Mitoxantrone: benefits and risks in multiple sclerosis patients
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- Martinelli, V., Radaelli, M., Straffi, L. et al. Neurol Sci (2009) 30: 167. doi:10.1007/s10072-009-0142-7
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Mitoxantrone (MTX) is a synthetic antineoplastic cytotoxic drug, active both on proliferative and non-proliferative cells. The efficacy of MTX has been suggested by many open-label or observational studies and demonstrated in four randomized controlled clinical trials (RCTs). It is indicated for reducing neurological disability and the frequency of clinical relapses in patients with progressive relapsing and worsening relapsing–remitting MS patients. The short-term most frequent adverse events observed in RCTs have been nausea/vomiting, alopecia, an increased risk of urinary and respiratory tract infections, phlebitis, transitory leukopenia, amenorrhea in female patients and infertility. However, the most serious risks of the drug are represented by potential cardiotoxicity and leukaemia, whose incidence seems to be higher than previously reported. Therefore, all potential serious adverse events should be carefully considered against the potential relevant benefits of MTX treatment on every single MS patient.
KeywordsMitoxantroneMultiple sclerosisAdverse eventsLeukaemia
Mitoxantrone (MTX) is a synthetic antineoplastic cytotoxic drug, active both on proliferative and non-proliferative cells, that inhibits both DNA replication and DNA-dependent RNA synthesis, inserting itself into DNA and decreasing cell proliferation and protein production. Moreover, MTX inhibits topoisomerase II activity and consequently interferes with DNA repairing mechanisms. It has been an approved oncology treatment for acute non-lymphocytic leukaemia since 1987 in the Unites States and subsequently for breast, hepatic and prostatic cancer, refractory to standard treatments.
The first observation of the immunosuppressive effects of MTX came from studies performed in experimental allergic encephalomyelitis (EAE), which showed that the i.v. administration of the drug was able to suppress disease evolution . MTX is a powerful immunosuppressive agent, able to determine a broad immunosuppression, targeting proliferating immune cells on all the main components of the immune reactions. It has been shown in vitro to decrease the proliferation of damaging B cells, T cells and macrophages. Moreover, it reduces the production of pro-inflammatory cytokines and inhibits macrophage-mediated myelin degradation. MTX is a very small molecule, which may easily cross the blood–brain barrier and interact with cells in the CNS, with a preferred intra-venous route of administration since it is poorly absorbed orally. MTX has a long-lasting immunosuppressive effect; it is rapidly absorbed by tissues and then sequestered in a large proportion for an extended period of time (up to 1 month) .
Clinical and MRI benefits
MTX is indicated for reducing neurologic disability and the frequency of clinical relapses in patients with secondary progressive (SP), progressive relapsing (PR) and worsening relapsing–remitting (RR) MS. The efficacy of MTX has been suggested by many open-label or observational studies and demonstrated in four randomized controlled clinical trials (RCTs) [3–6] which led to the approval of this treatment by the FDA in 2000 and subsequently worldwide. In a double-blind, placebo-controlled trial, which evaluated the safety and efficacy of MTX 5 mg/m2 and MTX 12 mg/m2 every 3 months in RRMS and SPMS patients (MIMS trial), the administration of the drug for 2 years led to a reduction of disability progression and of the annualised relapse rate by 64 and 60%, respectively, in the 12 mg/m2 MTX group . An Italian study conducted in RRMS patients confirmed the efficacy of MTX 8 mg/m2 versus placebo in the reduction of both disability progression (79%) and relapse rate (60%) . The French–British trial , which recruited RR and SPMS patients treated with MTX 20 mg and methylprednisolone 1 g monthly versus methylprednisolone 1 g monthly alone, revealed an 86% decrease in the proportion of patients with enhancing lesions (primary outcome), a reduction of the progression of the disability by 84% and of the relapse rate by 77%. A double-blind trial of MTX versus methylprednisolone in 49 MS patients with frequent exacerbations and rapid disease progression confirmed that MTX is effective in reducing the relapse rate and brain MRI activity .
