examined. AALL0434 and AALL1231 tested efficacy of novel agents incorporated into augmented Berlin-Frankfurt-Münster (aBFM) therapy. In addition to testing study-specific chemotherapy through randomization, the AALL0434 regimen delivered cranial radiation (CRT) to the majority of subjects (90.8%), while AALL1231 intensified chemotherapy to eliminate CRT in 88.2% of subjects. In combined analysis of 2,164 T-ALL subjects (AALL0434: 1,550; AALL1231: 614), 1,564 were CNS-1 (72.3%), 441 CNS-2 (20.4%), and 159 CNS-3 (7.3%). The 4-year event-free survival (EFS) was similar for CNS-1 (85.1±1.0%) and CNS-2 (83.2±2.0%), but lower for CNS-3 (71.8±4.0%); p=0.0004. Subjects with CNS-1 and CNS-2 had similar 4-year overall-survival (OS) (90.1±0.8% and 90.5±1.5%), with OS for CNS-3 (82.7±3.4%); p=0.005. Despite therapeutic differences, outcomes for CNS-1 and CNS-2 were similar regardless of CRT, intensified corticosteroids or novel agents. Except for significantly superior outcomes with nelarabine on AALL0434 (4-year disease-free survival 93.1%±5.2%), EFS/OS was inferior with CNS-3 status, all of whom received CRT. Combined analyses of over 2,000 subjects with T-ALL, found that those with CNS-1 and CNS-2 status at diagnosis had similar outcomes. Unlike with B-ALL, CNS-2 status in T-ALL does not impact outcome in the context of aBFM therapy, without additional intrathecal therapy, with or without CRT. Although nelarabine improved outcomes for those with CNS-3 status, novel approaches are needed for further improvements.
Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia
Escherich, Carolin S; Chen, Wenan; Miyamoto, Satoshi; Namikawa, Yui; Yang, Wenjian; Teachey, David T; Li, Zhenhua; Raetz, Elizabeth A; Larsen, Eric C; Devidas, Meenakshi; Martin, Paul L; Bowman, W Paul; Wu, Gang; Pui, Ching-Hon; Hunger, Stephen P; Loh, Mignon L; Takagi, Masatoshi; Yang, Jun J
Association of Inherited Genetic Factors With Drug-Induced Hepatic Damage Among Children With Acute Lymphoblastic Leukemia
Yang, Wenjian; Karol, Seth E; Hoshitsuki, Keito; Lee, Shawn; Larsen, Eric C; Winick, Naomi; Carroll, William L; Loh, Mignon L; Raetz, Elizabeth A; Hunger, Stephen P; Winter, Stuart S; Dunsmore, Kimberly P; Devidas, Meenakshi; Relling, Mary V; Yang, Jun J
IMPORTANCE:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Hepatotoxic effects, including hyperbilirubinemia and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, are common during all phases of therapy and are linked to several chemotherapeutic agents, including asparaginase, mercaptopurine, and methotrexate. OBJECTIVE:To determine which genetic variants were associated with hyperbilirubinemia and elevated ALT and AST levels in children, adolescents, and young adults treated for ALL. DESIGN, SETTING, AND PARTICIPANTS:This retrospective analysis of a multiethnic genome-wide association study was conducted between January 1, 2019, and April 15, 2022, including patients treated as part of Children's Oncology Group (COG) trials with centers in the United States, Canada, and Australia, which accrued data from December 29, 2003, to January 21, 2011 (AALL0232), and from January 22, 2007, to July 24, 2014 (AALL0434). Germline genotypes were interrogated using genome-wide arrays and imputed using a National Institutes of Health TOPMed Imputation server. Mixed-effects logistic regressions were used to account for multiple episodes for an individual patient. Genotype × treatment phase interaction was tested to uncover phase-specific genetic risk factors. EXPOSURES:Total duration of multiagent protocol chemotherapy ranging from 2.5 to 3.5 years. MAIN OUTCOMES AND MEASURES:The primary outcomes were National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) hyperbilirubinemia of grade 3 or higher and elevated liver ALT and AST levels. RESULTS:A total of 3557 participants were included in the analysis (2179 [61.3%] male; median age, 11.1 [range, 1-30] years). Among 576 known variants associated with these liver function test results in the general population, UGT1A1 variant rs887829 and PNPLA3 variant rs738409 were associated with increased risk of hyperbilirubinemia (odds ratio [OR], 2.18 [95% CI, 1.89-2.53]; P = 6.7 × 10-27) and ALT and AST levels (OR, 1.27 [95% CI, 1.15-1.40]; P = 3.7 × 10-7), respectively, during treatment for ALL. Corresponding polygenic risk scores were associated with hepatotoxic effects across all therapy phases and were largely driven by UGT1A1 and PNPLA3 variants. Genome-wide association analysis revealed an age-specific variant near the CPT1A gene that was only associated with elevated ALT and AST levels among patients younger than 10 years (OR, 1.28 [95% CI, 1.18-1.39]; P = 8.7 × 10-10). CONCLUSIONS AND RELEVANCE:These results suggest a strong genetic basis for interpatient variability in hyperbilirubinemia and aminotransferase level elevations during leukemia chemotherapy.
