Pharmacology of all‐<i>trans</i>‐retinoic acid in children with acute promyelocytic leukemia

Lanvers, Claudia; Reinhardt, Dirk; Dübbers, Angelika; Wagner-Bohn, Alexandra; Creutzig, Ursula; Ritter, J.; Boos, Joachim

doi:10.1002/mpo.10257

Cited by 27 publications

(22 citation statements)

References 45 publications

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“…Lanvers et al found that the plasma retinol level is related to ATRA-induced neurotoxicity in children [4]. In the present study, however, there was no difference of retinol levels between children with and without neurotoxicity (data not shown).…”

Section: Pharmacokinetics Of All-trans Retinoic Acid In Adults and Chcontrasting

confidence: 74%

Chronic parvovirus infection

Koduri¹

2006

American J Hematol

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Section: Pharmacokinetics Of All-trans Retinoic Acid In Adults and Chcontrasting

confidence: 74%

Chronic parvovirus infection

Koduri¹

2006

American J Hematol

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“…Oxidative metabolism has previously been observed in studies with ATRA (Muindi et al, 1992;Rigas et al, 1993) and fenretinide (Villani et al, 2004), and auto-induction of oxidative metabolism has been associated with disease relapse, following chronic administration of ATRA in APL (Muindi et al, 1992). This can be avoided by the use of intermittent ATRA dosing schedules (Adamson et al, 1995), an approach that has also been recommended to minimise the side effects of ATRA in children (Lanvers et al, 2003). Our results with 13-cisRA show an accumulation of the 4-oxo-metabolite between days 1 and 14 of treatment in all patients, with metabolite concentrations higher than those of the parent drug by day 14 in approximately 70% of patients.…”

Section: Discussionmentioning

confidence: 71%

“…The dosing regimen of 80 mg m À2 twice daily for 14 days was associated with significant inter-patient variation in 13-cisRA pharmacokinetics, comparable with that observed following ATRA administration for the treatment of APL (Lanvers et al, 2003). For 13-cisRA, pharmacokinetics may be influenced by a number of factors, including both the method of drug administration and the extent of metabolism.…”

Section: Discussionmentioning

confidence: 72%

Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group

et al. 2007

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The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m À2 b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h À1 , apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (Po0.02), with 2.44-and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (mean7s.d. 4.6773.17 mM) higher than those of 13-cisRA (2.8371.44 mM) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA.

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“…With this regimen, the hematologic complete remission (HCR) rate has improved significantly, to more than 90%; 5-year disease-free survival is more than 70%. [5][6][7][8][9][10] However, some problems still remain; notably, ATRA-related side effects appear to be more pronounced in children than in adult patients, 4,[11][12][13] the optimal postremission therapy still remains to be defined, and approximately 20% to 30% of patients eventually relapse and develop drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia

Zhou¹,

Zhang

Li³

et al. 2010

Blood

108

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The aim of this study was to determine the efficacy and safety of treatment of pediatric acute promyelocytic leukemia (APL) with single-agent arsenic trioxide (ATO). A total of 19 children (< 15 years of age) with newly diagnosed APL were treated with single-agent ATO for remission induction and postremission therapy. Seventeen of the children (89.5%) achieved complete hematologic remission, and 2 early deaths occurred from intracranial hemorrhage. ATO-induced leukocytosis was observed in 13 (68.4%) patients. Other ATO-related toxicities were minimal and transient. Postremission ATO therapy continued for 3 years; the most common side effect was ATO-induced neutropenia. With a median follow-up of 53 months (range, 23-76 months), the calculated 5-year overall survival and eventfree survival were 83.9% and 72.7%, respectively, which are comparable with results achieved by the use of ATRA plus chemotherapy, which is the standard therapy for APL. No chronic arsenic toxicity or second malignancies were found during the follow-up period, and arsenic retention was not significant in patients off treatment more than 24 months. IntroductionAcute promyelocytic leukemia (APL) accounts for approximately 10% of childhood acute myeloid leukemia. [1][2][3][4] APL is characterized by the French-American-British M3 subtype morphology, a distinctive immunophenotype, and, in the majority of cases, there is a t(15;17) chromosomal translocation that generates the promyelocytic leukemia-retinoic acid receptor-␣ (PML-RARa) fusion gene. This specific genetic lesion determines the unique response to treatment with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO). 5 Since the introduction of ATRA in the 1980s and ATO in the 1990s, the strategy for treating APL has shifted from conventional chemotherapy to cancer cell differentiation and cancer-targeted therapy. The combination of ATRA and anthracycline-based chemotherapy is currently the standard approach to treat newly diagnosed APL. With this regimen, the hematologic complete remission (HCR) rate has improved significantly, to more than 90%; 5-year disease-free survival is more than 70%. 5-10 However, some problems still remain; notably, ATRA-related side effects appear to be more pronounced in children than in adult patients, 4,11-13 the optimal postremission therapy still remains to be defined, and approximately 20% to 30% of patients eventually relapse and develop drug resistance.ATO has proven to be another highly effective agent in APL therapy. 14-21 ATO differs from ATRA because of its dual effects of inducing partial differentiation and apoptosis of APL cells. Although highly efficacious, ATO is most commonly used in refractory or relapsed APL for inducing remission. It has previously been shown that single-agent ATO is equally effective in inducing remission in newly diagnosed cases of adult APL. However, little is known about the use of single-agent ATO in the treatment of children with APL. The optimal dosage and route of administration during remission induction and ...

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Pharmacology of all‐trans‐retinoic acid in children with acute promyelocytic leukemia

Cited by 27 publications

References 45 publications

Chronic parvovirus infection

Chronic parvovirus infection

Pharmacokinetics and metabolism of 13-cis-retinoic acid (isotretinoin) in children with high-risk neuroblastoma – a study of the United Kingdom Children's Cancer Study Group

Single-agent arsenic trioxide in the treatment of children with newly diagnosed acute promyelocytic leukemia

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