Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

Clinical Proteomics

Kjeld Schmiegelow²  Louise Borst¹  Jacob Nersting¹ 

[1] Pediatric Oncology Research Laboratory, JMC-5704, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen;The Faculty of Medicine, Institute of Gynecology, Obstetrics and Pediatrics, University of Copenhagen, Denmark

关键词: clinical implementation;    maintenance therapy;    acute lymphoblastic leukemia;    individualized medicine;   

Others  :  1026372
DOI  :  10.1186/1559-0275-8-8

 received in 2011-04-15, accepted in 2011-06-03,  发布年份 2011

【 摘 要 】

Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit of acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process, but also multiplied the complex interaction of genetic and other laboratory parameters that can be used for therapy adjustments. Thus, with the advances in the laboratory techniques, post laboratory issues have become major obstacles for treatment individualization. Many of these challenges have been illustrated by studies involving childhood acute lymphoblastic leukemia (ALL), where each patient may receive up to 13 different anticancer agents over a period of 2-3 years. The challenges include i) addressing important, but low-frequency outcomes, ii) difficulties in interpreting the impact of single drug or single gene response data that often vary across treatment protocols, iii) combining disease and host genomics with outcome variations, and iv) physicians' reluctance in implementing potentially useful genotype and phenotype data into clinical practice, since unjustified downward or upward dose adjustments could increase the of risk of relapse or life-threatening complications. In this review we use childhood ALL therapy as a model and discuss these issues, and how they may be addressed.

【 授权许可】

   
2011 Nersting et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Bates S: Progress towards personalized medicine. Drug Discov Today 2010, 15:115-120.
• [2]Gardiner SJ, Begg EJ: Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006, 58:521-590.
• [3]Davidsen ML, Dalhoff K, Schmiegelow K: Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2008, 30:831-849.
• [4]Lund B, Åsberg A, Heyman M, et al.: Risk Factors for Treatment Related Mortality in Childhood Acute Lymphoblastic Leukemia. Pediatr Blood Cancer 2011, 56:551-9.
• [5]Schmiegelow K, Bretton-Meyer U: 6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia. Leukemia 2001, 15:74-79.
• [6]Schmiegelow K, Forestier E, Hellebostad M, et al.: Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia 2010, 24:345-354.
• [7]Schmiegelow K, Bjork O, Glomstein A, et al.: Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol 2003, 21:1332-1339.
• [8]Cunningham L, Aplenc R: Pharmacogenetics of acute lymphoblastic leukemia treatment response. Expert Opin Pharmacother 2007, 8:2519-2531.
• [9]Schmiegelow K: Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol 2009, 146:489-503.
• [10]Relling MV, Hancock ML, Rivera GK, et al.: Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 1999, 91:2001-2008.
• [11]Schmiegelow K, Forestier E, Kristinsson J, et al.: Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia 2009, 23:557-564.
• [12]Relling MV, Gardner EE, Sandborn WJ, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for thiopurine methyltransferase (TPMT) genotype and thiopurine dosing. Clinical Pharmacology & Therapeutics 2011, in press.
• [13]Skarby T, Jonsson P, Hjorth L, et al.: High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother Pharmacol 2003, 51:311-320.
• [14]Jacobs SA, Stoller RG, Chabner BA, Johns DG: 7-Hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest 1976, 57:534-538.
• [15]Rocha JC, Cheng C, Liu W, et al.: Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 2005, 105:4752-4758.
• [16]Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH: Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998, 338:499-505.
• [17]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, 42:266-272.
• [18]Lennard L, Welch J, Lilleyman JS: Mercaptopurine in childhood leukaemia: the effects of dose escalation on thioguanine nucleotide metabolites. Br J Clin Pharmacol 1996, 42:525-527.
• [19]Skarby TV, Anderson H, Heldrup J, Kanerva JA, Seidel H, Schmiegelow K: High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia 2006, 20:1955-1962.
• [20]Widemann BC, Balis FM, Kim A, et al.: Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 2010, 28:3979-3986.
• [21]Gregers J, Christensen IJ, Dalhoff K, et al.: The association of reduced folate carrier 80G > A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 2010, 115:4671-4677.
• [22]Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M: Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia. Blood 2002, 100:3832-3834.
• [23]Trevino LR, Shimasaki N, Yang W, et al.: Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 2009, 27:5972-5978.
• [24]Hulot JS, Villard E, Maguy A, et al.: A mutation in the drug transporter gene ABCC2 associated with impaired methotrexate elimination. Pharmacogenet Genomics 2005, 15:277-285.
• [25]Schmiegelow K, Al-Modhwahi I, Andersen MK, et al.: Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood 2009, 113:6077-6084.
• [26]McNeer JL, Nachman JB: The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. Br J Haematol 2010, 149:638-652.
• [27]Pinkel D, Hernandez K, Borella L, et al.: Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer 1971, 27:247-256.
• [28]Saarinen-Pihkala UM, Heilmann C, Winiarski J, et al.: Pathways through relapses and deaths of children with acute lymphoblastic leukemia: role of allogeneic stem-cell transplantation in Nordic data. J Clin Oncol 2006, 24:5750-5762.
• [29]Nersting J, Schmiegelow K: Pharmacogenomics of methotrexate: moving towards individualized therapy. Pharmacogenomics 2009, 10:1887-1889.
• [30]Baslund B, Gregers J, Nielsen CH: Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology (Oxford) 2008, 47:451-453.
• [31]Buitenkamp TD, Mathot RA, de H V, Pieters R, Zwaan CM: Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica 2010, 95:1106-1113.
• [32]Taub JW, Ge Y: Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer 2005, 44:33-39.
• [33]Pui CH, Sandlund JT, Pei D, et al.: Results of therapy for acute lymphoblastic leukemia in black and white children. JAMA 2003, 290:2001-2007.
• [34]Schmiegelow K, Heyman M, Gustafsson G, et al.: The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia 2010, 24:715-720.
• [35]Pui CH, Boyett JM, Relling MV, et al.: Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol 1999, 17:818-824.
• [36]Arico M, Valsecchi MG, Camitta B, et al.: Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia. N Engl J Med 2000, 342:998-1006.
• [37]Ansari M, Krajinovic M: Pharmacogenomics in cancer treatment defining genetic bases for inter-individual differences in responses to chemotherapy. Curr Opin Pediatr 2007, 19:15-22.