MYELOTOXICITY, PHARMACOKINETICS, AND RELAPSE RATE WITH METHOTREXATE 6-MERCAPTOPURINE MAINTENANCE THERAPY OF CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA/

White blood cell and absolute neutrophil counts (WBC, ANC), aminotrans ferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) dose s, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnose d from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBC(ON), mWBC(OFF), m ANC(ON), mANC(OFF)), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calcula ted, as well as the product of mE-MTX and mE-6TGN (mE-MTX6TGN), as MT X and GMP probably act synergistically. Beyond higher MTX and 6MP dose s to patients with high mWBC(ON), neither mWBC(ON), (median 3.5 x 10(9 )/L), mANC(ON), nor mAT was correlated with the dose of MTX and 6MP, m E-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX6TGN above or below 828 (nmol/mmol Hb)(2) (median value) had pEFS values of 0.84 an d 0.70, respectively (P = .16). All 5 patients who relapsed during the rapy had mE-MTX6TGN <828 (nmol/mmol Hb)(2) (P = .03). mWBC(OFF) and t he degree of myelosuppression (= mWBC(SHIFT) = mWBC(OFF) - mWBC(ON); m edian: 2.5 x 10(9)/L) were related to age (r(s) = -0.50, P = .001 and r(s) = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBC(SHIFT) <2.5 x 10(9)/L (P = .02). WBC le vels during MTX/6MP therapy may underestimate the degree of MTX/6MP tr eatment intensity, especially in older children. Pharmacokinetic monit oring could be useful for optimizing MTX/6MP maintenance therapy.