Kimberly P Dunsmore1, Stuart S Winter2, Meenakshi Devidas3, Brent L Wood4, Natia Esiashvili5, Zhiguo Chen6, Nancy Eisenberg7, Nikki Briegel8, Robert J Hayashi9, Julie M Gastier-Foster10,11, Andrew J Carroll12, Nyla A Heerema11, Barbara L Asselin13, Karen R Rabin14, Patrick A Zweidler-Mckay15, Elizabeth A Raetz16, Mignon L Loh17, Kirk R Schultz18, Naomi J Winick19, William L Carroll16, Stephen P Hunger20. 1. Virginia Tech Carilion School of Medicine and Carilion Clinic, Roanoke, VA. 2. Children's Minnesota Cancer and Blood Disorders Program, Minneapolis, MN. 3. Department of Global Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN. 4. Laboratory Medicine, Seattle Children's Hospital, Seattle, WA. 5. Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA. 6. Department of Biostatistics, Colleges of Medicine and Public Health and Health Professions, University of Florida, Gainesville, FL. 7. Pediatric Hematology/Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM. 8. Pharmacy Department, Perth Children's Hospital, Nedlands, Western Australia, Australia. 9. Pediatric Hematology/Oncology, Washington School of Medicine, St Louis Children's Hospital, St Louis, MO. 10. Nationwide Children's Hospital, Columbus OH. 11. Department of Pathology, The Ohio State University, Columbus, OH. 12. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL. 13. Department of Pediatrics, University of Rochester Medical Center and Wilmot Cancer Institute, Rochester, NY. 14. Pediatric Hematology/Oncology, Baylor College of Medicine/Dan L. Duncan Comprehensive Cancer Center, Houston TX. 15. ImmunoGen, Waltham, MA. 16. Laura and Isaac Perlmutter Cancer Center at New York University Langone Health, New York, NY. 17. Department of Pediatrics, University of California, San Francisco Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA. 18. Pediatric Hematology-Oncology, British Columbia Children's Hospital, Vancouver, British Columbia, Canada. 19. Pediatric Hematology/Oncology, University of Texas Southwestern/Simmons Cancer Center, Dallas, TX. 20. Department of Pediatrics and The Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Abstract
PURPOSE:Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receiveescalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) receivedHDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
RCT Entities:
PURPOSE:Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. PATIENTS AND METHODS: From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. RESULTS: The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. CONCLUSION: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.
Authors: Teresa Palomero; Duncan T Odom; Jennifer O'Neil; Adolfo A Ferrando; Adam Margolin; Donna S Neuberg; Stuart S Winter; Richard S Larson; Wei Li; X Shirley Liu; Richard A Young; A Thomas Look Journal: Blood Date: 2006-04-18 Impact factor: 22.113
Authors: Kimberly P Dunsmore; Meenakshi Devidas; Stephen B Linda; Michael J Borowitz; Naomi Winick; Stephen P Hunger; William L Carroll; Bruce M Camitta Journal: J Clin Oncol Date: 2012-06-25 Impact factor: 44.544
