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Mitoxantrone

A Review of its Pharmacological Properties and Use in Acute Nonlymphoblastic Leukaemia

  • Drug Evaluation
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Summary

Synopsis

Acute nonlymphoblastic leukaemia (ANLL) is a malignant condition strongly associated with advancing age. Of adult acute leukaemias, 80 to 85% are classified as ANLL, with more than half of all patients being aged over 60 years.

Although advancing age has been reported to be a poor prognostic factor in ANLL, recent clinical trials have shown good results in patients aged 60 years and over after coadministration of the anthracenedione antineoplastic agent mitoxantrone with cytarabine. In 1 study in particular, which involved patients aged 60 to 81 years, no correlation was found between increasing age and response rate. However, results of a major clinical trial showed age greater than 60 years to be associated with poorer outcomes.

Mitoxantrone as initial induction treatment is at least as effective as daunorubicin when either drug is given in combination with cytarabine to patients with previously untreated ANLL. Complete response rates in randomised comparative trials were 53 to 67% after mitoxantrone with cytarabine and 37 to 70% after daunorubicin with cytarabine. In a major US study, significantly more patients achieved a complete response after 1 treatment cycle of mitoxantrone and cytarabine than after daunorubicin and cytarabine. Mitoxantrone has also been effective in inducing complete remissions in patients with relapsed or refractory ANLL, mainly in combination with other antineoplastic agents.

Overall survival appears similar after treatment with regimens containing either mitoxantrone or daunorubicin in patients with ANLL, although there have been reports of trends towards increased survival rates with mitoxantrone.

The incidence of cardiotoxicity appears low in patients with ANLL who have received mitoxantrone. Lower cardiotoxicity of mitoxantrone relative to daunorubicin has not been conclusively demonstrated in patients with ANLL, although trials in patients with breast cancer have shown mitoxantrone to cause fewer cardiac adverse effects than doxorubicin. This is of particular interest in the elderly, as this group of patients is especially susceptible to the effects of anthracycline-induced cardiac toxicity.

Thus, mitoxantrone is a suitable first-line agent for the induction of remission in patients with ANLL, with clearly demonstrated efficacy in patients aged 60 years and over.

Pharmacodynamic Properties

Mitoxantrone is believed to exert its cytotoxic effects by interfering with the function of topoisomerase II (thereby preventing religation of DNA strand breaks). The drug may also inhibit protein kinase C activity and may enhance induce apoptosis in leukaemic cells.

Mitoxantrone is active against a variety of tumour systems (both leukaemias and solid tumours). Additive or synergistic effects in inducing cellular DNA damage are obtained when cells are exposed to mitoxantrone in combination with cytarabine, amsacrine, cisplatin, doxorubicin, etoposide and a number of other agents. Enhanced cellular damage has also been reported after sequential exposure to mitoxantrone and cytarabine.

Overview of Pharmacokinetic Properties

After intravenous administration, mitoxantrone has a rapid distribution (α) phase of up to approximately 10 minutes’ duration and a subsequent β phase which lasts for up to approximately 3 hours. The drug has a very large volume of distribution (1000 to 4000L). Animal data suggest that the extent of plasma protein binding is 78%. In patients with acute nonlymphoblastic leukaemia (ANLL), mitoxantrone appears to be concentrated in leukaemic cells.

Mitoxantrone is thought to be metabolised by the liver and eliminated mainly in bile. Renal clearance accounts for up to approximately 10% of the total clearance of the drug. The terminal elimination (γ) half-life of mitoxantrone has been reported to be 1 to 215 hours; the precise nature and duration of this phase remain to be defined.

Therapeutic Use of Mitoxantrone in Acute Nonlymphoblastic Leukaemia

Complete response rates of 48 to 83% were reported in noncomparative trials in patients with previously untreated ANLL, most of whom received mitoxantrone 10 mg/m2/day for 3 to 5 days with cytarabine 100 to 200 mg/m2/day for 5 to 7 days (all results reported in this section were obtained after intravenous administration). Notably, no correlation was demonstrated between patient age and response in one of these studies which involved patients aged 60 to 81 years.

Mitoxantrone and daunorubicin showed similar efficacy in terms of rates of complete response and survival in comparative clinical trials where either drug was coadministered with cytarabine. Complete response rates were 53 to 67% for mitoxantrone-treated patients and 37 to 70% for those who received daunorubicin. Differences between groups were statistically nonsignificant, but there was a trend towards increased response rates with mitoxantrone in 3 of 4 trials. In a major comparative US study, poorer complete response rates were seen in patients aged over 60 years than in younger patients after either mitoxantrone and cytarabine or daunorubicin and cytarabine. Significantly more patients achieved complete remission after 1 treatment cycle with mitoxantrone than with daunorubicin in this trial.

