Management of worsening multiple sclerosis with mitoxantrone: A review

Clinical Therapeutics/Volume 28, Number 4, 2006

Management of Worsening Multiple Sclerosis with Mitoxantrone: A Review E d w a r d J. Fox, M D, P h D

Multiple Sclerosis Clinic of Central Texas, Round Rock, Texas ABSTRACT Background: Mitoxantrone, an intravenously administered immunosuppressant that inhibits T-cell, B-cell, and macrophage proliferation, is indicated for reducing neurologic disability and relapse frequency in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing MS, or worsening relapsing-remitting MS (RRMS). Objective: This article reviews the pathogenesis and natural history of MS and examines the available treatment options for patients with RRMS, worsening RRMS, or SPMS, with a focus on mitoxantrone. Methods: MEDLINE (1966-present) and the Cochrane Central Register of Controlled Trials (1994present) were searched for relevant randomized, blinded, controlled clinical trials using the terms mitoxantrone, Novantrone, and multiple sclerosis. Results: Five randomized, blinded, controlled trials and an ongoing open-label Phase IV safety study were identified and included in this review. In one randomized, double-blind trial (N = 25), patients with RRMS who received mitoxantrone 8 mg/m 2 monthly had significantly reduced relapse rates at 1 year compared with those who received placebo (P = 0.014). In a 2-year, randomized, partially blinded trial (N = 51), patients with active RRMS who received mitoxantrone 8 mg/m 2 monthly had significantly fewer relapses compared with those who received placebo (P < 0.001), and significantly fewer patients had confirmed progression of disability (1-point increase in Expanded Disability Status Scale [EDSS] score) (P = 0.02). In a randomized, double-blind trial (N = 49), patients with relapsing SPMS who received mitoxantrone 12 mg/m 2 monthly for 3 months followed by 12 mg/m 2 q3mo for up to 32 months had significant improvements in EDSS scores compared with those who received methylprednisolone I g IV monthly for 3 months followed by 1 g IV q3mo (P = 0.002 at 1 year, P = 0.045 at 2 years) and significant reductions in the number of gadolinium-enhancing lesions on magnetic April 2006

resonance imaging (MRI) (P = 0.002 at 1 and 2 years, P = 0.03 at 3 years). In a randomized, partially blinded Phase II trial in 42 patients with active RRMS or SPMS, patients who received mitoxantrone 20 mg IV monthly and methylprednisolone 1 g IV monthly had significantly fewer new gadolinium-enhancing lesions on MRI (P < 0.001) and significantly fewer relapses (P < 0.01) at 6 months compared with those who received methylprednisolone alone. In a pivotal Phase III trial (N = 194), patients with worsening RRMS or SPMS who received mitoxantrone 12 mg/m 2 q3mo for 2 years had significantly fewer relapses (P < 0.001) and significantly less deterioration in disability, as measured by change in EDSS score (P = 0.019), compared with those who received placebo. In a nonrandomized subgroup of patients from this study (n = 110), those who received mitoxantrone 12 mg/m 2 q3mo had a significant reduction in the number of T2-weighted MRI lesions at 24 months (P = 0.027). The most common adverse events in these studies included nausea and/or vomiting (18%-85%), alopecia (33%-61%), amenorrhea (8%-53%), urinary tract infections (6%-32%), and upper respiratory tract infections (4%-53%). Leukopenia was reported in 10% to 19% of patients. Use of mitoxantrone can lead to serious adverse effects, particularly cardiotoxicity, myelosuppression, and, rarely, leukemia. Long-term use of mitoxantrone may compromise left ventricular function. Limited cardiotoxicity was reported in the clinical studies; in the pivotal clinical trial, 2 patients who received mitoxantrone 12 mg/m 2 had decreases in left ventricular ejection fraction to <50% of baseline. Conclusions: In the available clinical trials, mitoxantrone provided effective treatment for worsening

Accepted for publication February28, 2006. doi:l 0.1016/].clinthera.2006.04.013 0149-2918/06/$19.00 Printed in the USA. Reproduction in whole or part is not permitted.

Copyright © 2006 Excerpta Medica, Inc.

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RRMS or SPMS. When mitoxantrone is used as recommended, the risks of substantial myelosuppressive and cardiotoxic effects can be reduced by careful patient selection, drug administration, and monitoring. The lifetime cumulative dose should be strictly limited to 140 mg/m 2, or 2 to 3 years of therapy. (Clin Tber. 2006;28:461-474) Copyright © 2006 Excerpta Medica, Inc. Key words: multiple sclerosis, mitoxantrone, Novantrone.

INTRODUCTION

Insidious and often progressive, multiple sclerosis (MS) poses a complex treatment challenge for clinicians attempting to delay the disability associated with this disease. MS affects -400,000 individuals in the United States and 2.5 million worldwide, with a typical onset during the productive years between the ages of 20 and 50.1 Although the natural history of MS is variable and unpredictable, 50% of patients will require assistance with walking within 15 years of disease onset. 2 This article reviews the pathogenesis and natural history of MS and examines the available treatment options. The focus is on mitoxantrone,* the only agent approved in the United States and some European countries for the treatment of secondary progressive MS (SPMS), progressive relapsing MS (PRMS), and worsening relapsing-remitting MS (RRMS). M ETH O DS

MEDLINE (1966-present) and the Cochrane Central Register of Controlled Trials (1994-present) were searched for relevant randomized, blinded, controlled clinical trials using the terms mitoxantrone, Novantrone, and multiple sclerosis. PATH OG EN ESI S

