Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

Abstract

High-dose methotrexate (HDM) given concurrently with oral 6-mercaptopurine (6 MP) may be followed by myelotoxicity, which may necessitate treatment interruption and thus interfere with the efficacy of the treatment of childhood acute lymphoblastic leukemia (ALL). Through inhibition of purine de novo synthesis and enhancement of the bioavailability, HDM may increase the incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6 MP.A total of 26 children diagnosed 3/1996-4/2001 with ALL received five courses of HDM (5 g/m 2 /24 h with leucovorin rescue) at 8 weeks intervals during their first year of maintenance therapy with oral methotrexate (20 mg/m 2 /week) and 6MP (75 mg/m 2 /day). The dose of oral 6MP was reduced to a median of 51% (75% range: 39-62%, maximum 74%) of the standard dose from 2 weeks prior to until 2 weeks after HDM, because the previous HDM had led to a thrombocyte nadir p60 Â 10 9 /l and/or a neutrophil nadir p0.7 Â 10 9 /l. The 6MP dose reductions raised the median thrombocyte nadir following HDM from 46 Â 10 9 /l (range: 6-214) to 133 Â 10 9 /l (range: 21-305; Po0.001) and the median neutrophil nadir from 0.5 Â 10 9 /l (range: 0.0-1.4) to 0.9 Â 10 9 /l (range: 0.2-3.2; Po0.001). The effect of 6MP dose reductions was not significantly related to risk group, gender, age, or thiopurine methyltransferase genotype. With 6MP dose reductions, the median duration of treatment interruption following HDM was reduced from 8 to 0 days (Po0.001).The reduction of 6MP dosage during HDM can significantly reduce the risk of severe myelotoxicity and prevent treatment interruptions.

Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

“…53 However, (1) only genotyping and not phenotyping was used in the BFM study; (2) the backbone maintenance therapy dose of 6MP was 75 mg/m 2 in the NOPHO protocol compared with only 50 mg/m 2 in the BFM protocol; (3) the total duration of therapy for the SR-ALL patients was 27 months in NOPHO ALL-92, whereas maintenance therapy lasts only approximately 18 months for SR-patients in BFM protocols 54 ; and (4) the BFM protocol only give 6MP 25 mg/m 2 concurrent with HD-MTX (so-called protocol M), whereas the NOPHO ALL-92 protocol prescribed HD-MTX (5 g/m 2 ) 5 times together with concurrent 6MP at 75 mg/m 2 during maintenance therapy, which could have increased 6MP-induced DNA damage. 49,55 Although the pattern of second cancers may change with longer follow-up, the high relative frequency of t-AML/MDS and their genetic aberrations in the present study is different from many previous reports, in which solid tumors were relatively more common and t-AML/MDS frequently harbored 11q23-aberrations because of more extensive exposure to topoisomerase II inhibitors such as epipodophyllotoxins and anthracyclines. 34,44,54 Furthermore, t-AML/MDS with deletions of all or part of chromosomes 5 and 7 have previously been linked to exposures to alkylating agents or radiation therapy.…”

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

“…5,29 Accordingly, some studies have shown that the cure rates or the degree of toxicity can be influenced by individualization of therapy based on the patients drug disposition or previous degree of toxicity. 41,42 One of the important challenges for hematologists is to improve the cure rates for adolescents and young adults to the level of that obtained for children. 43 To examine the biology of their leukemias, their pharmacology, treatment efficacy and pattern of side effects, as well as their compliance to therapy, adult hematologists in Denmark, Norway and Sweden will treat young adults between 18 and 45 years of age according to the NOPHO ALL-2008 protocol.…”

Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study

“…36 Second, as the dose of 6MP is increased, so is the degree of myelotoxicity, even if the HD-MTX dose is unchanged, and individual adjustments of the 6MP dose can reduce the degree of bone-marrow suppression. 36,37 Third, patients with TPMT deficiency are at especially high risk for myelosuppression when 6MP is coadministered with HD-MTX. 38 Fourth, it is possible that i.t.…”