Improving infectious adverse event reporting for children and adolescents enrolled in clinical trials for acute lymphoblastic leukemia: A report from the Children's Oncology Group
Elgarten, Caitlin W; Thompson, Joel C; Angiolillo, Anne; Chen, Zhiguo; Conway, Susan; Devidas, Meenakshi; Gupta, Sumit; Kairalla, John A; McNeer, Jennifer L; O'Brien, Maureen M; Rabin, Karen R; Rau, Rachel E; Rheingold, Susan R; Wang, Cindy; Wood, Charlotte; Raetz, Elizabeth A; Loh, Mignon L; Alexander, Sarah; Miller, Tamara P
Infections cause substantial morbidity for children with acute lymphoblastic leukemia (ALL). Therefore, accurate characterization of infectious adverse events (AEs) reported on clinical trials is imperative to defining, comparing, and managing safety and toxicity. Here, we describe key processes implemented to improve reporting of infectious AEs on two active phase III Children's Oncology Group (COG) ALL trials. Processes include: (a) identifying infections as a targeted toxicity, (b) incorporation of infection-specific case report form questions, and (c) physician review of AEs with real-time data cleaning. Preliminary assessment of these processes suggests improved reporting, as well as opportunities for further improvement.
How do mTOR inhibitors fit in the relapsed acute lymphoblastic leukemia treatment landscape?
Pinchinat, Ashley; Raetz, Elizabeth
Molecular mechanisms of ARID5B-mediated genetic susceptibility to acute lymphoblastic leukemia
Zhao, Xujie; Qian, Maoxiang; Goodings, Charnise; Zhang, Yang; Yang, Wenjian; Wang, Ping; Xu, Beisi; Tian, Cheng; Pui, Ching-Hon; Hunger, Stephen P; Raetz, Elizabeth A; Devidas, Meenakshi; Relling, Mary V; Loh, Mignon L; Savic, Daniel; Li, Chunliang; Yang, Jun J
BACKGROUND:There is growing evidence for the inherited basis of susceptibility to childhood acute lymphoblastic leukemia (ALL). Genome-wide association studies have identified non-coding ALL risk variants at the ARID5B gene locus, but their exact functional effects and the molecular mechanism linking ARID5B to B-ALL leukemogenesis remain largely unknown. METHODS:We performed targeted sequencing of ARID5B in germline DNA of 5,008 children with ALL. Variants were evaluated for association with ALL susceptibility using 3,644 subjects from the UK10K cohort as non-ALL controls, under an additive model. Cis-regulatory elements in ARID5B were systematically identified using CRISPRi enhancer screen in ALL cells. Disruption of transcription factor binding by ARID5B variant was predicted informatically and then confirmed using chromatin immunoprecipitation and co-immunoprecipitation. ARID5B variant association with hematological traits was examined using UK Biobank dataset. All statistical tests are two-sided. RESULTS:We identified 54 common variants in ARID5B significantly associated with leukemia risk, all of which were non-coding. Six cis-regulatory elements at the ARID5B locus were discovered using CRISPR-based high-throughput enhancer screening. Strikingly, the top ALL risk variant (rs7090445, P=5.57â€‰Ã—â€‰10-45) is located precisely within the strongest enhancer element, which is also distally tethered to the ARID5B promoter. The variant allele disrupts the MEF2C binding motif sequence, resulting in reduced MEF2C affinity and decreased local chromosome accessibility. MEF2C influences ARID5B expression in ALL, likely via a transcription factor complex with RUNX1. Using the UK Biobank dataset (nâ€‰=â€‰349,861), we showed that rs7090445 was also associated with lymphocyte percentage and count in the general population (P=8.6â€‰Ã—â€‰10-22 and 2.1â€‰Ã—â€‰10-18, respectively). CONCLUSION/CONCLUSIONS:Our results indicate that ALL risk variants in ARID5B function by modulating cis-regulatory elements at this locus.