Although the pathogenesis of MS has yet to be established definitively, accumulating evidence implicates an aberrant immune response in which T cells and other immune-effector cells target the myelin sheath surrounding neurons in the central nervous system (CNS). The early immunopathogenic mechanisms in MS are poorly understood. Nevertheless, studies in animal models suggest that unidentified neural anti*Trademark: Novantrone® (Serono, Massachusetts). 462

Inc., Rockland,

gens may be processed by antigen-presenting cells in regional lymph nodes and presented to T cells. 3 Once activated, sensitized T cells lead to the release of a host of proinflammatory cytokines--tumor necrosis factor (TNF)-cz, interferon (IFN)-7, and interleukin (IL)-I, IL-2, IL-6, and IL-12--that disrupt the blood-brain barrier, promote expression of adhesion molecules by the vascular endothelium, attract another round of inflammatory mediators to the site of inflammation, and permit sensitized T cells to migrate to the CNS, spurring axonal demyelination and damage. 3,4 Recently, a proinflammatory T-helper type 1 (Thl) cytokine environment has been identified in patients with MS and linked to the clinical and magnetic resonance imaging (MRI) abnormalities associated with the disease. 4 Immunomodulatory therapy tends to alter this Thl environment, interfering with the proinflammatory cascade. Yet, axonal loss and symptomatic progression of MS may continue despite attenuation of MRI-detected inflammatory lesions. 5 Indeed, an immunologic basis for inflammation and axonal injury has been proposed. According to this hypothesis, acute inflammatory lesions in MS may result predominantly from Thl autoimmunity, whereas progressive axonal damage may be triggered by Th2 and B-cell/antibody-mediated activity.6,7 In MS, cytokine-mediated demyelination is characterized histologically by the presence of circumscribed hypocellular plaques with loss of myelin, preserved axolemma, and formation of astrocytic scars. Pathologic changes occur preferentially in the optic nerves, periventricular white matter, brain stem, cerebellum, and spinal cord white matter. 7 These changes can be linked to symptoms commonly seen on presentation in patients with MS, such as sensory deficit (the initial presentation in -45% of patients), optic neuritis (-17%), and insidious motor deficit (-14%). 8 Axonal demyelination induces conduction block and erratic neuronal excitability secondary to ectopic impulse generation, which are pathologic features linked to the cardinal symptoms of MS. Conduction block, for instance, underlies the emergence of prominent early "negative" MS symptoms, including visual loss, paralysis, and numbness. 9 Patients with MS also may exhibit an array of "positive" symptoms--chiefly persistent paresthesias, movement-induced abnormal sensations, and pain--that can result from axonal hyperexcitability secondary to demyelination and perhaps from elevations in inflammatory cytokines. Volume 28 Number 4

EJ. Fox

Acute demyelination can result in a period of absolute conduction block because the newly exposed axolemma contains too few sodium channels to maintain conduction. Furthermore, the upregulation of inflammatory cytokines--IFN-T and TNF-o~, for example-can amplify conduction block in demyelinated neurons in MS. Inflammation in MS damages not only axons, but synapses, particularly in areas with high synaptic density, such as the cerebral cortex. Both TNF-o~ and IFN-T have been reported to block synaptic transmission in normal tissue and thus may contribute to negative symptoms in patients with MS. 9 Various compensatory mechanisms can efficiently restore lost function early in the course of MS. Newly exposed axolemma typically undergoes remodeling, enhancing sodium-channel expression and promoting remyelination. These adaptive changes theoretically yield symptom remission; however, conduction still remains abnormally slow and prone to interruption. 9 Moreover, once demyelinated, axons are more susceptible to injury, even in the absence of inflammation. Chronic demyelination renders axons more vulnerable to delayed anterograde, retrograde, and perhaps transsynaptic degradation, culminating in axonal loss and persistent, irreversible cerebral atrophy--alterations that are resistant to immunomodulatory therapy.9,1° N A T U R A L H ISTORY

In a minority of patients, MS has a benign course, but most (80%) have RRMS. 3 RRMS may begin with sensory disturbances, unilateral optic neuritis, diplopia, Lhermitte's sign (paresthesias of the trunk and limbs triggered by neck flexion), limb weakness, clumsiness, gait ataxia, neurogenic bladder and bowel symptoms, and fatigue that worsens in the afternoon and with increased body temperature. 7 Within a decade of the onset of MS, as observed in a cohort of 1099 untreated patients who were followed for up to 12 years, 30% to 40% of patients with a diagnosis of RRMS develop progressive disease. 8 Eventually, -70% of patients with RRMS experience secondary disease progression, s Generally, indices of a poor prognosis include frequent relapses during the first 2 years, male sex, a progressive course from onset, and early permanent motor or cerebellar sequelae. 7 Patients with SPMS manifest varying degrees of disability. In these patients, cerebral impairments--eg, depression, emotional lability, dysarthria, vertigo, sexual dysfunction--become more prominent. 7 April 2006

