Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia

Purpose: To study the risk of non-B-cell acute lymphoblastic leukemia (ALL) relapse in relation to the routines of administration of oral methotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyglutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN). Patients and Methods: E-MTX and E-6TGN levels were measured at least three times (medians, eight and nine) in 294 children with non-B-cell ALL during oral MTX and 6MP therapy. For each patient, we registered (a) the individual circadian schedule of drug administration and (b) the coadministration of food, and (c) calculated a mean (m) of all E-MTX and E-6TGN measurements and (d) the product of mE-MTX and mE-6TGN (mE-MTX * 6TGN), due to their synergistic action. Results: A total of 42 patients were on a morning schedule, 219 were on an evening schedule, and 33 had miscellaneous routines. A total of 149 patients took the drugs with meals, 106 took the drugs between meals, and 39 had varying routines. With a median follow-up of 78 months, ALL has recurred in 66 patients. The patients on an evening schedule had a superior outcome [probability of event-free survival (pEFS) = 0.82 +/- 0.03 vs. 0.57 +/- 0.08; p = 0.0002], whereas the coadministration of food did not significantly influence outcome. Patients with a mE-MTX * 6TGN < 813 [product of median mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol Hb)] had an inferior outcome (pEFS = 0.70 +/- 0.04 vs. 0.85 +/- 0.03;p = 0.003), even if only patients on an evening schedule were analyzed. Thus, 109 patients on the MTX/6MP evening schedule with an mE-MTX * 6TGN less than or equal to 813 (nmol/mmol Hb)(2) had a pEFS of 0.89 +/- 0.03 and a probability of continuous hematopoietic remission of 0.91 +/- 0.03. Conclusions: An evening schedule should be recommended for oral MTX/6MP maintenance therapy. The value of individual dose adjustments by E-MTX and E-6TGN remains to be determined in prospective randomized trials.