Three different reviews [7–9], using different techniques of data analysis, have recently confirmed the short-term efficacy of the drug in worsening MS patients. Clerico et al. , in their critical evaluation considering evidence-based parameters and comparing the results from different RCTs of natalizumab and of MTX, demonstrated a great efficacy for both drugs, without significant differences between number needed to treat (NNT) data, when relapse rate, disability progression or patients with activity on brain MRI were evaluated.
In the clinical practice MTX is generally used as a second-line treatment, “rescue therapy”, in patients who are non-responder or partial-responder to immunomodulant agents (interferon beta or glatiramer acetate). MTX has also been administered as first-line treatment to patients naive to any disease-modifying therapy (DMT) with an aggressive RR course, improving the EDSS in a consistent proportion of patients and obtaining significant beneficial MRI effects . In an observational study of 100 consecutive patients (50 patients were DMT naives) with an aggressive RRMS, Le Page et al.  demonstrated that monthly MTX, used as “induction therapy” for 6 months, followed by maintenance treatment (21 patients) or by IFN (25 patients), had sustained clinical beneficial effects up to 5 years. A short course of MTX as “induction therapy”, with sequential maintenance with glatiramer acetate has also been demonstrated to be safe and effective on both clinical and MRI parameters , with the advantage of a limited exposure to the drug. Finally, a multicentre, single-blind, controlled trial evaluating monthly MTX for 6 months versus high-dose interferon beta in patients with a recent diagnosis of MS is going on in Italy and in a few other European countries. The rationale for the use of an induction course of MTX in patients during the first year of the disease and with a bad prognosis is both the rapid management of active and destructive inflammatory processes and higher immunosuppressive and immunomodulant effects of MTX on the immune system, in the early phases of the disease.
Analysing all the clinical and MRI efficacy data already published together with our results obtained in patients with different disease courses (unpublished data), we can conclude that MTX is indicated in patients with aggressive RRMS, RRMS patients, non-responder to standard immunomodulant therapies or patients with PRMS, when clinical or MRI data confirm that clinical worsening could be mainly related to the underlying acute inflammatory processes. On the other hand, MTX does not show significant beneficial effects in PP or SPMS patients, when the neurodegenerative processes are predominant, making the global risk/benefit profile unfavourable for these patients.
Different protocols of drug administration have been used in different MS centres or countries, but up to now no conclusion can be drawn on the best schedule to adopt. MTX may be dosed every 3 months (12 mg/m2), with an average of 8–12 infusions over 2–3 years, or monthly for 6 months (8–12 mg/m2 or 20 mg, with or without 1,000 mg of methylprednisolone), followed by a MTX infusion every 3 months, not exceeding a cumulative dose of 140 mg/m2. It has been suggested to use variable regimens of drug administration, tailored to the specific pattern of disease activity, considering before every infusion, clinical, MRI and haematological findings, as well as the previous short-term side effects, related to the patient to treat.
Short- and long-term risks of MTX treatment
The side effects related to MTX treatment are well known and represent a relevant limitation in its use for a long period of time. Several studies have so far described short-term clinical or laboratory adverse events [3–14]. Short- and long-term safety and tolerability of MTX are being evaluated in RENEW, a multicentre, prospective, phase IV study, planned according to FDA monitoring advice. A total of 505 worsening MS patients were enrolled in the USA during 2001–2002, but no recent safety data have been reported to our knowledge.
The short-term most frequent adverse events, demonstrated considering all the data of RCTs , have been nausea/vomiting (62%), alopecia (47%) and an increased risk of infections, most of all urinary tract infections (25%) and respiratory tract infections (35%), especially in patients who have little mobility. With the standard regimens of administration, severe and persistent thrombocytopenia and anaemia are uncommon, but a modest increase of liver enzymes and bilirubin can be observed as well. Moreover, in the long-term period, MTX may be associated with amenorrhea (26%) in female patients, infertility or persistent amenorrhea (8%). The actual evaluation of the safety profile of this drug is hampered by the different treatment schemes adopted in the different clinical trials, the modality to detect the adverse events and the duration of the follow-up.