In primary progressive MS (PPMS), which affects -20% of patients, the disease progresses inexorably for at least 6 months without remission or relapse; it has been suggested that this form may represent a distinct disease entity. 7,11 PPMS is characterized by progressive chronic myelopathy that leads gradually to quadripareses, cognitive decline, and visual loss, as well as the emergence of cerebellar, bowel, bladder, and sexual dysfunction. 7 This form of MS has thus far proved resistant to all forms of treatment. PRMS is similar to PPMS, but is associated with documented clinical relapses. 11 It is worth noting that clinicians do not completely agree on the definitions of these MS subtypes, given an absence of clear biologic markers. 11 The heterogeneous natural history of MS suggests genetic complexity and a variable genetic influence on disease susceptibility, progression, and capacity for endogenous repair. In fact, the concordance rate for MS among monozygotic twins (31%) is 6 times greater than that among dizygotic twins (5%). This finding would appear to support a genetic role in the pathophysiology of M S . 12 C U R R E N T THERAPIES

Given its unpredictable course, diverse pathogenic mechanisms, and unknown etiology, MS is a challenge to treat. Pharmacologic strategies have been largely empiric, focusing on the underlying immunologic mechanisms. With an early onset and often progressive course, MS can lead to decades of physical, social, and emotional impairment if not effectively treated. 13 The disease has long-term effects and an uncertain prognosis. Therefore, patients with MS must become informed about the disease, and a multidisciplinary approach to management is essential for optimal care. 7 The approach should involve a neurologist, nurse, pharmacist, social worker, and allied therapists with MS expertise. It should also incorporate information from national and local MS organizations. In the absence of a cure, the long-term goals of MS management are to decrease relapse rates, delay disease progression, and reduce morbidity. For many years, immunosuppressive therapies, chiefly corticosteroids, were the only treatment option for managing the symptoms of MS. 13 The newer disease-modifying therapies are the first agents capable of diminishing disease activity in relapsing forms of MS (Table I). 14-17 They consist of the beta463

Clinical Therapeutics

Table I. Immunomodulators and immunosuppressants approved for the treatment of multiple sclerosis (MS). Generic (Brand) Glatiramer acetate (Copaxone ®, Teva Neuroscience, Inc.)

Indication

Major Clinical Trials

20 mg/d SC

Johnson et al, 18,19 Wolinsky et al 2°

Reduction in frequency of clinical relapses in patients with relapsing forms of MS ~f or secondary progressive Msf

0.25 mgSC QOD

IFN l] MS Study Group, 2L22 Kappos et al, 23 NASPMS 24

(Avonex®, Biogen Idec)

Reduction in frequency of clinical relapses and delay in progression of physical disability in patients with relapsing forms of MS~f or in patients who have experienced a single demyelinating event with inflammation and are at high risk for developing clinically definite MSf

30 IJg IM qwk

Jacobs el: a[, 25,26 Cohen et a127

(Rebif ®, Serono, Inc.)

Reduction in frequency of clinical relapses and delay in progression of physical disability in patients with relapsing forms of MS ~f

Starting dose 20% of final dose (4.4 IJg SC TIW for final dose of 22 IJg SC TIW; 8.8 IJg SC TIW for final dose of 44 IJg SC TIW), increased to final dose over 4-wk period

PRISMS 28,29 Panitch et al, 3° SPECTRI MS 31

Reduction in neurologic disability and/or frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsingremitting MS (ie, patients whose neurologic status is significantly abnormal between relapses) ~t

12 mg/m 2 given as a short IV infusion (-5-15 min) q3mo

Bastianello et al, 32 Millefiorini et al, 33 van de Wyngaert et al, 34 Edan et al, 3s Hartung et al, 36 Fox et a137

IFNiB-lb (Betaseron®/ Betafero n®, Berlex, Inc.)

Reduction in frequency of

Dosage

relapses in patients with relapsing-remitting MS ~

IFN~-la

Mitoxantrone (Novantrone ®, Serono, Inc.)

IFN = interferon; NASPMS = North American Study Group on Interferon beta-lb in Secondary Progressive MS; PRISMS = Prevention of Relapses and Disability by Interferon 13-1a Subcutaneously in Multiple Sclerosis; SPECTRIMS = Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1 a in MS. *US Food and Drug Administration-approved indication. fEuropean Agency for the Evaluation of Medicinal Products-approved indication. tApproved indication in some European countries.

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EJ. Fox interferons IFNI3-1b* and IFNl3-1at* and glatiramer acetate.§ Although not completely understood, the mechanism of action of the beta-interferons in MS appears to be related to their immunomodulatory properties. 4 Multiple mechanisms have been proposed based on the numerous cytokine and chemokine changes reported with beta-interferons, which may in turn lead to changes in nonimmunomodulatory pathways. 3s,39 For example, IFN]3-1b has been found to downregulate receptors for the inflammatory cytokine IL-2 that is secreted from activated T cells and thereby block the formation of gelatinase, a metalloproteinase capable of degrading myelin and subendothelial basementmembrane constituents. 3s Furthermore, IFN]3-1a has shown immunomodulatory action in MS by upregulation of IL-10, a cytokine with immunosuppressive properties. 39 Several clinical trials have reported the efficacy of various forms of IFN]3-1a and IFN]3-1b in patients with MS, with significant reductions in relapse rates (P < 0.05 to P < 0.001), 22,26,28-30 decreases in gadolinium-enhancing lesions on MRI (P = 0.05 to P < 0.001), 26,30 and delays in progression of disability (P < 0.05) 22,26,28 in patients with RRMS. IFN]3-1a and IFN]3-1b also have been evaluated in patients with SPMS, but the results of these studies have been equivocal. For example, a randomized, doubleblind, placebo-controlled European study in 718 patients with SPMS who received IFN]3-1b 250 lag QOD for up to 36 months found significant efficacy in terms of disability progression (P = 0.007), relapse rates (P = 0.003), and MRI measures (eg, P < 0.001 for change in total lesion volume from baseline to last scan) compared with placebo. 23,4° However, no significant effects on disability progression were found in several other studies: a similarly designed North American study in 939 patients with SPMS who received IFN]3-1b 250 lag or 160 lag/m2 QOD for 3 years24; a randomized, double-blind, placebocontrolled trial in 618 patients with SPMS who received IFN]3-1a 22 or 44 lag SC for 3 years31,41; and a randomized, double-blind, placebo-controlled study

