Division of Pediatric Hematology-Oncology, Department of Pediatrics, King George’s Medical University, Lucknow, India.
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The issue of folic acid supplementation to children with acute lymphoblastic leukemia (ALL) remains unresolved pending adequate clinical data. Folic acid supplementation is believed to reduce chemotherapy related complications and improve tolerance allowing adequate drug dosages, particularly for methotrexate, but the fear of rescuing leukemic clones prevents routine supplementation [1]. However, folic acid is unlikely to interfere with anti-neoplastic action of methotrexate as: (i) there is apparently no competition between folic acid and methotrexate as the former preferentially utilizes the human folate receptor for entry into the cell whereas the latter and its antagonist folinic acid (reduced folic acid) use reduced folate carrier for their uptake (Fig. 1); (ii) Folic acid needs to be reduced by dihydrofolatereductase (DHFR) (an enzyme blocked by methotrexate but can be circumvented by folinic acid) in order to take part in DNA synthesis; (iii) Folic acid gets active upon regeneration of the DHFR enzyme only after methotrexate is eliminated from the system; (iv) methotrexate and folinic acid are administered at thousand-fold higher dosages as compared to the recommended daily allowance of folic acid; and (v) the proposed competition of folic acid with methotrexate for renal excretion may in fact increase the exposure of leukemic cells to methotrexate in presence of adequate folic acid [1].

Fig.1 Interaction between methotrexate and folic acid.

Nutritional deficiency of folate and its further depletion with chemotherapy is common in children with ALL, especially in countries with high prevalence of malnutrition and lack of folate fortification [2]. Despite a documented higher infection-related deaths during induction, and interruption of maintenance chemotherapy in folate deficient children, the theoretical concern of increased relapse has prevented us from supplementing with folic acid. Developed countries with mandatory folate fortification have not encountered increased relapses in the post-fortification era; this is further supported by data from adults where routine folate use during chemotherapy helps in improving the chemo-therapy tolerance without compromising efficacy [3].

We propose that careful consideration should be given towards folic acid supplementation in deficient children undergoing chemotherapy for ALL, especially in countries without mandatory folate fortification.

1. Robien K Folate during antifolate chemotherapy: What we know... and do not know. Nutr Clin Pract. 2005;20:411-22.

2. Sadananda Adiga MN, Chandy S, Ramaswamy G, Appaji L, Krishnamoorthy L. Homocysteine, vitamin B12 and folate status in pediatric acute lymphoblastic leukemia. Indian J Pediatr. 2008;75:235-8.