Thiopurine EnhAnced Maintenance Therapy

Summary

Acute Lymphoblastic Leukaemia (ALL) is the most frequent cancer in children. The survival rate has improved significantly during the last decades, but the treatment still fails to cure 15 % of the patients. Within the Nordic/Baltic countries, children are treated according to the same protocol, i.e. NOPHO ALL-2008 protocol. Children and adolescents with Lymphoblastic Non-Hodgkin's Lymphoma (LBL) are treated in accordance with the EURO-LB 02 protocol, whereas adults with Lymphoblastic Non-Hodgkin's Lymphoma in Denmark are commonly treated in accordance with the NOPHO ALL-2008 protocol. The longest treatment phase in both protocols is maintenance therapy, which is composed of 6-Mercaptopurine (6MP) and Methotrexate (MTX). The cytotoxic property of 6MP relies upon conversion of 6MP into thioguanine nucleotides (TGN), which can be incorporated into DNA instead of guanine or adenine. This incorporation can cause nucleotide mismatching and cause cell death second to repetitive activation of the mismatch repair system. At Rigshospitalet investigators have developed pharmacological methods able to measure the incorporation of TGN into DNA (DNA-TGN). In a Nordic/Baltic study the investigators have demonstrated higher levels of DNA-TGN during maintenance therapy in children with ALL that do not develop relapse (Nielsen et al. Lancet Oncol. 2017 Apr;18(4)). Preliminary studies indicate that the best approach to obtain DNA-TGN within a target range could be a combination of 6MP, MTX and 6-thioguanine (6TG), as 6TG more readily can be converted into TGN. This study aims to explore if individual dose titration of 6TG added to 6MP/MTX therapy can achieve DNA-TGN levels above a set target above 500 fmol/µg DNA, and thus can be integrated into future ALL and LBL treatment strategies to reduce relapse rates in ALL and LBL. The investigators plan to include 30 patients, and A) give incremental doses of 6TG until a mean DNA-TGN level above 500 fmol/µg DNA is obtained; and B) analyze the changes in DNA-TGN as well as cytosol levels of TGN and methylated 6MP metabolites (the latter inhibits purine de novo synthesis and thus enhance DNA-TGN incorporation), and C) occurrence of bone-marrow and liver toxicities during 6TG/6MP/MTX therapy.