*Trademark: Betaseron ® (Berlex, Inc., Wayne, NewJersey). fTrademark: Avonex® (Biogen Idec, Cambridge, Massach u setts). +Trademark: Rebif® (Serono, Inc., Rockland, Massachusetts). §Trademark: Copaxone ® (Teva Neuroscience, Inc., Kansas Ciw,

Missouri). April 2006

in 436 patients with SPMS who received IFNI3-1a 60 pg IM for 24 months. 27 However, some of these studies reported significant improvements in relapse rates (P = 0.023 for IM IFN]3-1a, 27 P < 0.001 for SC IFN]3-1a 31) and MRI measures (P < 0.001 for IM IFN]3-1a, 27 P = 0.005 to P < 0.001 for SC IFN]3-1a41). The immunomodulatory agent glatiramer acetate is a mixture of synthetic polypeptides composed of 4 amino acids that are abundant in myelin basic protein: glutamic acid, alanine, tyrosine, and lysine. 42 Clinical trials have found a reduction in relapse rates (P = 0.007) 19 and fewer MS-related lesions on MRI (P < 0.003 for new gadolinium-enhancing lesions and new T2-weighted lesions 43) in patients with RRMS who received treatment with this agent. Elucidating the complex nature of the immunomodulatory and nonimmunomodulatory actions of beta-interferons and glatiramer acetate is beyond the scope of this review. Readers are directed to the reviews by Noseworthy et al 7 and Neuhaus et al. 44 The National Multiple Sclerosis Society recommends initiating immunomodulatory treatment once relapsing MS is definitively diagnosed and continuing it indefinitely unless contraindicated. 45 Mitoxantrone was approved in the United States in 2000 for use in reducing neurologic disability and the frequency of clinical relapses in patients with SPMS, PRMS, or worsening RRMS, including patients with persistent neurologic disability after MS relapses. 46 This intravenously administered agent is the focus of the following sections. MECHANISM OF ACTION

Mitoxantrone, an anthracenedione that is inserted into DNA through hydrogen bonding, causes cross-links and strand breaks. 4<47 It also interferes with RNA and inhibits topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. In vitro, mitoxantrone inhibits proliferation of B cells, T cells, and macrophages. 46 In animals with experimental allergic encephalomyelitis (EAE), which can closely mimic the symptoms of MS, mitoxantrone ameliorated the disease and induced a profound reduction in immune response, depressing myelin-directed T- and B-cell responses -3- to 9-fold (P = 0.03 to P = 0.001). 48 In mice with EAE, mitoxantrone inhibited macrophagemediated demyelination (P < 0.001) but not phagocytosis. 47 Animal studies also found that mitoxantrone suppressed B-cell function, with a particular affinity 465

Clinical Therapeutics for certain immunoglobulin (Ig) subtypes, mainly Igm. 49 The suppression of B cells appears to be at least partially the result of macrophage-mediated B-cell inhibition. 5° Moreover, results of in vitro studies suggest that mitoxantrone may induce macrophage-mediated abrogation of helper T-cell function while bolstering T-suppressor cell function. 51 After infusion, mitoxantrone was extensively distributed and sequestered in deep tissue compartments, with a steady-state distribution volume >1000 Elm2. 46,52 Mitoxantrone levels in tissue appear to exceed those in blood during the terminal elimination phase. 52 Owing to mitoxantrone's extended tissue sequestration and slow release in blood, immunocompetent cells are exposed to drug for at least 4 weeks. 52 Thus, mitoxantrone appears to function as a long-acting immunosuppressant. 53

CLINICAL TRIALS IN MULTIPLE SCLEROSIS Preliminary Trials In a 2-year, randomized, double-blind, placebocontrolled trial, 25 patients with RRMS received mitoxantrone 8 mg/m 2 or placebo once monthly. In results presented after 1 year of treatment, 32 significantly fewer patients who received mitoxantrone had relapses compared with those who received placebo (5/13 vs 10/12, respectively; P = 0.02). In addition, mitoxantrone recipients had significantly lower relapse rates at 1 year compared with placebo recipients (0.54 vs 1.67; P = 0.014). However, perhaps as an effect of the small number of patients and short study duration, no significant between-group differences were detected in the number of gadolinium-enhancing lesions on MRI or in scores on the Expanded Disability Status Scale (EDSS). The EDSS is used to evaluate neurologic impairment in MS, measuring disability in terms of pyramidal, cerebellar, brain-stem, sensory, visual, bowel and bladder, cerebral or mental, and other functions. 54 A 2-year, randomized trial compared the efficacy of monthly mitoxantrone 8 mg/m 2 and placebo in 51 patients with RRMS who had experienced at least 2 relapses in the previous 2 years. 33 Patients and the neurologists who evaluated the EDSS score were blinded to treatment assignment, but the treating neurologists who evaluated relapses were not blinded. Over the 2-year period, significantly fewer patients who received mitoxantrone had confirmed progression, as measured by a 1-point increase in EDSS score, 466

compared with those who received placebo (2/27 vs 9/24, respectively; P = 0.02). The reduction in the mean number of relapses was -68% in patients who received mitoxantrone, compared with a reduction of - 6 % in those who received placebo (mean of years 0-2:0.89 vs 2.62; P < 0.001).

