Mitoxantrone treatment of multiple sclerosis

Types.

One of the more serious adverse events associated with mitoxantrone treatment is cardiac toxicity. The potential for myocardial damage resulting in congestive heart failure is the factor limiting the total dose in MS patients. The risk for myocardial toxicity increases with cumulative doses >100 mg/m², and the total approved dose for use in worsening MS is 140 mg/m². Consequently, cardiac function monitoring is required periodically and is recommended before every infusion once a cumulative dose of 100 mg/m² has been reached.

Mitoxantrone should not be used in MS patients with pre-existing cardiomyopathy, patients with active or documented cardiovascular disease, patients who have received previous treatment with anthracyclines or mediastinal radiation, or patients whose baseline pretreatment systolic left ventricular ejection fraction (LVEF) is <50%. In individuals with baseline LVEFs in the low-normal range, it is prudent to reassess cardiac function more frequently. In the case of anthracyclines, cardiac toxicity is, in part, related to peak plasma concentration.2,3⇓ Because of the increased risk for cardiotoxicity with more rapid infusions, it has been suggested that mitoxantrone should be infused over at least 30 minutes.4 An uncommon cardiac toxicity reported in non-MS patients given mitoxantrone is an acute cardiac arrhythmia during the infusion, which is believed to be related to the infusion rate.

Putative mechanism.

Mitoxantrone intercalates into DNA, causing strand breaks and crosslinks. It is also a potent inhibitor of topoisomerase II, thus impairing DNA repair, and it exerts cytocidal effects on both proliferating and non-proliferating cells. The drug is taken up by myocardial cells, in which it chelates with iron and forms complexes. Cardiomyopathy is thought to result from intracellular generation of reactive oxygen intermediates via iron or enzyme-mediated oxidation–reduction reactions. Cardiac myocytes appear to be selectively susceptible to mitoxantrone-induced damage due to their relative lack of defense mechanisms such as catalase and superoxide dismutase.5,6⇓

Histopathology.

In animal models, the histopathologic changes associated with mitoxantrone, an anthracenedione, are similar to those produced by anthracyclines such as doxorubicin but appear to require higher doses than with anthracyclines. Reported histopathologic findings include myofibrillar degeneration, focal mitochondrial enlargement, sarcoplasmic reticulum tubule dilatation, intracellular edema and vacuolization, and myocyte drop-out. Mitochondrial alterations were found to be more pronounced in an animal model after exposure to mitoxantrone in comparison to doxorubicin.5 The modest reduction in myocytes is consistent with the hypothesis that cardiac toxicity due to these agents results from structural changes in the myocytes rather than from necrosis or apoptosis.5,6⇓

Clinical experience with mitoxantrone in MS.

Experience with mitoxantrone in clinical practice suggests that the doses used for treating MS are infrequently associated with symptomatic congestive heart failure. A review of the data from three clinical trials revealed only two cases in 1378 patient records, resulting in an estimated prevalence of 0.15%. Asymptomatic reduction in LVEF of <50% occurred more commonly, being observed in 2.18% of 779 patients who underwent both baseline and follow-up LVEF testing. The risk appeared to be dose-related, with a strong trend to increase with cumulative doses ≥100 mg/m² (1.8% versus 5%; p = 0.06).7 In clinical practice, the risk for LVEF reduction may be greater,8 supporting more frequent measurements of LVEF before a cumulative dose of 100 mg/m².

Diastolic measures of contractility may be more sensitive to changes induced by mitoxantrone than systolic LVEF. In a comparison of 30 matched MS subjects, 15 of whom were given ≥5 infusions (mean dose 75 ± 0.9 mg/m²) and 15 additional healthy controls, a significant reduction of the mean velocity gradient in early diastole (using Doppler myocardial imaging) was observed in the patients receiving mitoxantrone.9

There is evidence that prostacyclin, generated from cyclooxygenase-2 (COX-2), is cardioprotective.10 Therefore, a potential risk factor for mitoxantrone-induced myocardial toxicity is concurrent treatment with COX-2 inhibitors. Inhibition of COX-2 has been shown to aggravate doxorubicin-mediated cardiac injury.11 Although no data exist regarding the safety of COX-2 inhibitors in patients receiving mitoxantrone, a similar interaction might occur. These findings suggest that prostacyclin analogues might be cardioprotective against injury and that COX-2 inhibitors should be avoided or used with caution in patients receiving mitoxantrone.

