Page 178 - Haematologica April 2020
P. 178

M. Kroll et al.
compared to NDS-ALL one could further argue that DS- ALL patients do not require MTX doses as high as 5 g/m2 to get the same plasma levels and subsequent effect with respect to relapse prevention.
In an attempt to shed further light on MTX susceptibil- ity in DS-ALL patients we genotyped the rs1051266 80G>A SNP of the folate and MTX transporter SLC19A1 on chromosome.21 The allele frequencies in our DS-ALL cohort are consistent with previous published frequencies in a healthy DS cohort.22 Since Baslund et al. found the A-variant of the transporter to be more effective in taking up fluorescence labeled MTX into lymphocytes of healthy euploide blood donors,11 we speculated that more MTX might be taken up into cells of DS-ALL patients that are homozygous for the presumably higher active A-variant (AAA) and that this may lead to higher rates of severe MTX-related toxicities compared to patients with the GGG allele combination. Thus, we hypothesized that genotyping of rs1051266 might be a diagnostic tool to pre- dict the severity of toxicities in DS-ALL patients, but we were unable to confirm this hypothesis. However, phar- macokinetics of a single drug or the impact of a single SNP of a transporter in complex chemotherapy regimens may have limited power to explain the differences in effects and side effects. Other SNP in SLC19A1 and SNP in other
genes of transporters or enzymes in the folate/MTX metabolism may also play a role. Therefore, further research including haplotype analysis, investigations of the effect of trisomy 21 on MTX metabolism by using transcriptomics or microarrays and the evaluation of SLC19A1 expression profile on mRNA and protein level as well as its transportation activity are needed. Moreover, 6-MP co-medication during consolidation should be con- sidered as differences in DS patients with regards to 6-MP metabolism have been described.23 This might be impor- tant in HD-MTX consolidation but also in maintenance therapy, in which both MTX and 6-MP are administered since up to 40% of treatment-related deaths in DS-ALL occur during maintenance therapy.6,24
In conclusion, dose reduction in the first HD-MTX course of consolidation therapy led to a decrease of severe MTX-associated toxicities without increasing the risk of relapse for DS-ALL patients.
Funding
The authors would like to thank Deutsche Krebshilfe, Deutsche José Carreras Leukämie-Stiftung (DJCLS), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), José Carreras-GPOH Promotionsstipendium 03 PSG/2017 for financial support.
References
1. Hasle H, Friedman JM, Olsen JH, Rasmussen SA. Low risk of solid tumors in persons with Down syndrome. Genet Med. 2016;18(11): 1151-1157.
2. Dordelmann M, Schrappe M, Reiter A, et al. Down's syndrome in childhood acute lymphoblastic leukemia: clinical character- istics and treatment outcome in four con- secutive BFM trials. Berlin-Frankfurt- Münster Group. Leukemia. 1998;12(5): 645-651.
3. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol. 2006;135(5):595-602.
4. Arico M, Ziino O, Valsecchi MG, et al. Acute lymphoblastic leukemia and Down syndrome. Cancer. 2008;113(3):515-521.
5. Goto H, Inukai T, Inoue H, et al. Acute lymphoblastic leukemia and Down syn- drome: the collaborative study of the Tokyo Children“s Cancer Study Group and the Kyushu Yamaguchi Children”s Cancer Study Group. Int J Hematol. 2011; 93(2):192-198.
6. Buitenkamp TD, Izraeli S, Zimmermann M, et al. Acute lymphoblastic leukemia in children with Down syndrome: a retro- spective analysis from the Ponte di Legno study group. Blood. 2014;123(1):70-77.
7. Taub JW, Ge Y. Down syndrome, drug metabolism and chromosome 21. Pediatr Blood Cancer. 2004;44(1):33-39.
8. Buitenkamp TD, Mathot RAA, de Haas V, Pieters R, Zwaan CM. Methotrexate- induced side effects are not due to differ- ences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia. Haematologica. 2010;95(7):
1106-1113.
9. Schmiegelow K. Advances in individual
prediction of methotrexate toxicity: a review. Br J Haematol. 2009;146(5):489- 503.
10. Matherly LH, Wilson MR, Hou Z. The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biolo- gy and role in antifolate chemotherapy of cancer. Drug Metabolism and Disposition. 2014;42(4):632-649.
11. Baslund B, Gregers J, Nielsen CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology. 2007;47(4):451-453.
12. Whetstine JR, Gifford AJ, Witt T, et al. Single nucleotide polymorphisms in the human reduced folate carrier: characteriza- tion of a high-frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers. Clin Cancer Res. 2001;7(11):3416-3422.
13. Radtke S, Zolk O, Renner B, et al. Germline genetic variations in methotrex- ate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood. 2013; 121(26):5145-5153.
14. Whitlock JA, Sather HN, Gaynon P, et al. Clinical characteristics and outcome of children with Down syndrome and acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2005;106(13):4043-4049.
15. Shah N, Al-Ahmari A, Al-Yamani A, Dupuis L, Stephens D, Hitzler J. Outcome and toxicity of chemotherapy for acute lymphoblastic leukemia in children with down syndrome. Pediatr Blood Cancer. 2009;52(1):14-19.
16. Derouet A, Petit A, Baruchel A, et al.
Impact of therapy in a cohort of unselected children with Down Syndrome-associated Acute Lymphoblastic Leukaemia. Br J Haematol. 2016;174(6):983-985.
17. Wadhwa A, Kutny MA, Xavier AC. Blinatumomab activity in a patient with Down syndrome B-precursor acute lym- phoblastic leukemia. Pediatr Blood Cancer. 2017;65(2):e26824.
18. Schmiegelow K, Müller K, Mogensen SS, et al. Non-infectious chemotherapy-associat- ed acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017;6:444.
19. Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19(6):453–456.
20. Garneau AP, Riopel J, Isenring P. Acute methotrexate-induced crystal nephropa- thy. N Engl J Med. 2015; 373(27):2691– 2693.
21. Park JA, Shin HY. Influence of genetic poly- morphisms in the folate pathway on toxic- ity after high-dose methotrexate treatment in pediatric osteosarcoma. Blood Res. 2016; 51(1):50-57.
22. Chango A, Willequet F, Fillon-Emery N, Nicolas JP, Bléhaut H. The single nucleotide polymorphism (80G-->A) of reduced folate carrier gene in trisomy 21. Am J Clin Nutr. 2004;80(6):1667-1669.
23. Palle J, Frost BM, Britt-Marie F, et al. Thioguanine pharmacokinetics in induc- tion therapy of children with acute myeloid leukemia. Anti-Cancer Drugs. 2009;20(1):7-14.
24. O'Connor D, Bate J, Wade R, et al. Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003. Blood. 2014;124(7): 1056-1061.
1020
haematologica | 2020; 105(4)


































































































   176   177   178   179   180