Comparative Study of Mitoxantrone and Methylprednisolone In a 32-month, double-blind trial, 34 49 patients with relapsing SPMS were randomized to receive either 13 infusions of mitoxantrone 12 mg/m 2 (n = 28) or methylprednisolone 1 g (n = 21). The first 3 infusions were an induction treatment administered once monthly; the remaining 10 infusions served as maintenance treatment and were administered once every 3 months. Twenty-four patients in the mitoxantrone group and 19 in the methylprednisolone group completed 1 year, but only 10 and 14, respectively, remained through the third year. At 1 year, disability progression was significantly decreased in patients who received mitoxantrone compared with those who received methylprednisolone (proportion of patients with EDSS scores _>5: 41% decrease vs 25% increase, respectively; P < 0.002). This significant difference persisted in the second year (P = 0.045) but not the third year, perhaps as a result of the smaller sample size. In the second and third years, the mitoxantrone group had a significant decrease in the mean number of relapses/patient per year compared with the methylprednisolone group (2 years: 0.3 vs 1.1, P = 0.016; 3 years: 0.2 vs 1.1, P = 0.03) and a significant decrease in the total number of gadolinium-enhancing lesions on MRI in all 3 years (1 year: 15 vs 146, P = 0.002; 2 years: 10 vs 59, P = 0.002; 3 years: 6 vs 20, P = 0.03). Adverse events that were more frequent in mitoxantrone recipients compared with methylprednisolone recipients included nausea and vomiting (24 [85.7%] vs 7 [33.3%], respectively; P = 0.001) and alopecia (15 [53.6%] vs 5 [23.8%]; P = 0.036). The results of this study provided preliminary evidence for the therapeutic value of mitoxantrone in progressive or worsening relapsing MS and led to the conduct of further large controlled trials. Phase II Clinical Trial In a pivotal Phase II, partially blinded trial, 35 42 patients with confirmed active RRMS or SPMS (based on both clinical and MRI assessments) were random-

Volume 28 Number 4

EJ. Fox ized to receive 6 months of treatment with either mitoxantrone 20 mg IV monthly + methylprednisolone 1 g IV monthly or methylprednisolone 1 g IV monthly alone. Only patients who had 2 relapses with sequelae or a 2-point increase in EDSS score within the past 12 months and who developed at least 1 new active lesion on MRI during the 2-month baseline period were included in the study. The primary end point was the proportion of patients developing new gadoliniumenhancing lesions on monthly serial MRI. At the end of the study, blinded analysis of the MRI data indicated a significantly higher proportion of patients with no new MRI lesions in the mitoxantrone + methylprednisolone group compared with the group that received methylprednisolone alone (90% vs 31%, respectively; P < 0.001) (Figure). At month 6, the mean number of new T2-weighted lesions was 80% lower in those who received mitoxantrone + methylprednisolone compared with those who received methylprednisolone alone (1.1 vs 5.5, respectively; P < 0.05). 35 Mitoxantrone recipients had significantly fewer new lesions by month (months 1-4: P < 0.05; month 5: P < 0.01; month 6: P < 0.001) and a significantly lower total number of enhancing lesions (months 1, 2, and 4: P < 0.05; months 3 and 5:

P < 0.01; month 6: P < 0.001) compared with those who received methylprednisolone alone. In the open-label analysis of the clinical results, a significantly smaller proportion of patients who received mitoxantrone + methylprednisolone had a 1-point increase in EDSS score over the study period compared with those who received methylprednisolone alone (4.8% vs 28.6%, respectively; P < 0.01). 35 In addition, patients who received mitoxantrone + methylprednisolone had significantly fewer relapses compared with those who received methylprednisolone alone (7 vs 31; P < 0.01). In fact, 14 (67%) of 21 patients receiving mitoxantrone + methylprednisolone were relapse free during treatment, compared with 7 (33%) of 21 patients who received methylprednisolone monotherapy (P < 0.05). Eighteen mitoxantrone + methylprednisolone recipients experienced adverse events, compared with 6 recipients of methylprednisolone alone. None of these events were serious, and cardiotoxicity was not observed. 35 The most frequently reported adverse events in patients who received mitoxantrone were amenorrhea (53%), alopecia (33%), nausea (29%), and asthenia (24%); none of these adverse events were reported in patients who received methylprednisolone alone. 35,46 Other adverse events that occurred in >5% [] Mitoxantrone + methylprednisolone • Methylprednisolone

100

80

=

",~

60

0

6 Z

4O

20

-I

0

1

2

T i m e Relative [o

3

4

5

6

Study Inclusion (mo)

Figure. Proportion o f patients without new active lesions on magnetic resonance imaging after monthly treatment with mitoxantrone 20 mg IV + methylprednisolone 1 g IV or methylprednisolone alone, by month. ~P < 0.01; tp < 0.05; SP < 0.001. Adapted with permission. 3s

April

2006

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of patients receiving mitoxantrone and more frequently than in patients who received methylprednisolone alone included pharyngitis/throat infection, gastralgia/ stomach burn/gastric pain, aphthosis, cutaneous mycosis, rhinitis, and menorrhagia. Hematologic adverse events included mild leukopenia (World Health Organization [WHO] grade 2) (2 patients mitoxantrone + methylprednisolone, 0 methylprednisolone alone)and mild anemia (WHO grade 1) (4 and 1 patient, respectively).

