Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia

Summary

The primary objective of this study (TOTXVI) is to compare the clinical benefit, the pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG) asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in conventional dose (CD PEG) during the continuation phase. This study has several secondary objectives: Therapeutic Objectives: To estimate the event-free survival and overall survival of children with ALL who are treated with risk-directed therapy. To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 MRD \> 5%, will result in improved leukemia cytoreduction in this subgroup compared to TOTXV. To assess whether intensification of central nervous system (CNS)-directed intrathecal and systemic chemotherapy will improve outcome in patients at high risk of CNS relapse. Exploratory Pharmacologic Objectives: To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol. To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose (3,500 or 3,000 units/m2) versus those of PEG-asparaginase given in conventional dose (2,500 units/m2) in the continuation phase. Exploratory Biologic Objectives: To determine the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of remission induction. To validate new markers and methods for MRD detection. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and before reinduction, and to associate these features with treatment outcome. To identify new prognostic factors by applying new technologies to study patient material (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells). Exploratory Neuroimaging Objectives: To use quantitative MR measures (Diffusion Tensor Imaging and high resolution volumetric imaging) to assess differences in myelin and cortical thickness development in patients treated for ALL relative to healthy controls matched for age and gender. To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness development and neurocognitive performance. To assess the impact of frontal-parietal lobe myelin and cortical thickness development on neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning and processing speed.

Timeline

Start

2007-10-29

Primary completion

2020-09-26

Completion

2022-03-26

Publications

• Purvis K, Zhou Y, Karol SE, Rubnitz JE, Ribeiro RC, Lee S, Yang JJ, Bowman WP, Wang L, Dixon SB, Roberts KG, Gao Q, Cheng C, Mullighan CG, Jeha S, Pui CH, Inaba H. Outcomes in patients with ETV6::RUNX1 or high-hyperdiploid B-ALL treated in the St. Jude Total Therapy XV/XVI studies. Blood. 2025 Jan 9;145(2):190-201. doi: 10.1182/blood.2024024936.
• Chang TC, Chen W, Qu C, Cheng Z, Hedges D, Elsayed A, Pounds SB, Shago M, Rabin KR, Raetz EA, Devidas M, Cheng C, Angiolillo A, Baviskar P, Borowitz M, Burke MJ, Carroll A, Carroll WL, Chen IM, Harvey R, Heerema N, Iacobucci I, Wang JR, Jeha S, Larsen E, Mattano L, Maloney K, Pui CH, Ramirez NC, Salzer W, Willman C, Winick N, Wood B, Hunger SP, Wu G, Mullighan CG, Loh ML. Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia. J Clin Oncol. 2024 Oct 10;42(29):3491-3503. doi: 10.1200/JCO.23.02238. Epub 2024 Aug 9.
• Panetta JC, Liu Y, Bottiglieri T, Arning E, Cheng C, Karol SE, Yang JJ, Zhou Y, Inaba H, Pui CH, Jeha S, Relling MV. Pharmacodynamics of cerebrospinal fluid asparagine after asparaginase. Cancer Chemother Pharmacol. 2021 Oct;88(4):655-664. doi: 10.1007/s00280-021-04315-0. Epub 2021 Jun 25.
• Finch ER, Smith CA, Yang W, Liu Y, Kornegay NM, Panetta JC, Crews KR, Molinelli AR, Cheng C, Pei D, Ramsey LB, Karol SE, Inaba H, Sandlund JT, Metzger M, Evans WE, Jeha S, Pui CH, Relling MV. Asparaginase formulation impacts hypertriglyceridemia during therapy for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2020 Jan;67(1):e28040. doi: 10.1002/pbc.28040. Epub 2019 Oct 14.
• Liu Y, Smith CA, Panetta JC, Yang W, Thompson LE, Counts JP, Molinelli AR, Pei D, Kornegay NM, Crews KR, Swanson H, Cheng C, Karol SE, Evans WE, Inaba H, Pui CH, Jeha S, Relling MV. Antibodies Predict Pegaspargase Allergic Reactions and Failure of Rechallenge. J Clin Oncol. 2019 Aug 10;37(23):2051-2061. doi: 10.1200/JCO.18.02439. Epub 2019 Jun 12.
• Hakim H, Dallas R, Wolf J, Tang L, Schultz-Cherry S, Darling V, Johnson C, Karlsson EA, Chang TC, Jeha S, Pui CH, Sun Y, Pounds S, Hayden RT, Tuomanen E, Rosch JW. Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia. Clin Infect Dis. 2018 Aug 1;67(4):541-548. doi: 10.1093/cid/ciy153.
• Wolf J, Tang L, Flynn PM, Pui CH, Gaur AH, Sun Y, Inaba H, Stewart T, Hayden RT, Hakim H, Jeha S. Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia. Clin Infect Dis. 2017 Nov 13;65(11):1790-1798. doi: 10.1093/cid/cix644.
• Bhojwani D, Darbandi R, Pei D, Ramsey LB, Chemaitilly W, Sandlund JT, Cheng C, Pui CH, Relling MV, Jeha S, Metzger ML. Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer. 2014 Oct;50(15):2685-94. doi: 10.1016/j.ejca.2014.06.023. Epub 2014 Jul 30.
• Fernandez CA, Smith C, Yang W, Date M, Bashford D, Larsen E, Bowman WP, Liu C, Ramsey LB, Chang T, Turner V, Loh ML, Raetz EA, Winick NJ, Hunger SP, Carroll WL, Onengut-Gumuscu S, Chen WM, Concannon P, Rich SS, Scheet P, Jeha S, Pui CH, Evans WE, Devidas M, Relling MV. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014 Aug 21;124(8):1266-76. doi: 10.1182/blood-2014-03-563742. Epub 2014 Jun 26.

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