Preliminary data from a meta-analysis of 6 clinical studies in 1020 patients with ANLL have shown complete response rates of 57% in patients who received induction chemotherapy with mitoxantrone and cytarabine, compared with 50% in those who received daunorubicin and cytarabine. Five-year overall and disease-free survival was similar for both regimens.

Mitoxantrone 10 mg/m2/day plus etoposide 100 mg/m2/day for 5 days resulted in complete response rates of 50 to 57% in 3 trials in patients with previously untreated ANLL, 2 of which involved only patients aged 60 years and over. The addition of cytarabine further improved the complete response rate (to 64 to 74%).

Patients with relapsed or refractory ANLL have also responded to treatment with mitoxantrone, given either as monotherapy or in combination with other agents. Clinical trials of mitoxantrone monotherapy (10 to 14 mg/m2/day for 3 to 5 days) resulted in complete response rates of 32 to 48%. Complete response rates of 28 to 67% were recorded in studies ranging in size from 15 to 151 patients after salvage chemotherapy with mitoxantrone and cytarabine, with incomplete cross-resistance between mitoxantrone and daunorubicin or doxorubicin being reported in some trials. In a randomised study of 151 patients in which patients were stratified according to age (< years or ≥60 years), there was no significant difference in response between age groups. Complete response rates of 16 to 61 % after coadministration of mitoxantrone with etoposide, and 33 to 66% after mitoxantrone with cytarabine plus etoposide, have been reported in patients with relapsed or refractory ANLL.

Attempts have been made to enhance the cytotoxicity of mitoxantrone and other cytotoxic agents in patients with ANLL by ‘priming’ leukaemic bone marrow with granulocyte colony-stimulating factors before administering chemotherapy. However, the results of these small studies are inconclusive.

Tolerability

Leucopenia, the major dose-limiting adverse effect of mitoxantrone chemotherapy, is of particular concern in elderly patients. Comparative data have shown similar granulocyte recovery times after chemotherapy with cytarabine plus either mitoxantrone or daunorubicin (median 30 and 33 days, respectively, to attain granulocyte counts ≥1000/µ1 in one study). Platelet recovery times were also similar for these 2 regimens. No significant difference between treatment groups in the number of deaths secondary to hypoplastic or aplastic marrow was observed after either mitoxantrone or daunorubicin with cytarabine in a major comparative US trial. These results also showed no statistically significant effect of age on aplastic death rates after treatment with mitoxantrone or daunorubicin, although there was a trend towards higher death rates in patients aged 60 years and over.

Studies in patients with breast cancer have shown significantly less cardiotoxicity with mitoxantrone than with doxorubicin. The incidence of cardiotoxicity appears low in patients with ANLL who have received mitoxantrone; a major comparative trial reported a similar incidence of congestive heart failure (CHF) [mainly attributable to fluid overload due to supportive therapy] after treatment with cytarabine plus either mitoxantrone or daunorubicin. Anthracyclines show cumulative cardiotoxicity, and patients treated with mitoxantrone are stated to have a cumulative 2.6% probability of developing clinical CHF after a cumulative dose of 140 mg/m2.

Other nonhaematological adverse effects associated with mitoxantrone therapy include nausea and vomiting, diarrhoea, abdominal pain, stomatitis, infections and alopecia. Comparative data have shown the incidence of these and other effects to be similar in patients with ANLL after treatment with regimens incorporating either mitoxantrone or daunorubicin.

Dosage and Administration

Mitoxantrone should be given at a dosage of 12 mg/m2/day on days 1 to 3 of treatment, together with a continuous infusion of cytarabine 100 mg/m2/day on days 1 to 7. The concentrated aqueous solution of mitoxantrone should be diluted to at least 50ml with sodium chloride 0.9%, dextrose 5% or dextrose 5% with sodium chloride 0.9% and introduced into a freely running intravenous infusion over not less than 3 minutes.

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    Christopher J. Dunn & Karen L. Goa

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Various sections of the manuscript reviewed by: M.K. Adwankar, Chemotherapy and Stem Cell Biology Division, Cancer Research Institute, Tata Memorial Centre, Bombay, India; E. Archimbaud, Service d’Hématologie, Hôpital Édouard Herriot, Lyon, France; M. Björkholm, Department of Medicine, Karolinska Hospital, Stockholm, Sweden; G. Capranico, Istituto Nazionale per lo Studio e la Cura dei Tumori, Division of Experimental Oncology B, Milan, Italy; A. Gruber, Division of Medicine, Section of Hematology and Medical Immunology, Karolinska Hospital, Stockholm, Sweden; A.S. Juvekar, Chemotherapy and Stem Cell Biology Division, Cancer Research Institute, Tata Memorial Centre, Bombay, India; P.K. MacCallum, MRC Epidemiology and Medical Care Unit, The Medical College of St. Bartholomew’s Hospital, London, England.

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Dunn, C.J., Goa, K.L. Mitoxantrone. Drugs & Aging 9, 122–147 (1996). https://doi.org/10.2165/00002512-199609020-00007

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