Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2021; 20: 128-135
Клинические наблюдения тиопурининдуцированной миелотоксичности у пациентов с острыми лейкозами и обоснование преимуществ фармакогенетического подхода при назначении 6-меркаптопурина
https://doi.org/10.24287/1726-1708-2021-20-1-128-135Аннотация
Меркаптопурин (МР) – это химиопрепарат, являющийся ключевым элементом поддерживающей терапии при острых лейкозах. В связи с фармакокинетическими различиями у пациентов, получающих одинаковые расчетные дозы препарата, может синтезироваться разное количество активных и токсических метаболитов. Этим обусловлены неодинаковая переносимость препарата и необходимость подбора индивидуальной дозы. Долгое время единственным инструментом для титрования дозы 6-MP являлся уровень лейкоцитов и гранулоцитов периферической крови. По мере изучения генетических факторов, влияющих на метаболизм 6-МР, и развития технологии высокопроизводительного секвенирования появились клинические рекомендации по подбору доз тиопуринов, основанные на фармакогенетическом подходе. В настоящей статье мы описали двух пациентов, принадлежащих к малому этносу России, с аномальным толерированием 6-МП и проанализировали состояние проблемы фармакогенетики тиопуринов с обоснованием преимущества персонализированного, основанного на фармакогенетике подхода к назначению 6-МР. Родители пациентов дали согласие на использование информации, в том числе фотографий детей, в научных исследованиях и публикациях.
Список литературы
1. Burchenal J.H. Therapy of acute leukemia. Dia Med 1952; 24 (72): 1883–4.
2. Dibenedetto S.P., Guardabasso V., Ragusa R., Cataldo A.D., Miraglia V., D'Amico S., et al. 6-Mercaptopurine cumulative dose: A critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1994; 11: 251–8.
3. Relling M.V., Hancock M.L., Boyett J.M., Pui C.H., Evans W.E. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 1999; 93: 2817–28.
4. Pui C.H., Evans W.E. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–78.
5. Fenaux P., Chastang C., Chevret S., Sanz M., Dombret H., Archimbaud E., et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94 (4): 1192–200.
6. Tallman M.S., Andersen J.W., Schiffer C.A., Appelbaum F.R., Feusner J.H., Woods W.G., et al. All-trans retinoic acid in acute promyelocytic leukemia: Longterm outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100 (13): 4298–302.
7. Lafolie P., Hayder S., Björk O., Ahström L., Liliemark J., Peterson C. Large interindividual variations in the pharmacokinetics of oral 6-mercaptopurine in maintenance therapy of children with acute leukaemia and non-Hodgkin lymphoma. Acta Paediatr Scand 1986; 75: 797–803.
8. de Beaumais T.A., Fakhoury M., Medard Y., Azougagh S., Zhang D., Yakouben K., et al. Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol 2011; 7 1 (4): 575–84.
9. Relling M.V., Gardner E.E., Sandborn W.J., Schmiegelow K., Pui C.-H., Yee S.W., et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89 (3): 387–91.
10. McLeod H.L., Krynetski E.Y., Relling M.V., Evans W.E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000; 14 (4): 567–72.
11. Bostrom B., Erdmann G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1993; 15 (1): 80–6.
12. Bökkerink J.P., Stet E.H., de Abreu R.A., Damen F.J., Hulscher T.W., Bakker M.A., et al. 6-Mercaptopurine: Cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem Pharmacol 1993; 45 (7): 1455–63.
13. McLeod H.L., Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics 2002; 3 (1): 89–98.
14. Schaeffeler E., Fischer C., Brockmeier D., Wernet D., Moerike K., Eichelbaum M., et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identifi cation of novel TPMT variants. Pharmacogenetics 2004; 14: 407–17.
15. Yates C.R., Krynetski E.Y., Loennechen T., Fessing M.Y., Tai H.L., Pui C.H., et al. Molecular diagnosis of thiopurine S-methyltransferase defi ciency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126: 608–14.
16. Evans W.E., Hon Y.Y., Bomgaars L., Coutre S., Holdsworth M., Janco R., et al. Preponderance of thiopurine S-methyltransferase defi ciency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293–301.
17. Higgs J.E., Payne K., Roberts C., Newman W.G. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010; 11: 177–88.
18. Samochatova E.V., Chupova N.V., Rudneva A., Makarova O., Nasedkina T.V., Fedorova O.E., et al. TPMT genetic variations in populations of the Russian Federation. Pediatr Blood Cancer 2009; 52 (2): 203–8.
19. Yang J.J., Landier W., Yang W., Liu C., Hageman L., Cheng C., et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 2015; 33: 1235–42.
20. Moriyama T., Nishii R., Perez-Andreu V., Yang W., Klussmann F.A., Zhao X., et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016; 48: 367–73.
21. Доступно по: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205919s004lbl.pdf. Ссылка активна на 09.03.2021.
22. Yang S.K., Hong M., Baek J., Choi H., Zhao W., Jung Y., et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014; 46 (9): 1017–20.
23. Relling M.V., Schwab M., Whirl-Carrillo M., Suarez-Kurtz G., Pui C.H., Stein C.M., et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther 2019; 105 (5): 1095–105.
24. Choi R., Sohn I., Kim M.J., Woo H.I., Lee J.W., Ma Y., et al. Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia. Br J Clin Pharmacol 2019; 85 (7): 1585–97.
