Daunorubicin-Induced Cell Kill with 1-Hour Versus 24-Hour Infusions: A Randomized Comparison in Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Escherich, Gabriele; Göbel, U; Jorch, Norbert; Hj, Spaar; Ge, Janka-Schaub

doi:10.1055/s-2007-973849

Cited by 19 publications

(15 citation statements)

References 15 publications

(17 reference statements)

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“…It was shown that a 24-h and a 1-h infusion were equally cytotoxic to ALL cells. 6 Consequently, since 1994 the infusion time has been set to 24 h for all anthracycline applications. Future analyses are needed to evaluate the long-term effect of this mode of application on cardiac function in childhood cancer survivors.…”

Section: Discussionmentioning

confidence: 99%

“…4 COALL 92 also focussed on the mode of administration of anthracyclines and on the drug of choice in maintenance therapy. 5,6 The reduction in central nervous system (CNS) irradiation has been an important issue in all trials. The cutoff for the WBC as an indication for CNS irradiation was gradually increased in patients with B-precursor ALL.…”

Section: Introductionmentioning

confidence: 99%

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Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

et al. 2009

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In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significantly from the first two trials conducted in the 1980s (COALL 82 and COALL 85) to the three trials conducted in the 1990s (COALL 89, 92 and 97) (P ¼ 0.001). Through all COALL studies, age X10 years and initial white blood cell count (WBC) X50 Â 10 9 /l and pro-B immunophenotype were of significant prognostic relevance. A refinement of risk assessment has been achieved by in vitro drug sensitivity testing in COALL 92 and 97. In patients with very sensitive leukaemic cells, therapy could be reduced without loss of efficacy. In COALL 97, a further improvement in risk stratification was gained by the molecular assessment of minimal residual disease (MRD) under treatment, which proved to have a superior prognostic effect when compared with in vitro drug sensitivity testing. Importantly, the gradual reduction in central nervous system (CNS) irradiation led to a decreased incidence of brain tumours as a second malignancy. In general, the prevention of treatmentrelated late effects will be one of the major issues in future studies. It remains to be shown whether prolonged infusions of anthracyclines, which have been implemented into the COALL studies after equal efficacy compared with short-time infusions was confirmed, will be associated with fewer cardiac late effects. Another way to prevent late effects may be a more refined risk assessment allowing for a reduction in cumulative treatment burden. A great challenge in the future will be to improve the overall treatment results, which very likely can only be achieved by the identification of molecularly defined subgroups to which novel, rational therapeutic strategies can be applied.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

et al. 2009

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“…One study on DNR treatment of 77 patients with acute lymphoblastic leukemia showed that a 24-h continuous infusion resulted in lower relapse rates than a 30-min infusion of DNR [24]. Alternatively, another study on 178 children with ALL was unable to find any difference in patient outcome between a 1-h and a 24-h DNR infusion protocol [25]. Most studies have compared anthracycline plasma concentrations in patients receiving different infusion protocols, even though it has been shown that there is no clear correlation between plasma concentration and the intracellular concentration of anthracyclines in patients undergoing treatment [5,6].…”

Section: Discussionmentioning

confidence: 99%

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Bogason

Bhuiyan

Masquelier

et al. 2009

Eur J Clin Pharmacol

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Aims To study anthracycline-induced apoptosis in leukemic cells isolated from patients with acute myelogenous leukemia (AML) in vitro and to compare intracellular anthracycline concentrations causing apoptosis in vitro with those obtained in vivo during anthracycline treatment. Methods Mononuclear blood cells from AML patients were isolated before (n=20) and after anthracycline infusion (n= 24). The pre-treated cells were incubated in vitro with daunorubicin (DNR) and/or idarubicin (IDA). Anthracycline concentrations were determined by high-performance liquid chromatography, and apoptosis was detected by propidium iodine staining using a flow cytometer. Results There was a clear concentration-response relationship between intracellular anthracycline levels and apoptosis albeit with a large interindividual variation. Intracellular levels >1200 μM always led to high apoptosis development (>60%) in vitro. The intracellular concentrations of DNR in vivo (n=24) were more than tenfold lower than the concentrations needed to induce effective apoptosis in vitro, although a significant relation between in vivo concentrations and clinical remission was found. We also found a significant relation between apoptosis induction in leukemic cells by IDA in vitro and clinical remission. Conclusions Our results indicate that intracellular anthracycline levels in vivo are suboptimal and that protocols should be used that increase intracellular anthracycline levels.

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“…The results did not demonstrate a statistically significant difference in the left ventricle structure or function between the two groups, and the investigators concluded prolonged infusion time was not beneficial in this population [15]. Escherich et al [14] evaluated the white blood cell count after daunorubicin was given as a continuous, 48 h, versus bolus infusion in leukemia patients. The authors concluded that since there was no statistical difference between the blast count after 7 days that it would be feasible to give daunorubicin as a continuous infusion [14].…”

Section: Prolonged Infusion Of Anthracyclinesmentioning

confidence: 98%

“…The three trials with pediatric patients included in the Cochrane review were all performed in patients with leukemia [14][15][16]. In the study performed by Lipshultz et al [15], patients had high-risk ALL and were randomized to receive 30 mg/m 2 of doxorubicin either by bolus (n=57) or over 48 h (n=64) for a total cumulative dose of 360 mg/ m 2 .…”

Section: Prolonged Infusion Of Anthracyclinesmentioning

confidence: 99%

Can Anthracycline Therapy for Pediatric Malignancies Be Less Cardiotoxic?

et al. 2010

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Anthracyclines have a central role in the treatment of cancer in pediatric patients but confer an increased risk of cardiac dysfunction. Several strategies have been employed to help reduce anthracycline-induced cardiotoxicity, including pretreating the patient with the iron chelator dexrazoxane and infusing the dose of anthracycline over a longer period. Much focus has also been placed on the development of methods that decrease the toxicity of parent compounds, specifically through the use of drug carriers such as liposomes, and on the development of new, potentially less toxic anthracycline derivatives, such as amrubicin and pixantrone. We provide a review of these strategies, focusing on studies in pediatric patients when available, and support the idea that anthracycline therapy can be less cardiotoxic in pediatric patients.

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Daunorubicin-Induced Cell Kill with 1-Hour Versus 24-Hour Infusions: A Randomized Comparison in Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Abstract: We conclude that in children with ALL a 24-h infusion of DNR has the same in vivo cytotoxicity for leukemic cells as a 1-h infusion. This offers the possibility to use prolonged infusions with hopefully less cardiotoxicity without loss of efficacy.

Cited by 19 publications

References 15 publications

Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

Uptake of anthracyclines in vitro and in vivo in acute myeloid leukemia cells in relation to apoptosis and clinical response

Can Anthracycline Therapy for Pediatric Malignancies Be Less Cardiotoxic?

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