Newly-diagnosed Pediatric T-cell ALL Protocol

Summary

This is a prospective, multicenter study conducted within the Chinese Children's Cancer Group (CCCG). The study aims to evaluate whether the addition of three novel agents, dasatinib, venetoclax and homoharringtonine, can improve the minimal residual disease (MRD)-negative remission rate, enhance event-free survival (EFS), and reduce the cumulative incidence of relapse (CIR) in pediatric patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).

Timeline

Start

2025-03-11

Primary completion

2030-06

Completion

2031-06

Publications

• Background Teachey DT, Devidas M, Wood BL, Chen Z, Hayashi RJ, Hermiston ML, Annett RD, Archer JH, Asselin BL, August KJ, Cho SY, Dunsmore KP, Fisher BT, Freedman JL, Galardy PJ, Harker-Murray P, Horton TM, Jaju AI, Lam A, Messinger YH, Miles RR, Okada M, Patel SI, Schafer ES, Schechter T, Singh N, Steele AC, Sulis ML, Vargas SL, Winter SS, Wood C, Zweidler-McKay P, Bollard CM, Loh ML, Hunger SP, Raetz EA. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022 Jul 1;40(19):2106-2118. doi: 10.1200/JCO.21.02678. Epub 2022 Mar 10.
• Background Raetz EA, Rebora P, Conter V, Schrappe M, Devidas M, Escherich G, Imai C, De Moerloose B, Schmiegelow K, Burns MA, Elitzur S, Pieters R, Attarbaschi A, Yeoh A, Pui CH, Stary J, Cario G, Bodmer N, Moorman AV, Buldini B, Vora A, Valsecchi MG. Outcome for Children and Young Adults With T-Cell ALL and Induction Failure in Contemporary Trials. J Clin Oncol. 2023 Nov 10;41(32):5025-5034. doi: 10.1200/JCO.23.00088. Epub 2023 Jul 24.
• Background Polonen P, Di Giacomo D, Seffernick AE, Elsayed A, Kimura S, Benini F, Montefiori LE, Wood BL, Xu J, Chen C, Cheng Z, Newman H, Myers J, Iacobucci I, Li E, Sussman J, Hedges D, Hui Y, Diorio C, Uppuluri L, Frank D, Fan Y, Chang Y, Meshinchi S, Ries R, Shraim R, Li A, Bernt KM, Devidas M, Winter SS, Dunsmore KP, Inaba H, Carroll WL, Ramirez NC, Phillips AH, Kriwacki RW, Yang JJ, Vincent TL, Zhao Y, Ghate PS, Wang J, Reilly C, Zhou X, Sanders MA, Takita J, Kato M, Takasugi N, Chang BH, Press RD, Loh M, Rampersaud E, Raetz E, Hunger SP, Tan K, Chang TC, Wu G, Pounds SB, Mullighan CG, Teachey DT. The genomic basis of childhood T-lineage acute lymphoblastic leukaemia. Nature. 2024 Aug;632(8027):1082-1091. doi: 10.1038/s41586-024-07807-0. Epub 2024 Aug 14.
• Background He Y, Zhang J, Zhang Y, Hu Z, Wang P, Gan W, Xie S, Qian M, Pui CH, Jiang H, Zhu X, Zhang H, Zhang W. Dasatinib-therapy induced sustained remission in a child with refractory TCF7-SPI1 T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer. 2022 Aug;69(8):e29724. doi: 10.1002/pbc.29724. Epub 2022 Apr 20.
• Background Simonin M, Vasseur L, Lengline E, Lhermitte L, Cabannes-Hamy A, Balsat M, Schmidt A, Dourthe ME, Touzart A, Graux C, Grardel N, Cayuela JM, Arnoux I, Gandemer V, Huguet F, Ducassou S, Lheritier V, Chalandon Y, Ifrah N, Dombret H, Macintyre E, Petit A, Rousselot P, Lambert J, Baruchel A, Boissel N, Asnafi V. NGS-based stratification refines the risk stratification in T-ALL and identifies a very-high-risk subgroup of patients. Blood. 2024 Oct 10;144(15):1570-1580. doi: 10.1182/blood.2023023754.
• Background Teachey DT, O'Connor D. How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children. Blood. 2020 Jan 16;135(3):159-166. doi: 10.1182/blood.2019001557.
• Background Summers RJ, Teachey DT, Hunger SP. How I treat ETP-ALL in children. Blood. 2025 Jan 2;145(1):43-52. doi: 10.1182/blood.2023023155.
• Background Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C, Moorman AV, Wade R. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014 Jul;15(8):809-18. doi: 10.1016/S1470-2045(14)70243-8. Epub 2014 Jun 9.
• Background Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke A, Parasole R, Zimmermann M, Dworzak M, Buldini B, Reiter A, Basso G, Klingebiel T, Messina C, Ratei R, Cazzaniga G, Koehler R, Locatelli F, Schafer BW, Arico M, Welte K, van Dongen JJ, Gadner H, Biondi A, Conter V. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011 Aug 25;118(8):2077-84. doi: 10.1182/blood-2011-03-338707. Epub 2011 Jun 30.