Phase III Clinical Study The pivotal Phase III Mitoxantrone in Multiple Sclerosis study, 36,55 a 2-year, double-blind trial, enrolled 194 patients with worsening RRMS or SPMS who were randomly assigned to receive mitoxantrone 5 mg/m 2 IV, mitoxantrone 12 mg/m 2 IV, or placebo every 3 months for 2 years. Patients assigned to the placebo group were administered a solution mixed with methylene blue

3 mg to match the color of the mitoxantrone infusion. For study entry, patients were required to have an EDSS score of 3 to 6, with a worsening in score of at least 1 point over the previous 18 months. The main end point, disease progression, was assessed using a composite measure that included changes from baseline in EDSS score, ambulatory index, and neurologic status, as well as the number of relapses treated with corticosteroids and the time to first relapse. Patients who received mitoxantrone 12 mg/m 2 had a significant improvement in the composite measure (P < 0.001) and its individual components (P = 0.031 to P < 0.001) compared with those who received placebo (Table II). 36 Patients in the group that received mitoxantrone 5 mg/m 2, which was included for exploratory purposes, also had a significant improvement in the composite measure compared with those who received placebo (P = 0.005). Furthermore, the

Table II. Overview o f results for the primary efficacy variables in the Mitoxantrone in Multiple Sclerosis study. 36

Variable

Mitoxantrone 12 mg/m 2

Placebo

EDSS change (last value - baseline) Mean (SD) Median (range)

-0.13 (0.90) 0 (-2.5 to 2.s)

0.30 (1.24) 0 (-2 to s)

Ambulation index change (last value - baseline) Mean (SD) Median (range) Number o f treated relapses Adjusted total in group Median (range) per patient Time to first treated relapse Median, mo Lowest quartile, mo Change in SNS (last value - baseline) Mean (SD) Median (range)

Mann-Whitney Difference (95% CI)

P*

0.23 (I .01) o.s (-3 to 2)

0.24 (0.04 to 0.44)


0.77 (1.26) 0 (-1 to s)

0.21 (0.02 to 0.40)

<0.031f

0.39 (0.18 to 0.59)

<0.001}

24.08

76.77

0 (0 to 2)

1 (0 to s)

Not reached within 24 mo 20.4

14.19 6.7

0.44 (0.20 to 0.69)

<0.001t

-1.07 (8.61) -1.5 (-19 to 35)

0.77 (6.79) 0 (-13 to 25)

0.23 (0.03 to 0.43)

<0.027f

0.30 (0.17 to 0.44)

<0.001

Global difference, Wei-Lachin test EDSS = Expanded Disability Status Scale; SNS = Standardized Neurologic Status scale. *Two-sided test, mitoxantrone 12 mg/m 2 versus placebo. fWilcoxon-Man n-Wh itney test. t Log-ran k test.

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proportion of patients whose EDSS scores increased 1 point was significantly lower with mitoxantrone 12 mg/m 2 than with placebo (8% vs 25%, respectively; P = 0.013). Patients who received mitoxantrone 12 mg/m 2 also had a significant improvement in EDSS score compared with those who received placebo (difference between last value and baseline, -0.13 vs 0.24; P = 0.019). Annualized relapse rates with mitoxantrone 12 mg/m 2 compared with placebo were 63% lower for year 1 (P < 0.001), 68% lower for year 2 (P < 0.001), and 66% lower for the 2 years combined (P = 0.001). Moreover, significantly more patients receiving mitoxantrone were relapse free during the 2-year trial compared with those receiving placebo (57% vs 36%; P = 0.021). At the end of the study, analysis of a nonrandomized subgroup of 110 patients recruited at 8 centers with MRI units found gadolinium-enhancing lesions in 3.2% of those who received mitoxantrone 12 mg/m 2 and 15.6% of patients who received placebo (P = NS). The mean increase in the number of lesions on T2-weighted scans was 85% greater with placebo than with mitoxantrone (1.94 vs 0.29, respectively; P = 0.027). 55 Adverse events were more common among mitoxantrone recipients. 36 The most commonly observed adverse events in patients who received mitoxantrone that occurred more frequently than in patients who received placebo were nausea (5 rag/m2: 55%; 12 rag/m2: 76%; placebo: 20%), menstrual disorder (51%, 61%, and 26%, respectively), alopecia (38%, 61%, and 31%), urinary tract infection (UTI) (29%, 32%, and 13%), amenorrhea (0%, 25%, and 0%), and leukopenia (9%, 19%, and 0%). There was no evidence of serious cardiotoxicity, although arrhythmia or abnormal electrocardiographic (ECG) findings were reported in more patients who received mitoxantrone 12 mg/m 2 than in those who received mitoxantrone 5 mg/m 2 or placebo (arrhythmia: 18%, 6%, and 8%, respectively; abnormal ECG findings: 11%, 5%, and 3%). In addition, 2 patients in each of the active-treatment groups had a decrease in left ventricular ejection fraction (LVEF) to <50% of baseline.

