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).
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.
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 ≤ 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.
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.
From Copenhagen, Denmark (K.S.); Oslo, Norway (A.G.); Reykjavik, Iceland (J.K.); Turku, Finland (T.S.); Århus, Denmark (H.S.); and Stockholm, Sweden (O.B.). See Appendix 1 for participating pediatric departments.
on behalf of the Nordic Society for Pediatric Hematology and Oncology (NOPHO)
Submitted for publication May 7, 1996. Accepted November 12, 1996.
Address correspondence and reprint requests to Dr. Kjeld Schmiegelow, Section of Clinical Hematology and Oncology, Juliane Marie Center, University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.