• Background Suo S, Zhao D, Li F, Zhang Y, Rodriguez-Rodriguez S, Nguyen LXT, Ghoda L, Carlesso N, Marcucci G, Zhang B, Jin J. Homoharringtonine inhibits the NOTCH/MYC pathway and exhibits antitumor effects in T-cell acute lymphoblastic leukemia. Blood. 2024 Sep 19;144(12):1343-1347. doi: 10.1182/blood.2023023400.
• Background Chen R, Guo L, Chen Y, Jiang Y, Wierda WG, Plunkett W. Homoharringtonine reduced Mcl-1 expression and induced apoptosis in chronic lymphocytic leukemia. Blood. 2011 Jan 6;117(1):156-64. doi: 10.1182/blood-2010-01-262808. Epub 2010 Oct 22.
• Background Chen XJ, Zhang WN, Chen B, Xi WD, Lu Y, Huang JY, Wang YY, Long J, Wu SF, Zhang YX, Wang S, Li SX, Yin T, Lu M, Xi XD, Li JM, Wang KK, Chen Z, Chen SJ. Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-kappaB repressing factor. Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2220-2225. doi: 10.1073/pnas.1818539116. Epub 2019 Jan 18.
• Background Lu S, Wang J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. J Hematol Oncol. 2014 Jan 3;7:2. doi: 10.1186/1756-8722-7-2.
• Background Saygin C, Giordano G, Shimamoto K, Eisfelder B, Thomas-Toth A, Venkataraman G, Ananthanarayanan V, Vincent TL, DuVall A, Patel AA, Chen Y, Tan F, Anthony SP, Chen Y, Shen Y, Odenike O, Teachey DT, Kee BL, LaBelle J, Stock W. Dual Targeting of Apoptotic and Signaling Pathways in T-Lineage Acute Lymphoblastic Leukemia. Clin Cancer Res. 2023 Aug 15;29(16):3151-3161. doi: 10.1158/1078-0432.CCR-23-0415.
• Background Shi Y, Beckett MC, Blair HJ, Tirtakusuma R, Nakjang S, Enshaei A, Halsey C, Vormoor J, Heidenreich O, Krippner-Heidenreich A, van Delft FW. Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia. Haematologica. 2021 Apr 1;106(4):1056-1066. doi: 10.3324/haematol.2019.241026.
• Background Yoshimura S, Panetta JC, Hu J, Li L, Gocho Y, Du G, Umezawa A, Karol SE, Pui CH, Mullighan CG, Konopleva M, Stock W, Teachey DT, Jain N, Yang JJ. Preclinical pharmacokinetic and pharmacodynamic evaluation of dasatinib and ponatinib for the treatment of T-cell acute lymphoblastic leukemia. Leukemia. 2023 Jun;37(6):1194-1203. doi: 10.1038/s41375-023-01900-5. Epub 2023 Apr 19.
• Background Gocho Y, Liu J, Hu J, Yang W, Dharia NV, Zhang J, Shi H, Du G, John A, Lin TN, Hunt J, Huang X, Ju B, Rowland L, Shi L, Maxwell D, Smart B, Crews KR, Yang W, Hagiwara K, Zhang Y, Roberts K, Wang H, Jabbour E, Stock W, Eisfelder B, Paietta E, Newman S, Roti G, Litzow M, Easton J, Zhang J, Peng J, Chi H, Pounds S, Relling MV, Inaba H, Zhu X, Kornblau S, Pui CH, Konopleva M, Teachey D, Mullighan CG, Stegmaier K, Evans WE, Yu J, Yang JJ. Network-based systems pharmacology reveals heterogeneity in LCK and BCL2 signaling and therapeutic sensitivity of T-cell acute lymphoblastic leukemia. Nat Cancer. 2021 Mar;2(3):284-299. doi: 10.1038/s43018-020-00167-4. Epub 2021 Jan 21.
• Background Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response. Nat Med. 2023 Jan;29(1):170-179. doi: 10.1038/s41591-022-02112-7. Epub 2023 Jan 5.
• Background Chonghaile TN, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB, Loh ML, Hunger SP, Wood B, DeAngelo DJ, Stone R, Harris M, Gutierrez A, Kelliher MA, Letai A. Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov. 2014 Sep;4(9):1074-87. doi: 10.1158/2159-8290.CD-14-0353. Epub 2014 Jul 3.
• Background Borah P, Dayal N, Pathak S, Naithani R. Short-course Venetoclax With Standard Chemotherapy Is Effective in Early T-cell Precursor Acute Lymphoblastic Leukemia. J Pediatr Hematol Oncol. 2023 Jul 1;45(5):271-274. doi: 10.1097/MPH.0000000000002672. Epub 2023 Apr 4.
• Background Richard-Carpentier G, Jabbour E, Short NJ, Rausch CR, Savoy JM, Bose P, Yilmaz M, Jain N, Borthakur G, Ohanian M, Alvarado Y, Rytting M, Kebriaei P, Konopleva M, Kantarjian H, Ravandi F. Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk. 2020 Apr;20(4):212-218. doi: 10.1016/j.clml.2019.09.608. Epub 2019 Sep 30.