It is not known whether treatment with mitoxantrone monotherapy in doses used for MS might be associated with a late cardiac toxicity. No current data on MS patients beyond 4 years after completion of treatment are available. Later cardiac disease is seen in cancer patients after anthracycline therapy, with the greatest incidence observed in pediatric populations.12 This late cardiac toxicity has been associated with mediastinal radiotherapy and combination chemotherapy with paclitaxel and cyclophosphamide. In patients with previous exposure to potentially cardiotoxic agents, it is prudent to consider the possibility of an increased risk with mitoxantrone and to follow such patients with more frequent cardiac monitoring. Studies (e.g., RENEW, which is discussed later) are under way that may help to clarify the risk for late cardiac toxicity.

Possible cardioprotective strategy with dexrazoxane.

Dexrazoxane chelates iron, thereby preventing its complexing with mitoxantrone and potentially inhibiting the generation of reactive oxygen intermediates.6 Dexrazoxane has established efficacy in mitigating high-dose anthracycline cardiotoxicity and is given 30 minutes before infusion of the chemotherapeutic agent in a 10–20:1 dose ratio. Based on comparative potency with mitoxantrone, this would correspond to a ∼50:1 dose ratio.13–15⇓⇓ Potential adverse effects are associated with the concomitant use of dexrazoxane, such as additive myelosuppression and an increased risk for local phlebitis. At present there are not sufficient data to mandate the routine use of dexrazoxane in combination with mitoxantrone.

In a safety study, Mikol et al.16 found that dexrazoxane suppressed a decrease in LVEF after 48 mg/m². It is, of course, important to show that dexrazoxane does not interfere with mitoxantrone’s efficacy, and studies are under way that address this question. Nevertheless, it is somewhat reassuring that dexrazoxane increased the therapeutic efficacy of mitoxantrone in an experimental autoimmune encephalomyelitis model of MS.17 Therefore, dexrazoxane might have both a cardioprotective and an additive therapeutic effect on mitoxantrone-induced immune suppression.

Cardioprotective strategy using liposomes.

Different delivery systems can favorably alter the pharmacokinetics and safety profile of a given drug. Liposome-entrapped mitoxantrone regimens have been compared to conventional mitoxantrone infusions in murine leukemia models. The liposomal form had lower concentrations in cardiac muscle, along with a maintained efficacy against leukocytes.18 The significant decrease in toxicity observed with the liposomal form might provide a safer alternative formulation for clinical use in MS patients.

Putative mechanism.

Mitoxantrone causes topoisomerase II inhibition, which impairs DNA repair mechanisms. Intercalation of mitoxantrone into DNA and RNA might cause direct damage. Topoisomerase II inhibitors are associated with characteristic toxic acute myelogenous leukemias (AMLs) that differ from those reported with alkylating agents. Topoisomerase II-related AMLs exhibit shorter latency (median 2 years), absence of a myelodysplastic phase, and characteristic chromosomal aberrations.19

Clinical experience with mitoxantrone.

Overview.

A phase IV study of long-term safety and tolerability is currently under way in 509 MS patients aged 18 to 65 years who have been treated with mitoxantrone. Patients were enrolled by December 2002 and will be followed for 5 years, including treatment and post-treatment periods. Fifty participating MS treatment centers are involved in the study. The results are reported to the FDA and study investigators every 3 months for the first 2 years and every 6 months for the remaining 3 years.

Specific study objectives.

The primary study objective is to evaluate the long-term safety of mitoxantrone used as monotherapy for MS. The long-term effects of mitoxantrone on cardiac function will be evaluated, as will hepatotoxic and myelosuppressive effects, including serious infectious complications. Serious adverse events will be collected and evaluated, patients will be monitored for clinical relapses, and effects will be evaluated as a function of cumulative mitoxantrone dose.

Demographic characteristics as of July 14, 2003.

A total of 509 patients have been enrolled in the study.28 Most of the patients are female (67%), white (88.5%), and middle-aged (mean age 46 years; range 19 to 68 years). Their most frequent diagnosis is SPMS (77.3%), followed by worsening RRMS (16.3%) and progressive relapsing MS (PRMS; 6.4%). The median Expanded Disability Status Scale (EDSS) score at entry is 6.0 (range 0 to 9.0); the median duration from onset of MS is 11.9 years (range 0.4 to 45.3 years); and the median time from MS diagnosis is 8.6 years (range 0.0 to 39.9 years). The median time between initiation of mitoxantrone therapy and the most recent relapse is 0.4 years (range 0.0 to 20.3 years).