Phase IV Clinical Study The safety and tolerability of mitoxantrone are being evaluated in RENEW (Registry to Evaluate Novantrone Effects in Worsening MS), 37 an ongoing open-label, prospective, Phase IV study. Five hundred seven patients with SPMS, PRMS, or worsening MS April 2006

are being followed for 5 years from the initiation of mitoxantrone therapy administered according to the US product information. To date, 90 patients enrolled in RENEW have experienced 128 serious adverse events. The most frequently reported have been infectious events (38%) and cardiac events (18%). One patient who developed secondary acute myelogenous leukemia recovered after treatment. Fifteen patients (3%) withdrew because of an LVEF <50%, 6 (1%) for a clinically significant decrease in LVEF or congestive heart failure (CHF), and 12 (2%) for other adverse events. Six patients have died in the course of the study; 2 of these deaths resulted from adverse events (acute meningitis and septic shock) that were considered possibly related to treatment. TREATMENT PRECAUTIONS AND R E C O M M EN D A T I O N S

Mitoxantrone therapy may be associated with immunosuppressive effects. Perhaps more importantly, as an anthracycline-related drug, mitoxantrone may induce serious dose-related cardiotoxicity. Given this potential for serious toxicity, careful adherence to the administration and monitoring guidelines in the product information for mitoxantrone is essential. Patients should be informed of the risks associated with the use of mitoxantrone, including cardiotoxicity-principally, cardiomyopathy, reduced LVEF, and CHE 56 Compared with patients with cancer, those with MS may experience greater cardiotoxic effects with mitoxantrone treatment. 53 There are reports that -25 % of patients with MS have subclinical ventricular dysfunction and decreased ventricular ejection fraction, potentially making them more susceptible to the cardiotoxicity of immunosuppressive drugsS The potential cardiotoxic effects of mitoxantrone were examined in a study that included data from 1378 patients in 3 clinical trials of mitoxantrone given as a single agent for the treatment of MS. 58 At a mean cumulative dose of 60.5 mg/m 2 over a median followup period of 29 months, the risk for CHF was <0.2%. A total of 2.2% of patients in all the studies combined developed asymptomatic reductions in LVEF (to <50%), as did 5.0% of patients receiving mitoxantrone at a cumulative dose of _>100 mg/m 2. It is worth noting that a stepwise logistic regression analysis found no significant relationship between cumulative dose and the incidence of LVEF <50%. 5s 469

Clinical Therapeutics Impairment of LVEF with mitoxantrone may continue after the termination of treatment, s6 Because of the risk of cardiotoxicity, the cumulative lifetime dose of mitoxantrone in patients with MS must be limited to 140 mg/m2, or 2 to 3 years of therapy at the approved dosage of 12 mg/m2 q3mo. 46 After 3 or 4 monthly infusions, mitoxantrone has been reported to induce marked immunosuppression--leukopenia (_<2000 leukocytes/mL) and lymphocytopenia (_<1000 lymphocytes/mL)--that is sustained throughout the course of treatment, even with subsequent trimonthly administration.53 Marked mitoxantrone-specific decreases in B-cell counts (to _<35/mL) also have been reported. 53 The use of mitoxantrone in MS has been associated with an increased risk for treatment-emergent acute leukemia. 46 It is not uncommon for patients with therapy-related acute leukemia to have preexisting myelodysplastic disorders. However, there are published reports involving 10 patients with MS and no previous diagnosis of a hematologic disorder who received mitoxantrone and subsequently developed therapy-related acute leukemia. 37,59-67 Given as a single agent for MS at the recommended doses, mitoxantrone appears to pose some risk for secondary acute leukemia, with a reported incidence ranging from 0.07% to 0.25%. 46,60 No data are available on the effects of combination therapy on the risk of leukemia in patients with MS. However, among patients with breast cancer who received mitoxantrone concomitantly with other cytotoxic agents and/or radiotherapy, the risk of leukemia ranged from 1.1% to 2.2% over periods ranging from 4 to 10 years.46 The potential risk of leukemia should be weighed against the potential benefits of mitoxantrone therapy on an individual basis. Prescribers and patients should be aware that mitoxantrone may induce fetal harm if administered to pregnant women. 46 In addition, treatment with mitoxantrone is associated with an increased risk of amenorrhea: up to 53% of women with MS experienced amenorrhea in clinical studies. 46

Patient Screening Given the potential for toxicity, candidates for mitoxantrone therapy should be chosen carefully to optimize treatment outcomes. Before mitoxantrone treatment is begun, patients' LVEF should be evaluated by echocardiogram or multiple gated acquisition (MUGA) scan. Patients with compromised left ventricular function, defined as an LVEF <50%, should 470

not receive mitoxantrone. Moreover, given the risk of immunosuppression and thrombocytopenia, patients should undergo a complete blood count (CBC) before treatment and, if symptoms of infection emerge, during treatment. Patients with baseline neutrophil counts <1500 cells/ram 3 should not be given mitoxantrone. In such cases, either mitoxantrone can be withheld until neutrophil counts improve or alternative therapies can be initiated. There are no other absolute contraindications to mitoxantrone therapy based on CBC parameters. 46 Because mitoxantrone is metabolized in the liver, each candidate for therapy should undergo liver function testing. If liver function is impaired, mitoxantrone therapy should be avoided. Patients with severe hepatic dysfunction (bilirubin >3.4 mg/dL) have a mitoxantrone AUC >3 times that in patients with normal hepatic function receiving the same dose. 46 Women of childbearing potential should undergo pregnancy testing before administration of each mitoxantrone dose, and the results should be made known to the patient before dosing. 46