• Background Gibson A, Trabal A, McCall D, Khazal S, Toepfer L, Bell DH, Roth M, Mahadeo KM, Nunez C, Short NJ, DiNardo C, Konopleva M, Issa GC, Ravandi F, Jain N, Borthakur G, Kantarjian HM, Jabbour E, Cuglievan B. Venetoclax for Children and Adolescents with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Cancers (Basel). 2021 Dec 29;14(1):150. doi: 10.3390/cancers14010150.
• Background Davids MS, Letai A. Targeting the B-cell lymphoma/leukemia 2 family in cancer. J Clin Oncol. 2012 Sep 1;30(25):3127-35. doi: 10.1200/JCO.2011.37.0981. Epub 2012 May 29.
• Background Moricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Arico M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rossig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. doi: 10.1182/blood-2015-09-670729. Epub 2016 Feb 17.
• Background Campbell M, Kiss C, Zimmermann M, Riccheri C, Kowalczyk J, Felice MS, Kuzmanovic M, Kovacs G, Kosmidis H, Gonzalez A, Bilic E, Castillo L, Kolenova A, Jazbec J, Popa A, Konstantinov D, Kappelmayer J, Szczepanski T, Dworzak M, Buldini B, Gaipa G, Marinov N, Rossi J, Nagy A, Gaspar I, Stary J, Schrappe M. Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Munster 2009 Trial. J Clin Oncol. 2023 Jul 1;41(19):3499-3511. doi: 10.1200/JCO.22.01760. Epub 2023 May 4.
• Background Patrick K, Wade R, Goulden N, Mitchell C, Moorman AV, Rowntree C, Jenkinson S, Hough R, Vora A. Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol. 2014 Aug;166(3):421-4. doi: 10.1111/bjh.12882. Epub 2014 Apr 8.
• Background Wood BL, Devidas M, Summers RJ, Chen Z, Asselin B, Rabin KR, Zweidler-McKay PA, Winick NJ, Borowitz MJ, Carroll WL, Raetz EA, Loh ML, Hunger SP, Dunsmore KP, Teachey DT, Winter SS. Prognostic significance of ETP phenotype and minimal residual disease in T-ALL: a Children's Oncology Group study. Blood. 2023 Dec 14;142(24):2069-2078. doi: 10.1182/blood.2023020678.
• Background Morita K, Jain N, Kantarjian H, Takahashi K, Fang H, Konopleva M, El Hussein S, Wang F, Short NJ, Maiti A, Sasaki K, Garcia-Manero G, Konoplev S, Ravandi F, Khoury JD, Jabbour E. Outcome of T-cell acute lymphoblastic leukemia/lymphoma: Focus on near-ETP phenotype and differential impact of nelarabine. Am J Hematol. 2021 May 1;96(5):589-598. doi: 10.1002/ajh.26144. Epub 2021 Mar 18.
• Background Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, Cheng C, Su X, Rubnitz JE, Basso G, Biondi A, Pui CH, Downing JR, Campana D. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009 Feb;10(2):147-56. doi: 10.1016/S1470-2045(08)70314-0. Epub 2009 Jan 13.
• Background Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, McCastlain K, Edmonson M, Pounds SB, Shi L, Zhou X, Ma X, Sioson E, Li Y, Rusch M, Gupta P, Pei D, Cheng C, Smith MA, Guidry Auvil JM, Gerhard DS, Relling MV, Winick NJ, Carroll AJ, Heerema NA, Raetz E, Devidas M, Willman CL, Harvey RC, Carroll WL, Dunsmore KP, Winter SS, Wood BL, Sorrentino BP, Downing JR, Loh ML, Hunger SP, Zhang J, Mullighan CG. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017 Aug;49(8):1211-1218. doi: 10.1038/ng.3909. Epub 2017 Jul 3.
• Background Bongiovanni D, Saccomani V, Piovan E. Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia. Int J Mol Sci. 2017 Sep 5;18(9):1904. doi: 10.3390/ijms18091904.
• Background Girardi T, Vicente C, Cools J, De Keersmaecker K. The genetics and molecular biology of T-ALL. Blood. 2017 Mar 2;129(9):1113-1123. doi: 10.1182/blood-2016-10-706465. Epub 2017 Jan 23.
• Background Teachey DT, Pui CH. Comparative features and outcomes between paediatric T-cell and B-cell acute lymphoblastic leukaemia. Lancet Oncol. 2019 Mar;20(3):e142-e154. doi: 10.1016/S1470-2045(19)30031-2.
• Background Inaba H, Mullighan CG. Pediatric acute lymphoblastic leukemia. Haematologica. 2020 Nov 1;105(11):2524-2539. doi: 10.3324/haematol.2020.247031.
• Background Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in Children. N Engl J Med. 2015 Oct 15;373(16):1541-52. doi: 10.1056/NEJMra1400972. No abstract available.

Drugs

Indications