Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Should Dosage Be Guided by White Blood Cell Counts?

Schmiegelow, Kjeld; Pulczynska, Malgorzata K.

doi:10.1097/00043426-199024000-00010

Cited by 33 publications

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“…Maintenance therapy of childhood ALL and NHL is traditionally monitored and adjusted by the degree of myelosuppression [3] which reXects the assumption that eYcacy and toxicity are interrelated, and that myelosuppression is required for a successful anticancer eVect [2]. The treatment intensity obtained during maintenance therapy reXects the dose adjustment guidelines of the relevant protocol, individual drug disposition, and the compliance to the protocol by both the physician and the patient [20,21].…”

Section: Discussionmentioning

confidence: 99%

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DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Hedeland

Hvidt

Nersting

et al. 2009

Cancer Chemother Pharmacol

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Purpose To explore the DNA incorporation of 6-thioguanine nucleotide levels (DNA-6TGN) during 6-mercaptopurine (6MP) therapy of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL) and its relation to erythrocyte levels of their metabolites: 6-thioguanine-nucleotides (E-6TGN), methylated metabolites (E-MeMP), Methotrexate polyglutamates (E-MTX), and to thiopurine methyltransferase activity (TPMT). Methods We studied these metabolites in 229 blood samples from 18 children with ALL (N = 16) or NHL (N = 2) on 6MP/Methotrexate maintenance therapy. Results DNA-6TGN levels were signiWcantly correlated to E-6TGN (r p = 0.66, p = 0.003) with a trend to reach a plateau at high E-6TGN levels. To explore the relative DNA incorporation of 6TGN in relation to cytosol 6TGN levels, a DNA-6TGN index was calculated as DNA-6TGN/ E-6TGN. The DNA-6TGN index was inversely correlated to E-6TGN (r p = ¡0.58, p = 0.012), which implies that with increasing levels of E-6TGN relatively less 6TGN are incorporated into DNA. E-MeMP levels were correlated to the DNA-TGN index (r p = 0.60, p = 0.008), indicating that high levels of MeMP result in enhanced DNA-6TGN incorporation, possibly due to inhibition of purine de novo synthesis, mediated by some of the methylated 6MP metabolites. Conclusions DNA-6TGN may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than the previously used erythrocyte 6MP metabolites levels. Prospective clinical trials are needed to evaluate the usefulness of DNA-6TGN for individual dose adjustments.

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Section: Discussionmentioning

confidence: 99%

“…Due to large interindividual variations in the metabolism of these antimetabolites, the response to standard 6MP/ MTX doses varies signiWcantly, and 6MP/MTX maintenance therapy of childhood ALL and NHL is usually adjusted and targeted to speciWed degrees of bone marrow suppression [2,3]. 6MP is a pro-drug with no intrinsic anticancer activity.…”

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confidence: 99%

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Hedeland

Hvidt

Nersting

et al. 2009

Cancer Chemother Pharmacol

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“…The mWBC, mANC and mPLATE were calculated as weighted means using as weight the interval between the sample in question and the next blood sample as previously described. 21 The Mann-Whitney U test, Wilcoxon's test, and Spearman's rank order correlation analysis were applied to compare the distributions of parameters between subgroups, in related samples, and the correlations between parameters (r S = correlation coefficient). 22 Since HDM was given right at the start of maintenance therapy for IR-ALL (at week 33) without preceding oral 6MP therapy, this HDM course was excluded from the multivariate regression analysis of the impact of oral 6MP on HDM toxicity.…”

Section: Statisticsmentioning

confidence: 99%

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

Schmiegelow

Bretton-Meyer

2001

Leukemia

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were compared, white cell and absolute neutrophil count (ANC) nadir, lymphocyte count nadir, thrombocyte count nadir, and hemoglobin nadir after HDM decreased significantly with increasing doses of oral 6MP. Three percent of the HDM courses given without oral 6MP (SR consolidation) were followed by an ANC nadir Ͻ0.5 × 10 9 /l compared to 50% of the HDM courses given during SR/IR maintenance therapy. Similarly, only 13% of the HDM courses given as SR-ALL consolidation induced a thrombocyte count nadir Ͻ100 × 10 9 /l compared to 58% of the HDM courses given during maintenance therapy. The best-fit model to predict the ANC nadir following HDM during maintenance therapy included the dose of 6MP prior to HDM (␤ = −0.017, P = 0.001), the average ANC level during maintenance therapy (␤ = 0.82, P = 0.004), and E-6TGN (␤ = −0.0029, P = 0.02). The best-fit model to predict the thrombocyte nadir following HDM during maintenance therapy included only mPLATE (␤ = 0.0057, P = 0.046). In conclusion, the study indicates that reductions of the dose of concurrently given oral 6MP could be one way of reducing the risk of significant myelotoxicity following HDM during maintenance therapy of childhood ALL. Leukemia (2001) 15, 74-79.

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“…8,[27][28][29][30][31][32][33] In general, the published studies support that low WBC levels during 6MP/MTX maintenance therapy is linked to a reduced risk of relapse. Furthermore, lack of physician compliance to dose titration has been associated with an increased risk of treatment failure.…”

Section: Discussionmentioning

confidence: 99%

“…Wherein relevant, the covariates were analyzed as time-dependent continuous parameters with recalculations of the weighted means of these variables every time a patient failed using as weight the interval between the sample in question and the next blood sample. 21 Survival analyses were carried out with a basic time scale defined by the date of diagnosis with delayed entry of patients at the start of their maintenance therapy. As events in the event-free survival (EFS) analyses, we included death in remission, relapse or the diagnosis of a second malignant neoplasm, whichever occurred first.…”

Section: 14mentioning

confidence: 99%

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

et al. 2010

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Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (X10 years) and 176 non-adolescents (o10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) o50 Â 10 9 /l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS 12y :0.71 vs 0.83, P ¼ 0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r S ¼ 0.36, P ¼ 0.02), which became nonsignificant for those who relapsed (r S ¼ 0.05, P ¼ 0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P ¼ 0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient ¼ 0.65, P ¼ 0.003) than for non-adolescents (coefficient ¼ 0.42, P ¼ 0.04). Adolescents had higher mean neutrophil counts (P ¼ 0.002) than nonadolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r S ¼ 0.38, P ¼ 0.02), which was not the case for those who developed a relapse (r S ¼ 0.15, P ¼ 0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

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Maintenance Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Should Dosage Be Guided by White Blood Cell Counts?

Cited by 33 publications

References 0 publications

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma

6-Mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

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