Administration Guidelines Clinicians who administer mitoxantrone should have experience in the use of cytotoxic chemotherapeutic agents. The current US Food and Drug Administration-approved regimen of mitoxantrone for the treatment of MS is 12 mg/m2 administered as a slow IV infusion every 3 months. 46 Slow mitoxantrone infusion over at least 30 minutes may reduce the risk of cardiotoxicity, as the cardiotoxicity of anthracyclines is related to peak plasma concentrations rather than to total systemic exposure or tissue concentration over time. 53 Some investigators have advocated use of an induction phase (not included in the US product information) consisting of 3 monthly infusions of mitoxantrone 12 mg/m2 before implementation of the trimonthly regimen.53 The rationale for use of an induction phase is rapid management of active inflammation linked to MS and control of progressing disease. 2,46 Nausea and vomiting, which affect 55% to 76% of patients at the start of mitoxantrone therapy, can be reduced through prophylactic use of an antiemetic agent. 46

Monitoring Guidelines LVEF assessment by echocardiogram or MUGA should be performed before administration of each Volume 28 Number 4

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dose of mitoxantrone. 46 If the LVEF decreases to <50% for any reason during therapy, mitoxantrone should be discontinued. In addition, it has been suggested that mitoxantrone therapy should be discontinued if the LVEF decreases by >10% from baseline. 27,36 Mobilityimpaired patients should be allowed to relax for a few minutes after being transferred so that a true resting LVEF measurement may be obtained. A CBC should be obtained before each administration of mitoxantrone. Mitoxantrone should not be administered to patients whose neutrophil counts are <1500 cells/mm3. 46 Drug discontinuation or dose reduction may be warranted if myelosuppression is detected on routine blood monitoring 3 weeks after the last infusion or 1 week before an infusion. In the case of an absolute neutrophil count <1000 cells/mm 3, the decision to reduce future doses is at the physician's discretion. 46 Because UTIs are more frequent in MS patients with myelopathic symptoms as a result of urinary retention and incomplete emptying of the bladder, it is not surprising that mitoxantrone further increases the risk of bladder infection. 68,69 Urinalysis with a culture and sensitivity study performed at the time of infusion may be helpful in determining the choice of antibiotic should a UTI develop. During IV administration of mitoxantrone, the clinician should be vigilant for the presence of extravasation, which may occur asymptomatically (without stinging or burning), even when robust blood return is evident on aspiration of the infusion needle. In severe cases, extravasation may result in tissue necrosis. If extravasation does occur or is suspected, the infusion should be discontinued, the arm elevated, and ice packs applied. The use of topical corticosteroids such as betamethasone may reduce inflammation and pain at the site. In the event of tissue necrosis, surgical debridement and skin grafting may be necessary. 46 CONCLUSIONS

Although the course of MS is unpredictable and sometimes benign, in most patients, the disease becomes progressive and disabling if not treated. Clinical trials have found mitoxantrone therapy effective in reducing relapse rates, improving MRI-based outcomes, and delaying disease progression in patients with worsening RRMS or SPMS. However, mitoxantrone is an anthracycline derivative and immunosuppressant; as such, it can lead to serious untoward effects, particuApril 2006

larly cardiotoxicity, myelosuppression, and, rarely, leukemia. Long-term use of mitoxantrone may compromise left ventricular function. Therefore, the duration of treatment is restricted to a lifetime cumulative dose of 140 mg/m 2, or 2 to 3 years of treatment at the recommended dosage. Patients and clinicians considering the use of mitoxantrone should be aware of its potential toxicities and take all necessary steps to limit those risks. Careful patient selection, administration by clinicians experienced in the use of chemotherapeutic agents, and vigilant monitoring are indispensable to limiting toxicity and improving clinical outcomes. Immunomodulators and immunosuppressants, including mitoxantrone, confer clear clinical benefits in patients with MS but also pose substantial risks of toxicity if not used judiciously. In patients with certain forms of progressive or worsening MS, mitoxantrone is the only available treatment option. Given the scarcity of studies and the small patient numbers and mostly short-term designs of the published studies, there is a need for long-term comparative studies to provide data on the relative risks and benefits of mitoxantrone in the treatment of worsening RRMS and SPMS. ACKNOWLEDGMENTS Serono, Inc., Rockland, Massachusetts, provided financial support for this article. Dr. Fox has served as a consultant and/or been an advisory panel member for Biogen Idec; Genzyme Corporation; Pharma Frontiers; Pfizer Inc.; Serono, Inc.; and Teva Neuroscience, Inc. Vicki Schwartz, PhD, provided editorial assistance. REFERENCES 1. Just the Facts: 2005-2006. Frequently Asked Questions About Multiple Sclerosis and the National MS Sociee/. Available at: http://www'nati°nalmss°ciee/'°rg/Br°chures Just% 20the.asp. Accessed December 20, 2005. 2. Weinshenker BG. Natural history of multiple sclerosis. Ann Neurol. 1994;36(SuppI):S6-S1 I.

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Address correspondence to: Edward J. Fox, MD, PhD, Multiple Sclerosis Clinic of Central Texas, 7200 Wyoming Springs Drive, #1100, Round Rock, TX 78681. E-maih [email protected] Volume 28 Number 4