Abstract
Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance. There is sufficient published data describing toxicities of high dose MTX (HD-MTX), but toxicities with escalating doses of MTX (Capizzi regimen) is not well documented. Capizzi regimen is thought to be relatively safe; we contend that even low escalating doses of MTX have significant toxicities. Our study intends to characterise such events with Capizzi MTX in comparison to that seen with HD-MTX. The retrospective study was conducted at a tertiary care centre of North India. We looked for the presence of six main toxicities: febrile neutropenia, thrombocytopenia, mucositis, hepatic toxicity, renal toxicity and skin toxicity from the clinical records of children with newly diagnosed acute lymphoblastic leukemia and lymphoma (intermediate and high risk disease), treated at our centre from November 2013 to July 2018. Intermediate risk ALL (IR-ALL) received Capizzi MTX, whereas high risk ALL (HR-ALL/T-NHL), received HD-MTX. Both these regimens do not use L-asparaginase. A total of 237 cycles of Capizzi escalating MTX and 151 cycles of HD-MTX (B cell: 3 gm/m2 and T cell ALL/T-NHL: 5 gm/m2) during interim maintenance were studied in 93 children. Fifty-four (54) children were of IR (all B cell ALL) and 39 of HR-ALL (21 B-ALL, 18 T-ALL/T-NHL). The combined incidence of toxicities, were similar between the two groups: 68/237 cycles (28.7%) of Capizzi MTX and 45/151 cycles (29.8%) of HD-MTX (P = 0.815). However, mucositis was more commonly witnessed in the later group at 22/151 cycle (14.6%) versus 13/237 cycles (5.5%) in Capizzi MTX (P = 0.002). Nephrotoxicity and skin toxicity was seen only in the HD-MTX group. There was no difference in the severity of toxicity, graded using NCI CTCAE v 5.0, between the two groups. There was no mortality directly attributable to methotrexate toxicity (Grade V toxicity). Serum MTX levels were available in 69/151 (45.7%) cycles of HD-MTX and showed no association with toxicity in this group. Also, there was no difference in the incidence of combined toxicities between groups with (19/69 cycles) or without (26/82 cycles) available serum MTX levels in the HR group (P = 0.577). Male gender, lower baseline ANC and lower BMI had significant association with toxicity. Methotrexate related toxicity is common with both Capizzi and HD-MTX schedule in childhood ALL with a correlation of lower BMI, baseline ANC and male gender. However, it is possible to administer Capizzi as well as HD-MTX in lower middle income countries, with manageable toxicity. Further studies will be required to substantiate our findings and determine the predictors of such events.
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References
Camitta BM, Kamen BA (2003) Role of methotrexate in the treatment of acute lymphoblastic leukemia. In: Pui CH (ed) Treatment of acute leukemias. Current clinical oncology. Humana Press, Totowa, NJ, pp 357–362
Freeman AI, Weinberg V, Brecher ML, Jones B, Glicksman AS, Sinks LF et al (1983) Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children. N Engl J Med 308(9):477–484
Evans WE, Stewart CF, Hutson PR, Cairnes DA, Bowman WP, Yee GC et al (1982) Disposition of intermediate-dose methotrexate in children with acute lymphocytic leukemia: drug. Intell Clin Pharm 16(11):839–842
Csordas K, Hegyi M, Eipel OT, Muller J, Erdelyi DJ, Kovacs GT (2013) Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Anticancer Drugs 24(2):189–197
Jaffe N, Takaue Y, Anzai T, Robertson R (1985) Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer 56(6):1356–1360
Howard SC, McCormick J, Pui C-H, Buddington RK, Harvey RD (2016) Preventing and managing toxicities of high-dose methotrexate. Oncologist 21(12):1471–1482
Stark AN, Jackson G, Carey PJ, Arfeen S, Proctor SJ (1989) Severe renal toxicity due to intermediate-dose methotrexate. Cancer Chemother Pharmacol 24(4):243–245
Mahoney DH, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N et al (1998) Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy–a pediatric oncology group study. J Clin Oncol 16(5):1712–1722
Uluoğlu C, Oğuz A, Timlioğlu Ö, Biberoğlu G, Hasanoğlu A (1999) Intermediate dose of methotrexate toxicity in non-Hodgkin lymphoma. Gen Pharmacol Vasc Syst 32(2):215–218
Neuman MG, Cameron RG, Haber JA, Katz GG, Malkiewicz IM, Shear NH (1999) Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytotoxicity. Clin Biochem 32(7):519–536
Shimasaki N, Mori T, Samejima H, Sato R, Shimada H, Yahagi N et al (2006) Effects of methylenetetrahydrofolate reductase and reduced F. J Pediatr Hematol Oncol 28(2):64–68
