A radioimmunoassay was used to measure vincristine sulfate concentrations in the serum of four children with malignancies (ages 5-16 years) following intravenous (IV) bolus injections. The pharmacokinetic data were analyzed by a non-linear least-square regression program NONLIN. A three-compartment open model fitted the raw data better than a two-compartment model in three patients. In the other patient the raw data fitted a two-compartment open model. The half-lives of the triphasic decay curves alpha, beta, and gamma were 2.6, 41, and 1,531 min (25.5 h), respectively. The mean apparent volume of the central compartment was 3.25 l, and the the volume of distribution per 1.73 m2 body surface area at steady state was 215.9 l. In a three-compartment open model, the first-order distribution and elimination rate constants (min-1) of vincristine were as follows: k12, 0.088; k13, 0.121; k21, 0.028; k31, 0.0026; k10, 0.045. The plasma clearance was 146.2 ml/min per 1.73 m2, while the AUC0 infinity was 27,816 nM . min. Urinary excretion in one patient demonstrated a drug concentration of greater than 1.0 X 10(-7) M in the urine up to 78 h after the injection. Up to 37% of the administered drug was excreted in the urine as vincristine and/or its metabolites by 90 h. The low elimination rate constant from poorly perfused tissues to blood plasma (k31), a large apparent volume of distribution, and a long biological half-life (25.5 h) indicate avid tissue binding from which a slow release of the drug from the body tissues occurs.
Twenty-two children with acute lymphocytic leukemia (ALL) who had relapsed while on therapy and for whom remissions were successfully reinduced were maintained with a combination of methotrexate, daunomycin, 6-mercaptopurine, prednisone, and vincristine (Djerassi-methotrexate with BOMB). The median duration of remission was 35 weeks (range, five to 364+ weeks). Of 8 children (36%) did not relapse while receiving this therapy, 4 are off all therapy (durations of remissions, 40+, 97+, 132+, and 216+ weeks). Improved responses were found in children with platelet counts of greater than 10(5)/mm3 at the time of index relapse. Intrathecal chemotherapy seemed to greatly prolong the duration of remission for 16 children when compared to those children who did not receive IT therapy (45.5 vs. 24 weeks). No central nervous system relapses occurred. This maintenance regimen for children with previously relapsed ALL appears to be effective and worth additional clinical trials.
; (spon. by S. Inoue), Children's Hospital of Michigan (CHI), Detroit, Michigan 48201.Recent reports have indicated that elevated CSF levels of B2m in AL patients may precede the cytologic diagnosis of central nervous system (CNS) involvement. This prompted us to reevaluate the CSF B m levels obtained on 42 AL patients at CHM during the years [1972][1973][1974][1975]. All but 3 had acute lymphoblastic leukemia (ALL) 36 ALL children were receiving CNS prophylaxis consisting of intrathecal (IT) Methotrexate (MTX) and fractional radiation to the CNS (IMFRA) given at 10 wks. intervals. CSF was obtained at the time of administration of IT MTX either for prophylaxis or for overt CNS relapse. The level of B m in the CNS prophylaxis group (36) varied from 0.4 to 3.65 mgl? < ; 1.55 mg + .79). 4 had elevated levels of B m 63mg/l,? +2SD) at a time when CSF was free of leukemic cel?s. Three eventually developed CNS leukemia 2 mos., 8 mos., and 4 yrs. later. The CSF B m level at the time of overt CNS relapse in 6 AL children varied2from 0.93 -5 mgll (f 3.18 + 1.78). This differed significantly (p: C.001) from the CNS prophylaxis group. B m level was > 3 mg/l in 516. These data confirm the prior obiervations of others that CSF B m levels 2 are elevated during CNS relapse. Thus elevated levels may indicate impending relapse. Prophylactic IT MTX in itself does not appear to significantly alter the normal CSF B2m levels. A marked increase in WBC count with blast cell predominance in blood is a well known hematological abnormality seen in neonates with Down's syndrome. Differentiation of true leukemia from a transient leukemoid reaction is often difficult. Examination of in vitro colony formation and maturation by circulating stem cells may be helpful in separating the two entities. We studied a newborn infant with trisomy 21 Down's syndrome who had juandice, 5 cm palpable liver and 1 cm palpable spleen. The Hb, WBC and platelet count at day 3 of life were 12.5 gm %, 62,300 with 58% blasts and 90.5x1031mm3, respectively. Blood group incompatibility and intrauterine infections were excluded. The marrow showed 17% blasts. Prominent large basophilic granules were present in late myeloid precursors. The patient was simply observed. During the next 6 weeks the hematological picture returned to normal. Cultures of blood stem cells using the methylcellulose system were done on two occasions at day 9 of age (WBC 38.5~103, 47% blasts), and at day 26 of age (WBC 17.7~103, 6% blasts). The first blood formed 1,525 myeloid and 213 erythroid, and the second blood 256 myeloid and 17 erythroid colonies/ml of blood, respectively. No maturational difficiency was observed by cytological study of representative colonies. This normal maturation pattern is consistent with the spontaneous resolution of the clinical picture. The technique may be a useful tool in predicting the outcome. These neuropsychological and electrophysiological t e s t s are valuable i n the evaluation o f the long-term nervous system sequel ae o f chi1 dhood leukemia and i t s t...
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