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 me thotrexate (MTX) and 6-mercaptopurine (6MP) and to the erythrocyte (E) levels of the intracellular cytotoxic metabolites, that is, MTX polyg lutamates and 6-thioguanine nucleotides (E-MTX and E-6TGN). Patients a nd 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 indi vidual circadian schedule of drug administration and (b) the coadminis tration 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 we re on a morning schedule, 219 were on an evening schedule, and 33 had miscellaneous routines. A total of 149 patients took the drugs with me als, 106 took the drugs between meals, and 39 had varying routines. Wi th a median follow-up of 78 months, ALL has recurred in 66 patients. T he 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 in fluence outcome. Patients with a mE-MTX 6TGN < 813 [product of media n mE-MTX (4.7 nmol/mmol Hb) and mE-6TGN (173 nmol/mmol Hb)] had an inf erior 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 pati ents on the MTX/6MP evening schedule with an mE-MTX 6TGN less than o r equal to 813 (nmol/mmol Hb)(2) had a pEFS of 0.89 +/- 0.03 and a pro bability of continuous hematopoietic remission of 0.91 +/- 0.03. Concl usions: An evening schedule should be recommended for oral MTX/6MP mai ntenance therapy. The value of individual dose adjustments by E-MTX an d E-6TGN remains to be determined in prospective randomized trials.