Daunorubicin continuous infusion induces more toxicity than bolus infusion in acute lymphoblastic leukemia induction regimen: a randomized study

Hunault, Mathilde; Milpied, Noël; Bernard, Marc; Jouet, Jean‐Pierre; Delain, Martine; Desablens, B; Sadoun, A.; Guilhot, Joëlle; Casassus, P.; Ifrah, Norbert

doi:10.1038/sj.leu.2402130

Cited by 18 publications

(7 citation statements)

References 19 publications

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“…10,19,20 The high incidence of Gram-negative bacteremia observed after CI-Dox treatment is reminiscent of our previous results with CI daunorubicin in younger ALL patients. 25 This is likely related to the CI doxorubicin, rather than to the CI vincristine, as it was also observed during the consolidation phases that included a standard 5-minute vincristine infusion. The use of dexamethasone in both arms might also have increased the rate of infections, especially invasive fungal infections.…”

Section: Discussionmentioning

confidence: 93%

A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Hunault¹,

Leguay²,

Thomas

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundThe prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia. Design and MethodsSixty patients received either continuous-infusion doxorubicin (12 mg/m 2 /day) and continuousinfusion vincristine (0.4 mg/day) on days 1-4 or pegylated liposomal doxorubicin (40 mg/m 2 ) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors. ResultsMyelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm. ConclusionsWith the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities. (ClinicalTrials.gov Identifier: NCT00600977).

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Section: Discussionmentioning

confidence: 93%

A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

Hunault¹,

Leguay²,

Thomas

et al. 2010

Haematologica

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“…Both studies were based on very few patients. 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].…”

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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“…A randomised study [253] and a review [252] indicate a modest advantage of a 3-day schedule over weekly anthracycline administration. The response rate is no better when anthacycline-type drugs (DNR, mitoxantrone) are given as continuous infusion rather than as a bolus [254,255]. There is uncertainty as to the best anthracycline compound.…”

Section: Remission Induction Chemotherapymentioning

confidence: 99%

Adult acute lymphoblastic leukaemia

Bassan

Gatta

Tondini

et al. 2004

Critical Reviews in Oncology/Hematology

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Daunorubicin continuous infusion induces more toxicity than bolus infusion in acute lymphoblastic leukemia induction regimen: a randomized study

Cited by 18 publications

References 19 publications

A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study

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

Adult acute lymphoblastic leukaemia

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