Authors: Stuart S Winter; Kimberly P Dunsmore; Meenakshi Devidas; Brent L Wood; Natia Esiashvili; Zhiguo Chen; Nancy Eisenberg; Nikki Briegel; Robert J Hayashi; Julie M Gastier-Foster; Andrew J Carroll; Nyla A Heerema; Barbara L Asselin; Paul S Gaynon; Michael J Borowitz; Mignon L Loh; Karen R Rabin; Elizabeth A Raetz; Patrick A Zweidler-Mckay; Naomi J Winick; William L Carroll; Stephen P Hunger Journal: J Clin Oncol Date: 2018-08-23 Impact factor: 44.544
Authors: J Kurtzberg; T J Ernst; M J Keating; V Gandhi; J P Hodge; D F Kisor; J J Lager; C Stephens; J Levin; T Krenitsky; G Elion; B S Mitchell Journal: J Clin Oncol Date: 2005-05-20 Impact factor: 44.544
Authors: Eric C Larsen; Meenakshi Devidas; Si Chen; Wanda L Salzer; Elizabeth A Raetz; Mignon L Loh; Leonard A Mattano; Catherine Cole; Alisa Eicher; Maureen Haugan; Mark Sorenson; Nyla A Heerema; Andrew A Carroll; Julie M Gastier-Foster; Michael J Borowitz; Brent L Wood; Cheryl L Willman; Naomi J Winick; Stephen P Hunger; William L Carroll Journal: J Clin Oncol Date: 2016-04-25 Impact factor: 44.544
Authors: Daniel J DeAngelo; Daohai Yu; Jeffrey L Johnson; Steven E Coutre; Richard M Stone; Alison T Stopeck; Jon P Gockerman; Beverly S Mitchell; Frederick R Appelbaum; Richard A Larson Journal: Blood Date: 2007-03-07 Impact factor: 22.113
Authors: Martin Schrappe; Stephen P Hunger; Ching-Hon Pui; Vaskar Saha; Paul S Gaynon; André Baruchel; Valentino Conter; Jacques Otten; Akira Ohara; Anne Birgitta Versluys; Gabriele Escherich; Mats Heyman; Lewis B Silverman; Keizo Horibe; Georg Mann; Bruce M Camitta; Jochen Harbott; Hansjörg Riehm; Sue Richards; Meenakshi Devidas; Martin Zimmermann Journal: N Engl J Med Date: 2012-04-12 Impact factor: 91.245
Authors: Roberta Taiane Germano de Oliveira; João Victor Alves Cordeiro; Bruna Ferreira Vitoriano; Mayara Magna de Lima Melo; Letícia Rodrigues Sampaio; Daniela de Paula Borges; Silvia Maria Meira Magalhães; Ronald Feitosa Pinheiro Journal: Med Oncol Date: 2021-02-17 Impact factor: 3.064
Authors: Xinjie Xu; Christian N Paxton; Robert J Hayashi; Kimberly P Dunsmore; Stuart S Winter; Stephen P Hunger; Naomi J Winick; William L Carroll; Mignon L Loh; Meenakshi Devidas; Thomas G Gross; Catherine M Bollard; Sherrie L Perkins; Rodney R Miles Journal: Blood Adv Date: 2021-07-27
Authors: Patrick A Brown; Lingyun Ji; Xinxin Xu; Meenakshi Devidas; Laura E Hogan; Michael J Borowitz; Elizabeth A Raetz; Gerhard Zugmaier; Elad Sharon; Melanie B Bernhardt; Stephanie A Terezakis; Lia Gore; James A Whitlock; Michael A Pulsipher; Stephen P Hunger; Mignon L Loh Journal: JAMA Date: 2021-03-02 Impact factor: 56.272
Authors: Sima Jeha; John Choi; Kathryn G Roberts; Deqing Pei; Elaine Coustan-Smith; Hiroto Inaba; Jeffrey E Rubnitz; Raul C Ribeiro; Tanja A Gruber; Susana C Raimondi; Seth E Karol; Chunxu Qu; Samuel W Brady; Zhaohui Gu; Jun J Yang; Cheng Cheng; James R Downing; Williams E Evans; Mary V Relling; Dario Campana; Charles G Mullighan; Ching-Hon Pui Journal: Blood Cancer Discov Date: 2021-07
Authors: Wenjian Yang; Meenakshi Devidas; Yiwei Liu; Colton Smith; Yunfeng Dai; Naomi Winick; Stephen P Hunger; Mignon L Loh; Elizabeth A Raetz; Eric C Larsen; William L Carroll; Stuart S Winter; Kimberly P Dunsmore; Leonard A Mattano; Mary V Relling; Seth E Karol Journal: Blood Date: 2021-03-18 Impact factor: 22.113