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Treating Relapsing Forms of Multiple Sclerosis: Infusion Therapies

Jenny J. Feng and Daniel Ontaneda

INTRODUCTION

Infusion therapies represent a category of MS disease-modifying agents (DMTs) administered by scheduled intravenous infusion (IV). Infusion therapies include both older chemotherapeutic medications (cyclophosphamide and mitoxantrone) and more recently developed monoclonal antibodies (natalizumab, ocrelizumab, rituximab, alemtuzumab). The group of infusion therapies as a whole tends to be more potent and have the advantage of being administered less frequently than oral or injectable therapies. Greater efficacy, however, may come at the price of higher risks. In prescribing infusion therapies, clinicians must take each drug’s risk and benefit profiles into consideration as well as patient demographics and preferences in order to develop personalized treatment plans. Infusion therapies are most commonly used in relapsing active disease that has not responded to first-line therapies and/or patients who are demonstrating signs of rapidly progressive disabling disease. However, improvement in safety profiles of more recently approved monoclonal infusion agents make first-line use 127increasingly common. In this review, we will highlight the mechanism of action, efficacy, and risks of the different infusion DMTs for relapsing forms of MS. We will review the available infusion medications for MS, starting with DNA-disrupting agents followed by monoclonal antibodies. Table 14.1 presents a summary of the infusion therapies reviewed.

MITOXANTRONE (NOVANTRONE)

Mitoxantrone, an anthracenedione compound that intercalates into DNA, causing disruptions in DNA synthesis, also acts as a type II topoisomerase inhibitor and interferes with DNA repair mechanisms. It was found to have immunomodulatory effects by suppressing T cells, B cells, macrophages, and reduces the level of inflammatory cytokines (1).

Mitoxantrone was originally developed as a chemotherapy agent and is Food and Drug Administration (FDA) approved for treatment of acute nonlymphocytic leukemia and drug-resistant prostate cancer. In 2000, it was approved for the treatment of relapsing MS based on evidence from several randomized controlled trials. In a randomized, placebo-controlled trial involving secondary progressive MS (SPMS) or worsening relapsing–remitting MS (RRMS) patients, mitoxantrone was shown to reduce disability progression and relapse rate (2). In another trial involving SPMS and RRMS patients, fewer patients who had received mitoxantrone combined with intravenous methylprednisolone (IVMP) had enhancing lesions at 6 months when compared to patients who received IVMP alone (3). Mitoxantrone monotherapy in SPMS reduced the relapse rate and number of enhancing lesions when compared to IVMP (4).

Although common side effects of mitoxantrone include nausea, alopecia, hypotension, rashes, urinary tract infection (UTI), and menstrual disorders, its most serious side effects—cardiotoxicity and leukemia, limit its clinical use. Cardiac function must be evaluated prior to starting each mitoxantrone dose, and in patients with left ventricular ejection fraction (LVEF) less than 50%, mitoxantrone is contraindicated. Similarly, in patients whose LVEF decreases by greater than 10%, mitoxantrone should be discontinued. Rapid infusion also carries a higher risk; thus, a slow infusion over 30 minutes is preferred. The cumulative lifetime dose of mitoxantrone is a primary risk factor for cardiotoxicity. Because of this, the lowest effective dose should be used and maximum total lifetime dose is limited at 140 mg/m² (5). Higher cumulative doses are also correlated with higher incidence of leukemia.

Postmarketing surveillance has indicated that the incidence of ventricular dysfunction, congestive heart failure, and therapy-related acute leukemia (TRAL) are 12%, 0.8%, and 0.3%, respectively (6).

Mitoxantrone is typically recommended to be administered for no longer than 2 years at the dosing of 12mg/m² intravenously every 3 months. It also has been studied as a short-term induction therapy given as 12mg/ m² monthly for 6 months in patients with aggressive form of relapsing MS (7).

Given that leukopenia, thrombocytopenia, and lymphopenia will be observed approximately 3 months after induction, complete blood count (CBC) with platelets should be checked prior to each treatment and the dosing of mitoxantrone should be adjusted depending on the degree of hematological suppression.

Despite its efficacy in reducing disability progression and relapse rate, mitoxantrone is now seldom used in North America. The concerns for cumulative dose-dependent side effects, and the availability of alternative DMTs with fewer treatment-related risks, has reduced its use over the past few years in the United States (8). It remains an option in patients with aggressive relapsing disease that is refractory to other treatments when other highly effective therapies are not available, and is still used in other regions such as Latin America.

CYCLOPHOSPHAMIDE (CYTOXAN)

Cyclophosphamide is an antineoplastic agent that was developed in the 1950s. It is metabolized in the liver into phosphoramide mustard, which acts as a DNA intercalating agent disrupting mitosis and leading to cell death. Rapidly dividing cells are especially affected. For this reason, it was FDA approved for the treatment of hematologic malignancies such as lymphomas, leukemia, and a variety of solid tumors. Cyclophosphamide was later found to have immunomodulatory and immunosuppressive effects via suppression of T and B cells, and alteration of pro- and anti-inflammatory cytokines secretion in favor of an anti-inflammatory state (9).