As of January 2004, the mean duration of therapy with mitoxantrone is 1.2 years (0 to 2.8) and the mean cumulative dose received is 59.7 mg/m².29 A total of 89 adverse events were noted in 67 patients, of which 21 were considered possibly related and 11 probably related, in addition to two cases of neutropenic fever that were definitely related to mitoxantrone therapy. Serious adverse events included two cases of congestive heart failure, a Zoster eruption, a case of cellulitis, two cases of urosepsis, two urinary tract infections, and two cases of neutropenic fever. No cases of leukemia have occurred to date. Asymptomatic depression of LVEF by ≥10% from baseline has occurred in 23 individuals, and 29 others have increased LVEF ≥10%. Five deaths have occurred, one from meningitis considered possibly related, one from a pulmonary embolus, one from a cardiac arrest, one from pneumonia, and one from sepsis.

In a French study of 802 patients treated with mitoxantrone at 12 centers, there was one case of congestive heart failure and 4.2% had asymptomatic reductions of LVEF ≥10% from baseline with 1% persistent reductions.1 Six patients had infection related to neutropenia, and prolonged amenorrhea occurred in 14% of women over 35 years of age and 7% of women younger than 35 years. There were two cases of toxic leukemia, one of which proved fatal.

Hematologic monitoring.

A CBC with platelets should be obtained before each infusion and treatment should be deferred in patients who fail to exhibit hematologic recovery. It has been suggested that, in cases where CBC parameters are below normal just before a scheduled mitoxantrone infusion, dosing should be reduced.4 The risk for infection is increased in the neutropenic state. Therefore, to minimize this potential risk, the absolute neutrophil count (ANC) should be ≥1,500 before each infusion of mitoxantrone. When CBC values are unacceptably low (e.g., when ANC<1,500), the infusion should be temporarily suspended. Administration of growth factors to stimulate neutrophil expansion, such as granulocyte colony-stimulating factor (GCSF), should be used with caution and only in cases of serious neutropenic infection, because GCSF has been shown to trigger attacks of MS.27

Hepatotoxicity monitoring.

Clearance of mitoxantrone is reduced in patients with hepatic impairment. Because mitoxantrone is cleared through biliary excretion, drug levels may increase markedly in patients with abnormal biliary function. Serum levels of bilirubin and alkaline phosphatase should be monitored. Both transaminases and biliary tract function should be assessed before each infusion. If there are LFT abnormalities, treatment should be deferred.

Pregnancy monitoring.

Mitoxantrone is teratogenetic. Therefore, the possibility of pregnancy should be excluded before each infusion in women of childbearing potential. Such women considered for mitoxantrone treatment should be willing to use effective birth control methods.

Other issues.

Clearance of mitoxantrone is not affected in patients with impaired renal function. Some authorities recommend urinary screening for urinary tract infection before each infusion and antibiotic prophylaxis during the period of induced immune suppression for patients who show evidence of bacterial colonization. Individuals receiving mitoxantrone should not be given live-virus vaccinations. Other types of vaccines should be given at least 4 to 6 weeks after the most recent dosing and when return of normal leukocyte counts has been established. Patients receiving mitoxantrone in combination with beta-interferon may require more frequent monitoring of blood counts and liver enzymes.

Cardiac monitoring.

At present it is recommended that therapy with mitoxantrone be initiated only in patients who have a baseline LVEF ≥50% and with no evidence of pre-existing cardiac disease. At our treatment centers, we prefer following multiple gated acquisition (MUGA) scans (over echocardiograms) because of their greater objectivity and easier reproducibility. We also obtain electrocardiograms and echocardiograms at baseline as part of the evaluation to exclude occult cardiac disease before mitoxantrone administration. Repeat measurement of LVEF is recommended by the FDA if the patient develops clinical symptoms or signs suggesting heart failure or at 2 years of therapy and before each infusion once the cumulative dose is 100 mg/m². We, as do many clinicians, recommend more frequent cardiac monitoring (every 6 to 12 months) before reaching a cumulative dose of 100 mg/m². In a patient with low (50% to 59%) LVEF at baseline, more frequent monitoring seems particularly prudent. Cardiac indications for discontinuing mitoxantrone include clinical cardiac disease, LVEF <50%, or a significant drop from baseline LVEF (defined as a 10% decrease from baseline).30 Although there are no data to indicate that COX-2 inhibitors potentiate treatment-induced cardiotoxicity, it appears sensible to avoid use of these agents in patients treated with mitoxantrone.