Timeline

Start

2016-10

Primary completion

2020-03

Completion

2020-04

Publications

• Background Gustafsson G, Schmiegelow K, Forestier E, Clausen N, Glomstein A, Jonmundsson G, Mellander L, Makipernaa A, Nygaard R, Saarinen-Pihkala UM. Improving outcome through two decades in childhood ALL in the Nordic countries: the impact of high-dose methotrexate in the reduction of CNS irradiation. Nordic Society of Pediatric Haematology and Oncology (NOPHO). Leukemia. 2000 Dec;14(12):2267-75. doi: 10.1038/sj.leu.2401961.
• Background Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Soderhall S, Taskinen M; Nordic Society of Paediatric Haematology and Oncology. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010 Feb;24(2):345-54. doi: 10.1038/leu.2009.251. Epub 2009 Dec 10.
• Background Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic leukaemia--current status and future perspectives. Lancet Oncol. 2001 Oct;2(10):597-607. doi: 10.1016/S1470-2045(01)00516-2.
• Background Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol. 2014 Oct;36(7):503-17. doi: 10.1097/MPH.0000000000000206.
• Background Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999 May 1;93(9):2817-23.
• Background Schmiegelow K, Schroder H, Gustafsson G, Kristinsson J, Glomstein A, Salmi T, Wranne L. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. J Clin Oncol. 1995 Feb;13(2):345-51. doi: 10.1200/JCO.1995.13.2.345.
• Background Schmiegelow K, Forestier E, Kristinsson J, Soderhall S, Vettenranta K, Weinshilboum R, Wesenberg F; Nordic Society of Paediatric Haematology and Oncology. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia. 2009 Mar;23(3):557-64. doi: 10.1038/leu.2008.316. Epub 2008 Nov 6.
• Background Cooper SL, Brown PA. Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 2015 Feb;62(1):61-73. doi: 10.1016/j.pcl.2014.09.006. Epub 2014 Oct 18.
• Background Hunger SP, Winick NJ, Sather HN, Carroll WL. Therapy of low-risk subsets of childhood acute lymphoblastic leukemia: when do we say enough? Pediatr Blood Cancer. 2005 Dec;45(7):876-80. doi: 10.1002/pbc.20501. No abstract available.
• Background Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008 Jan;8(1):24-36. doi: 10.1038/nrc2292.
• Background Hedeland RL, Hvidt K, Nersting J, Rosthoj S, Dalhoff K, Lausen B, Schmiegelow K. DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2010 Aug;66(3):485-91. doi: 10.1007/s00280-009-1184-5. Epub 2009 Dec 3.
• Background Ebbesen MS, Nersting J, Jacobsen JH, Frandsen TL, Vettenranta K, Abramsson J, Wesenberg F, Schmiegelow K. Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemia-the influence of thiopurine methyltransferase genotypes. J Clin Pharmacol. 2013 Jun;53(6):670-4. doi: 10.1002/jcph.81. Epub 2013 Apr 15. No abstract available.
• Background Jacobsen JH, Schmiegelow K, Nersting J. Liquid chromatography-tandem mass spectrometry quantification of 6-thioguanine in DNA using endogenous guanine as internal standard. J Chromatogr B Analyt Technol Biomed Life Sci. 2012 Jan 15;881-882:115-8. doi: 10.1016/j.jchromb.2011.11.032. Epub 2011 Nov 28.
• Background Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol. 1998;42(4):266-72. doi: 10.1007/s002800050816.
• Background Schmiegelow K, Bjork O, Glomstein A, Gustafsson G, Keiding N, Kristinsson J, Makipernaa A, Rosthoj S, Szumlanski C, Sorensen TM, Weinshilboum R. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol. 2003 Apr 1;21(7):1332-9. doi: 10.1200/JCO.2003.04.039.
• Background Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther. 2004 Apr;75(4):274-81. doi: 10.1016/j.clpt.2003.12.001.
• Background Nielsen SN, Frandsen TL, Nersting J, Hjalgrim LL, Schmiegelow K. Pharmacokinetics of 6-Thioguanine and 6-Mercaptopurine Combination Maintenance Therapy of Childhood ALL: Hypothesis and Case Report. J Pediatr Hematol Oncol. 2015 Apr;37(3):e206-9. doi: 10.1097/MPH.0000000000000246.
• Background Escherich G, Richards S, Stork LC, Vora AJ; Childhood Acute Lymphoblastic Leukaemia Collaborative Group (CALLCG). Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia. Leukemia. 2011 Jun;25(6):953-9. doi: 10.1038/leu.2011.37. Epub 2011 Mar 4.
• Background Stork LC, Matloub Y, Broxson E, La M, Yanofsky R, Sather H, Hutchinson R, Heerema NA, Sorrell AD, Masterson M, Bleyer A, Gaynon PS. Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial. Blood. 2010 Apr 8;115(14):2740-8. doi: 10.1182/blood-2009-07-230656. Epub 2010 Feb 1.
• Background Lancaster DL, Lennard L, Rowland K, Vora AJ, Lilleyman JS. Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia: a comparison of haematological toxicity and drug metabolite concentrations. Br J Haematol. 1998 Jul;102(2):439-43. doi: 10.1046/j.1365-2141.1998.00812.x.
• Background Nielsen SN, Grell K, Nersting J, Frandsen TL, Hjalgrim LL, Schmiegelow K. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2016 Nov;78(5):983-994. doi: 10.1007/s00280-016-3151-2. Epub 2016 Sep 6.
• Background Nielsen SN, Grell K, Nersting J, Abrahamsson J, Lund B, Kanerva J, Jonsson OG, Vaitkeviciene G, Pruunsild K, Hjalgrim LL, Schmiegelow K. DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial. Lancet Oncol. 2017 Apr;18(4):515-524. doi: 10.1016/S1470-2045(17)30154-7. Epub 2017 Mar 1.

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Indications