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Plasma Homocysteine in Children with Acute Lymphoblastic Leukemia: Changes during a Chemotherapeutic Regimen Including Methotrexate¹

The Clinical Pharmacology Unit, Department of Pharmacology and Toxicology [H. R., P. M. U.], and Department of Pediatrics [F. W.], University of Bergen, N-5021 Haukeland Hospital, Norway

Plasma homocysteine was determined in 12 children with acute lymphoblastic leukemia. The patients were investigated prior to chemotherapy (stage I), during seven weeks of induction chemotherapy (stage II), and thereafter during intermittent high-dose methotrexate (HD-MTX) therapy (stage III). The patients were followed for a period of three to 15 months, and the study included a total of 80 HD-MTX courses.

Before start of chemotherapy (stage I), the average plasma homocysteine level in the children with leukemia was 13.18 ± 6.23 (SD) µmol/liter, which is significantly (P < 0.001) higher than the level in control children (6.52 ± 1.21 µmol/liter). The plasma homocysteine level in the patients was positively correlated with the peripheral white blood cell count (P < 0.01) and negatively correlated with serum folate (P < 0.02). The serum folate was normal or subnormal in these patients.

During induction therapy with cytotoxic drugs such as vincristine, asparaginase, and intrathecal MTX (stage II), there was a drastic change in plasma homocysteine as a function of time. A reciprocal alteration in serum folate was observed, suggesting fluctuating intracellular folate status at this stage of therapy. At the end of stage II (about seven weeks), there was a significant (P < 0.01) reduction in total homocysteine (to 7.08 ± 3.84 µmol/liter).

HD-MTX (8 g/m²) therapy with 5-formyltetrahydrofolate "rescue" (stage III) was usually begun about seven weeks after start of chemotherapy, and the patients were followed for two to eight courses separated by three to eight weeks. Plasma homocysteine showed a transient increase (26–64%) following each MTX infusion. After three MTX infusions, basal total plasma homocysteine was reduced to 5.56 ± 1.12 µmol/liter. During most MTX infusions, there was a variable reduction (17–56%) in plasma methionine followed by a rebound increase.

It is concluded that plasma homocysteine in children with acute lymphoblastic leukemia is elevated prior to therapy, probably because of occasional folate deficiency and increased burden of proliferating cells. During induction therapy, monitoring plasma homocysteine and serum folate both suggest a labile folate homeostasis, usually a deficiency state. HD-MTX induced a temporary intracellular folate depletion before 5-formyl-tetrahydrofolate was administered, as judged by a transient homocysteinemia. The methionine depletion may interfere with the antileukemic effect of MTX.

¹ This work was supported by grants from the Norwegian Cancer Society, from Astri og Birger Torsteds legat til bekjempelse av kreft, and the Norwegian Research Council for Science and the Humanities.

² To whom requests for reprints should be addressed.

Received 9/10/90. Accepted 11/ 6/90.

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