Cyclophosphamide was initially tested for use in MS in 1966 (10); however, there has been a paucity of large-scale randomized clinical trials that investigate the effects of cyclophosphamide in relapsing forms of MS. The first clinical trial included relapsing MS and progressive MS patients demonstrated that IV infusion of cyclophosphamide did not produce significant effects compared to adrenocorticotropic hormone (ACTH) or cortisol (11). Subsequently, an open-label, uncontrolled trial demonstrated that IV cyclophosphamide stabilized neurological decline as well as relapse rate in relapsing MS (12). In another trial including RRMS patients with refractory disease and rapidly deteriorating neurological function, cyclophosphamide infusions led to improvement in radiologic measures of disease (13). In recent years, a randomized, double blind trial involving SPMS patients failed to reach significance in its primary end point on time to disability progression; however, it did demonstrate some effects in reducing risk of progression on secondary analysis. The group that received cyclophosphamide had low tolerability to the drug and experienced higher dropout rates. This may have affected statistical analysis of the outcome measure (14).

Cyclophosphamide is generally well tolerated, despite significant safety concerns. Common and transient side effects include nausea, vomiting, and alopecia. Urinary dysfunction can occur in many patients, and can be associated with a risk of bladder cancer and hemorrhagic cystitis. Since cyclophosphamide is metabolized through the hepatic system, in less than 10% of patients there can be elevation of hepatic enzymes and liver toxicity. It can also interfere with fertility in both males and females and menstruation in females. It is a pregnancy category D drug that can cause serious birth defects, and women who are breastfeeding should avoid cyclophosphamide since it can be excreted in breast milk (15).

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130There is no established treatment protocol for cyclophosphamide in MS. Commonly used IV regimen usually involves induction with every other day IV cyclophosphamide 600 mg/m² along with daily IVMP during the course of induction for 8 days and a 600 to 1,000 mg/m² dose given IV every 4 to 8 weeks with or without IVMP. In some cases cyclophosphamide can be combined with interferon beta or glatiramer acetate (16).

Despite mixed results in RRMS, cyclophosphamide does appear to exhibit some positive effects in disease activity due to its anti-inflammatory effects, especially in subgroup analysis involving patients with more active disease. Significant safety concerns limit the use of cyclophosphamide in clinical practice and for these reasons, in MS it remains a seldom-used medication.

NATALIZUMAB (TYSABRI)

Natalizumab is a selective humanized monoclonal antibody (Ab) that targets alpha 4 integrin, an adhesive molecule found on lymphocytic cell surfaces that mediates endothelial adhesion. Natalizumab blocks the adhesion of lymphocytes to central nervous system (CNS) endothelial cells, thus inhibiting the migration of lymphocytes into CNS space across the blood–brain barrier (BBB).

In placebo-controlled trials, natalizumab has been shown to have robust effects against relapses and radiographic evidence of disease activity. It significantly reduced the risk of confirmed disability progression (CDP) by 42%, relapse rate by 68%, and new or enlarging T2 lesions by 83% in a randomized placebo-controlled phase 3 trial involving RRMS patients (17). In patients who relapsed despite being on interferon beta therapy, the addition of natalizumab significantly reduced probability of progression, reduced annualized relapse rate (ARR), and improved radiographic disease burden (18).

Natalizumab has a half-life of approximately 16 days and its biological effects persist for 12 weeks. It is typically administered as 300 mg IV every 4 weeks. Baseline brain MRI with and without contrast should be obtained prior to initiating natalizumab as well as John Cunningham virus (JCV) Ab.

Natalizumab is a generally well-to-lerated agent. Common side effects include infusion-related reactions, which can occur in up to a quarter of patients, as well as headache, fatigue, gastrointestinal side effects, and infections such as UTI and upper respiratory infection (URI). Ab to natalizumab can develop in up to 6% of patients, which can block the biologic effects of natalizumab and render it ineffective, and can increase risk for hypersensitivity reactions. Timing to onset of hypersensitivity can be immediate or delayed, and is most common during the second dose; up to 1% of patients can potentially develop anaphylaxis. The hypersensitivity effects can be ameliorated with administration of antihistamines and corticosteroids in pretreatment.

The FDA approved natalizumab for treatment of relapsing MS in 2004. However, after three cases of progressive multifocal encephalopathy (PML) were associated with natalizumab, it was taken off the market in February 2005 until further investigations were made with regard to its relationship to PML. In July 2006, it was made commercially available once again for the treatment of RRMS.

PML is a progressive brain infection caused by the reactivation of JCV. The risk of PML in patients on natalizumab was initially reported to be 1/1,000 in 2006 (19). Since then, the total number of natalizumab-associated PML cases, as of June 2017, is 731 out of 170,900 patients, with 728 being MS patients. Total doses of natalizumab prior to PML diagnosis ranges from 8 to 134 doses, with an average duration of 49 months on natalizumab (Biogen data on-file).

Natalizumab-treated patients can be risk stratified based on history and clinical data (Table 14.2). JCV Ab should be checked prior to initiating natalizumab as JCV infections is a prerequisite for development of PML. Patients without anti-JCV antibodies are at lower risk of developing PML, approximately less than 0.09/1,000. It is important to note whether a patient has been on immunosuppressive treatment prior to natalizumab, as prior immunosuppression (IS) use confers a 2- to 4-fold increase in PML risk. The duration of natalizumab also positively correlates with risk of developing PML, with a time-responsive risk increase in approximately 14% of PML cases developed within the first 24 months and the majority developed in patients who received greater than 24 months of therapy (19).

In addition to the three factors mentioned earlier, JCV Ab index is another marker that may be able to assist in risk stratification—patients diagnosed with PML had higher titers than patients without PML (20). Currently in clinical practice, it is generally accepted that in natalizumab-treated patients with JCV index of greater than 1.5, the risk of PML is higher (21). For patients with JCV index less than 0.9, along with no prior IS, the risk of PML is considerably lower than those with JVC index greater than 1.5. Table 14.2 presents estimated risk of PML based on factors described earlier.

TABLE 14.2    Risk-Stratification for PML in Natalizumab-Treated Patients

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