The genomic landscape of pediatric acute lymphoblastic leukemia
Brady, Samuel W; Roberts, Kathryn G; Gu, Zhaohui; Shi, Lei; Pounds, Stanley; Pei, Deqing; Cheng, Cheng; Dai, Yunfeng; Devidas, Meenakshi; Qu, Chunxu; Hill, Ashley N; Payne-Turner, Debbie; Ma, Xiaotu; Iacobucci, Ilaria; Baviskar, Pradyuamna; Wei, Lei; Arunachalam, Sasi; Hagiwara, Kohei; Liu, Yanling; Flasch, Diane A; Liu, Yu; Parker, Matthew; Chen, Xiaolong; Elsayed, Abdelrahman H; Pathak, Omkar; Li, Yongjin; Fan, Yiping; Michael, J Robert; Rusch, Michael; Wilkinson, Mark R; Foy, Scott; Hedges, Dale J; Newman, Scott; Zhou, Xin; Wang, Jian; Reilly, Colleen; Sioson, Edgar; Rice, Stephen V; Pastor Loyola, Victor; Wu, Gang; Rampersaud, Evadnie; Reshmi, Shalini C; Gastier-Foster, Julie; Guidry Auvil, Jaime M; Gesuwan, Patee; Smith, Malcolm A; Winick, Naomi; Carroll, Andrew J; Heerema, Nyla A; Harvey, Richard C; Willman, Cheryl L; Larsen, Eric; Raetz, Elizabeth A; Borowitz, Michael J; Wood, Brent L; Carroll, William L; Zweidler-McKay, Patrick A; Rabin, Karen R; Mattano, Leonard A; Maloney, Kelly W; Winter, Stuart S; Burke, Michael J; Salzer, Wanda; Dunsmore, Kimberly P; Angiolillo, Anne L; Crews, Kristine R; Downing, James R; Jeha, Sima; Pui, Ching-Hon; Evans, William E; Yang, Jun J; Relling, Mary V; Gerhard, Daniela S; Loh, Mignon L; Hunger, Stephen P; Zhang, Jinghui; Mullighan, Charles G
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754â€‰childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376â€‰putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70â€‰putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosomeâ€‰21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.
Persistence of chemotherapy-induced peripheral neuropathy despite vincristine reduction in childhood b-acute lymphoblastic leukemia
Rodwin, Rozalyn L; Kairalla, John A; Hibbitts, Emily; Devidas, Meenakshi; Whitley, Moira K; Mohrmann, Caroline E; Schore, Reuven J; Raetz, Elizabeth; Winick, Naomi J; Hunger, Stephen P; Loh, Mignon L; Hockenberry, Marilyn J; Angiolillo, Anne L; Ness, Kirsten K; Kadan-Lottick, Nina S
BACKGROUND:Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine/dexamethasone (every 4-week [VCR/DEX4] vs. 12-week [VCR/DEX12]) during maintenance in the average-risk subset of NCI standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall, and by treatment group. METHODS:AALL0932â€‰SR AR B-ALL patients â‰¥3â€‰years old were evaluated at T1-T4 (end-consolidation, maintenance month-1, maintenance month-18, 12-months post-therapy). Physical/occupational therapists (PT/OT) measured motor CIPN (hand/ankle strength, dorsiflexion/plantarflexion range of motion [ROM]), sensory CIPN (finger/toe vibration and touch), and function (dexterity [Purdue Pegboard], walking efficiency [Six Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age/sex matched Z-scores and proportion impaired were measured longitudinally and compared between groups. RESULTS:Consent and data were obtained from 150 participants (mean age 5.1â€‰years [SDâ€‰=â€‰1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (p<.001) and walking efficiency (p=.02) improved from T1-T4 and only dorsiflexion ROM (46.7% vs. 14.7%, p=.008) and handgrip strength (22.2% vs. 37.1%, p=.03) differed in VCR/DEX4 vs. VCR/DEX12 at T4. Proxy-reported outcomes improved from T1 to T4 (P<.001) and most did not differ between groups. CONCLUSIONS:CIPN is prevalent early in B-ALL therapy and persists at least 12-months post-therapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.