The most serious risks of the drug are represented by short-and long-term potential cardiotoxicity and leukaemia [7, 8, 13]. The risk of cardiotoxicity has been the first important matter of concern among neurologists since the early use of the drug. A reduction of the left ventricular ejection fraction (LVEF) may be an early marker for MTX-induced cardiotoxicity. An increased risk of cardiotoxicity seems to be related to a more rapid infusion of the drug, suggesting that i.v. infusions must last at least 30 min. A patient’s baseline LVEF should be always evaluated and must be >50%. Clinical cardiotoxicity increases with a higher cumulative dose, leading to the recommendation not to go beyond the cumulative dose of 96–140 mg/m2 of body surface. Although clinically significant heart failure has been observed in 0.2–0.5% of patients, recent studies have found a high incidence of subclinical adverse cardiac events even in patients treated with doses well below the recommended level, without any apparent dose–response evidence . A recent warning of the FDA recommends performing a periodic and careful monitoring of cardiac function before every MTX cycle, particularly in individuals with LVEF at the low-normal value. If a 10% reduction of LVEF is observed at repetitive evaluations or LVEF is lower than 50%, the therapy should be discontinued. Up to now it is not known the real risk of late cardiac toxicity related to MTX use as well as the possible cardioprotective effects of dexrazoxane.
Therapy-related acute leukaemia (TRAL), especially myeloid leukaemia, is a major concern for neurologists and patients when considering the treatment with MTX, but for many years TRAL has been considered a rare complication in MS patients. However, the risk of TRAL in oncological patients, treated with MTX and other antineoplastic drugs or radiotherapy, ranges from 1 to 12%. TRAL is typically associated with the use of DNA-topoisomerase inhibitors, such as MTX; it is characterized by specific cytogenetic changes and its outcome seems similar to that of de novo acute promyelocytic leukaemia . In 1998 there was the first TRAL reported in MS patients  and up to 2005 only 9 cases of TRAL (2 patients died) in MS were described in medical literature ; the onset of TRAL ranged from 3 months to 5 years after the end of MTX treatment. Previous studies reported an incidence of TRAL ranging from 0.7 per 1,000 treated patients  to 2.5 per 1,000 . Only recently an incidence of 3.3 TRAL per 1,000 MS patients treated with MTX has been described, considering all the cohort series published so far . However, during the last year, individual local series, referring to small cohorts of patients, have reported higher frequencies. Moreover, in the USA 39 cases of TRAL were spontaneously reported from 2003 to 2007 in a post-marketing setting  with a total mortality rate of 35.5% (the number of TRAL increases from 4 cases in 2003 to 11 cases in 2007). The mean cumulative dose of MTX, available for 18 patients, was 83.2 mg/m2 (range 48–135 mg/m2).
In this uncertain context, our MS Centre is coordinating a multicentre, retrospective study to evaluate the incidence of TRAL, and other solid tumours, in MS patients treated with at least 1 cycle of MTX and followed for at least 1 year in the Italian MS Centres. The preliminary and partial results, obtained so far with the collaboration of 26 Italian MS centres which have identified 2,231 patients treated with MTX, showed a cumulative incidence of 6.7 per 1,000; so far 15 cases of TRAL have been observed in the Italian cohort . TRAL developed after an average period of 3 years from the beginning of MTX therapy and after a mean of 1.3 years from the end of the treatment. The final and definitive data, with a greater number of participating centres and of MS patients enrolled, will be available in the next months.
A careful evaluation of the benefits and risks
These data should be considered as a matter of concern from now on. The incidence of TRAL in Italian MS patients treated with MTX seems to be higher than previously reported. Both clinicians and patients must be aware of the long-term risk of developing acute leukaemia, as well as the dose-related cardiotoxicity and impairment of fertility. The overall potential serious adverse events should be carefully considered against the potential relevant benefits of MTX treatment on every single MS patient. During the decision making process, a thorough evaluation of all alternative available therapies should also be considered. Finally, since so far there are no tests to identify susceptible patients before the MTX treatment, all MS patients treated with MTX must undergo a prolonged and careful haematological follow-up after discontinuation of MTX, particularly if other immunosuppressive agents have also been used.
Conflict of interest statement
The authors declare that they have no conflict of interest related to the publication of this article.