Common Terminology Criteria for Adverse Events (CTCAE). Protocol Development cancer therapy evaluation program (CTEP) [Internet]. Available from: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_5x7.pdf. Accessed 12 Aug 2018
Cutler C, Li S, Kim HT, Laglenne P, Ford C, Ho V et al (2004) Oral mucositis incidence and severity after methotrexate and non-methotrexate containing GVHD prophylaxis regimens. Blood 104(11):351
Özdemir ZC, Bozkurt Turhan A, Düzenli Kar Y, Bör Ö (2016) The frequency of hepatotoxicity and myelotoxicity in leukemic children with different high doses of methotrexate. Int J Pediatr Adolesc Med. 3(4):162–168
Bhojwani D, Sabin ND, Pei D, Yang JJ, Khan RB, Panetta JC et al (2014) Methotrexate-induced neurotoxicity and leukoencephalopathy in childhood acute lymphoblastic leukemia. J Clin Oncol 32(9):949–959
Vaishnavi K, Bansal D, Trehan A, Jain R, Attri SV (2018) Improving the safety of high-dose methotrexate for children with hematologic cancers in settings without access to MTX levels using extended hydration and additional leucovorin. Pediatr Blood Cancer 16:e27241
Tiwari P, Ganesan P, Radhakrishnan V, Arivazhagan R, Ganesan TS, Dhanushkodi M et al (2018) Prospective evaluation of the toxicity profile, and predictors of toxicity of high dose methotrexate in patients of acute lymphoblastic leukemia/lymphoma. Pediatr Hematol Oncol J 3(1):1–5
Relling M, Fairclough D, Ayers D, Crom RW, Rodman HJ, Pui HC et al (1994) Patient characteristics associated with high-risk methotrexate concentration and toxicity. J Clin Oncol 12:1667–1672
Liu S-G, Gao C, Zhang R-D, Zhao X-X, Cui L, Li W-J et al (2017) Polymorphisms in methotrexate transporters and their relationship to plasma methotrexate levels, toxicity of high-dose methotrexate, and outcome of pediatric acute lymphoblastic leukemia. Oncotarget 8(23):37761–37772
Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L (2009) Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr 154(5):688–693
Erčulj N, Kotnik BF, Debeljak M, Jazbec J, Dolžan V (2012) Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia. Leuk Lymphoma 53(6):1096–1104
Zgheib NK, Akra-Ismail M, Aridi C, Mahfouz R, Abboud MR, Solh H et al (2014) Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia. Pharmacogenet Genomics 24(8):387–396
Csordas K, Lautner-Csorba O, Semsei AF, Harnos A, Hegyi M, Erdelyi DJ et al (2014) Associations of novel genetic variations in the folate-related and ARID5B genes with the pharmacokinetics and toxicity of high-dose methotrexate in paediatric acute lymphoblastic leukaemia. Br J Haematol 166(3):410–420
Moulik NR, Kumar A, Agrawal S, Mahdi AA, Kumar A (2016) Effect of folate status and methylenetetrahydrofolate reductase genotypes on the complications and outcome of high dose methotrexate chemotherapy in north Indian children with acute lymphoblastic leukemia. Indian J Med Paediatr Oncol Off J Indian Soc Med Paediatr Oncol. 37(2):85–89
Tandon S, Moulik NR, Kumar A, Mahdi AA, Kumar A (2015) Effect of pre-treatment nutritional status, folate and vitamin B12 levels on induction chemotherapy in children with acute lymphoblastic leukemia. Indian Pediatr 52(5):385–389
Dudeja S, Gupta S, Sharma S, Jain A, Sharma S, Jain P et al (2019) Incidence of vincristine induced neurotoxicity in children with acute lymphoblastic leukemia and its correlation with nutritional deficiencies. Pediatr Hematol Oncol 36(6):344–351
Cheng KKF (2008) Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer. Eur J Cancer Care (Engl) 17(3):306–311
Schmiegelow K, Bretton-Meyer U (2001) 6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia. Leukemia 15(1):74–79
Forster VJ, van Delft FW, Baird SF, Mair S, Skinner R, Halsey C (2016) Drug interactions may be important risk factors for methotrexate neurotoxicity, particularly in pediatric leukemia patients. Cancer Chemother Pharmacol 78(5):1093–1096
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PM was involved in data analysis and revision of manuscript. SS was involved in collection of the data, data analysis and writing the manuscript. JC conceived the study and was involved in manuscript revision. NP was involved in data collection. MG was involved in statistical analysis and manuscript preparation.
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Mandal, P., Samaddar, S., Chandra, J. et al. Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. Indian J Hematol Blood Transfus 36, 498–504 (2020). https://doi.org/10.1007/s12288-019-01245-z
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DOI: https://doi.org/10.1007/s12288-019-01245-z