Pediatric Hematology/Oncology and Immunopathology. 2021; 20: 128-135
Thiopurine-induced myelotoxicity in patients with acute leukemia and benefits of preemptive pharmacogenetic testing prior to 6-mercaptopurine prescription
https://doi.org/10.24287/1726-1708-2021-20-1-128-135Abstract
Mercaptopurine (МР) is a key element of the maintenance therapy of acute leukemias. Different amounts of active and toxic metabolites can be synthesized in patients who are receiving the same doses of the drug due to pharmacokinetic differences. This contributes to the unequal drug tolerability and the need of dose adjustment. For a long time, the only tool for adjusting 6-MP dose was the level of leukocytes and granulocytes in the peripheral blood. With the understanding of genetic factors affecting the metabolism of 6-MP and development of next-generation sequencing technology, clinical guidelines for thiopurine dosing based on a pharmacogenetic approach have been emerged. In this article, we report two patients belonging to a small ethnic group in Russia with abnormal 6-MP toleration and substantiate the advantages of a personalized, pharmacogeneticallybased approach to 6-MP administration. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.
References
1. Burchenal J.H. Therapy of acute leukemia. Dia Med 1952; 24 (72): 1883–4.
2. Dibenedetto S.P., Guardabasso V., Ragusa R., Cataldo A.D., Miraglia V., D'Amico S., et al. 6-Mercaptopurine cumulative dose: A critical factor of maintenance therapy in average risk childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 1994; 11: 251–8.
3. Relling M.V., Hancock M.L., Boyett J.M., Pui C.H., Evans W.E. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood 1999; 93: 2817–28.
4. Pui C.H., Evans W.E. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354: 166–78.
5. Fenaux P., Chastang C., Chevret S., Sanz M., Dombret H., Archimbaud E., et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94 (4): 1192–200.
6. Tallman M.S., Andersen J.W., Schiffer C.A., Appelbaum F.R., Feusner J.H., Woods W.G., et al. All-trans retinoic acid in acute promyelocytic leukemia: Longterm outcome and prognostic factor analysis from the North American Intergroup protocol. Blood 2002; 100 (13): 4298–302.
7. Lafolie P., Hayder S., Björk O., Ahström L., Liliemark J., Peterson C. Large interindividual variations in the pharmacokinetics of oral 6-mercaptopurine in maintenance therapy of children with acute leukaemia and non-Hodgkin lymphoma. Acta Paediatr Scand 1986; 75: 797–803.
8. de Beaumais T.A., Fakhoury M., Medard Y., Azougagh S., Zhang D., Yakouben K., et al. Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol 2011; 7 1 (4): 575–84.
9. Relling M.V., Gardner E.E., Sandborn W.J., Schmiegelow K., Pui C.-H., Yee S.W., et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011; 89 (3): 387–91.
10. McLeod H.L., Krynetski E.Y., Relling M.V., Evans W.E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000; 14 (4): 567–72.
11. Bostrom B., Erdmann G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol 1993; 15 (1): 80–6.
12. Bökkerink J.P., Stet E.H., de Abreu R.A., Damen F.J., Hulscher T.W., Bakker M.A., et al. 6-Mercaptopurine: Cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem Pharmacol 1993; 45 (7): 1455–63.
13. McLeod H.L., Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics 2002; 3 (1): 89–98.
14. Schaeffeler E., Fischer C., Brockmeier D., Wernet D., Moerike K., Eichelbaum M., et al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identifi cation of novel TPMT variants. Pharmacogenetics 2004; 14: 407–17.
15. Yates C.R., Krynetski E.Y., Loennechen T., Fessing M.Y., Tai H.L., Pui C.H., et al. Molecular diagnosis of thiopurine S-methyltransferase defi ciency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 1997; 126: 608–14.
16. Evans W.E., Hon Y.Y., Bomgaars L., Coutre S., Holdsworth M., Janco R., et al. Preponderance of thiopurine S-methyltransferase defi ciency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 2001; 19: 2293–301.
17. Higgs J.E., Payne K., Roberts C., Newman W.G. Are patients with intermediate TPMT activity at increased risk of myelosuppression when taking thiopurine medications? Pharmacogenomics 2010; 11: 177–88.
18. Samochatova E.V., Chupova N.V., Rudneva A., Makarova O., Nasedkina T.V., Fedorova O.E., et al. TPMT genetic variations in populations of the Russian Federation. Pediatr Blood Cancer 2009; 52 (2): 203–8.
19. Yang J.J., Landier W., Yang W., Liu C., Hageman L., Cheng C., et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 2015; 33: 1235–42.
20. Moriyama T., Nishii R., Perez-Andreu V., Yang W., Klussmann F.A., Zhao X., et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016; 48: 367–73.
21. Dostupno po: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/205919s004lbl.pdf. Ssylka aktivna na 09.03.2021.
22. Yang S.K., Hong M., Baek J., Choi H., Zhao W., Jung Y., et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014; 46 (9): 1017–20.
23. Relling M.V., Schwab M., Whirl-Carrillo M., Suarez-Kurtz G., Pui C.H., Stein C.M., et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther 2019; 105 (5): 1095–105.
24. Choi R., Sohn I., Kim M.J., Woo H.I., Lee J.W., Ma Y., et al. Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia. Br J Clin Pharmacol 2019; 85 (7): 1585–97.
