Thirdline Therapies

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Based on the formal approval of the European Medicines Agency (EMA) mitoxantrone is categorized as second-line therapy. However, it is now rather used as third-line treatment (Drr & Paul, 2015) Other third-line options include experimental therapies such as rituximab, ofatumumab and intense immunosuppression with autologous hematopoietic stem cell transplantation (Sorensen, 2014). These third-line treatments will be discussed below.

Mitoxantrone

Mitoxantrone is an immunosuppressive and immunomodulatory agent. This drug works by targeting with DNA repair which results in single- and double-stranded breaks and also by inhibiting topoisomerase, a nuclear enzyme (Zadeh et al.

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, 2019) In addition, Mitoxantrone has an immunosuppressive effect by inhibiting the proliferation of T cells, B cells and macrophages. The main action of Mitoxantrone is however to induce apoptosis by provoking toxic changes in the cell. The drug stops the synthesis of RNA and proteins (Cocco & Marrosu, 2014). It reduces inflammatory activity by decreasing the number of relapses and MRI lesions and decreasing the worsening of disability.

Mitoxantrone is an intravenous treatment for worsening RRMS, progressive-relapsing MS or SPMS, usually with a dosage of 12 mg/m 2 every 3 months until the maximum cumulative dose of 140 mg/m 2 is reached (Cocco & Marrosu, 2014) Furthermore, mitoxantrone is teratogenic and thus cannot be used in pregnancy (Torkildsen et al.

, 2016). The price for a dose of 5 ml Mitoxantrone is on average 79,93 (2 mg/ml) in the Netherlands, which can be reimbursed by health insurance (Zorginstituut Nederland, n.d.). The Cochrane collaboration analyzed randomized controlled trials in a meta-analysis (Cocco & Marrosu, 2014). In these randomized controlled trials mitoxantrone was compared with placebo or mitoxantrone plus steroids was compared with placebo and steroids.

This meta-analysis showed that mitoxantrone reduced the progression of disability at 24 months and that more mitoxantrone-treated patients were relapse-free patients after 1 and 2 years compared to control groups. Furthermore, the number of patients with an active scan on MRI at 6 or 12 months was reduced. In another study, the ARR and disability progression was reduced by 60% and 64% compared to the placebo group, after the administration of 12 mg/ 2 mitoxantrone for 24 months (Cocco & Marrosu, 2014).

The use of mitoxantrone is associated with side effects. Short-term side effects include nausea, vomiting, hair rarefaction, alopecia and blue coloring of the urine. The most common short term side effects were dizziness and vomiting in 62%, hair rarefaction in 47% and risk of infection in 30% of patients that were studied. Long term side effects are for instance leukopenia, therapy- related acute leukemia and cardiotoxicity (Zadeh et al., 2019; Cocco & Marossu, 2014). Some of these adverse effects, such as cardiotoxicity and therapy-related acute leukemia are life- threatening conditions.

Experimental therapies

It is common for physicians to use drugs off-label, meaning a medication approved for one condition is being used for treating other conditions (Bourdette, 2016). Rituximab, tested in phase II for RRMS and phase II/III for PPMS, is an example. Although not EMA-approved, current algorithms for treating MS include rituximab as a third-line therapy for RRMS (D?rr & Paul, 2015).

Rituximab is a chimeric mouse-human monoclonal antibody that targets CD20 on B cells and thereby causes a reduction of circulating B cells. This drug is administered intravenously. There is no established dosing schedule for MS (Krumbholz et al., 2012). In the Netherlands the price for 10 ml of solution for infusion (10 mg/ml) is on average 253,45, with a possibility of coverage by insurance (Zorginstituut Nederland, n.d.)

The use of rituximab can come along with a risk for adverse events. Infusion-associated side effects of rituximab include chills, headache, nausea, pyrexia, tiredness, throat irritation and pharyngolaryngeal pain (He et al., 2013). Research has shown that the use of rituximab frequently causes side effects in MS patients, but that these are mostly not serious adverse events. These side effects can be reduced with subsequent infusions, thus rituximab is safe enough for these patients (Castillo-Trivino et al., 2013). The safety profile of long-term dosing for MS patients is unknown, because there is not enough long term follow-up data for this population (Barra, 2016). In spite of that, attention should be given to the risk of progressive multifocal leukoencephalopathy (PML). In rheumatoid arthritis, 1 case of PML per 25,000 patients have been reported (Tanasescu et al., 2014). It is, however, unclear how this applies to MS patients, because they are usually younger and have fewer comorbidities than other groups that are treated with rituximab (Barra, 2016).

Ofatumumab, a fully humanized antibody, is another off-label drug. It also targets the CD20 molecule on B cells, like rituximab, but it binds to a different region of CD20 and has a higher binding affinity to CD20 compared to rituximab (Cross & Naismith, 2014). This drug depletes B cells by cytotoxicity. Additionally, it is shown in in-vitro studies that ofatumumab also depletes B- cells that are resistant to rituximab (Wierda et al., 2011).

This drug is currently approved for the treatment of chronic lymphocytic leukaemia and is administered intravenously on days 1 and 15 (Melzer & Meuth, 2014). The costs of treatment with ofatumumab for MS patients is unknown, but the predicted total costs of treatment with ofatumumab for chronic lymphocytic leukaemia is estimated between 0,8 and 1,1 million euros a year (Zorginstituut Nederland, 2011). The price for one injection vial of 5 ml is 231 and the costs for treatment can be (partly) covered by some insurances (FBTO, 2016). A trial conducted in RRMS showed B cell depletion and suppression of inflammatory disease activity by intravenous administration of ofatumumab (Sorensen et al., 2014). The MIRROR trial was conducted with 232 RRMS patients (Bar-Or et al., 2018). The patient population of this study was randomized to subcutaneous ofatumumab 3, 30 or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks for 24 weeks, or placebo followed by ofatumumab 3 mg at week 12. In this trial a reduction of 65% of new Gadolinium enhanced lesions was observed. The most common adverse events of ofatumumab for MS patients are infusion reactions, infections, rash, throat irritation and fatigue. Ofatumumab has been studied in chronic lymphocytic leukaemia and several other haematological conditions without major safety concerns (Gupta & Jewell., 2012).

Autologous hematopoietic stem cell transplantation (aHSCT)

As described above, the conventional disease-modifying drugs alter or suppress the immune system (Burman & Fox, 2017). Contrary to this, aHSCT is designed to reset the immune system and is performed once. This procedure is more seen as a surgical procedure rather than pharmacological treatment (Burman & Fox, 2017).

In aHSCT hematopoietic stem cells are being frozen after they have been harvested from the patient's blood or from bone marrow (Hauser, 2015). These steps take 5-15 days. These hematopoietic stem cells are used to reboot the immune system. They are at an early stage of development and lack flaws that trigger MS (Shroff, 2018). The immune system is first destroyed using (combinations of) chemotherapy, lymphocyte-depleting antibodies, thymocyte globulin or irradiation (Hauser, 2015). After this, the hematopoietic stem cells are replaced into the blood by infusion to reset the patient's immune system. These steps usually take place 2-4 weeks after harvesting. The stem cells make new blood and immune cells within 10 to 30 days after the transplant. This procedure can be strenuous. Patients have a higher chance of getting infections during this period, as their immune system is not working yet. Patients are usually admitted to the stem-cell transplantation ward for 3 weeks for close monitoring, standard supportive care and antibiotics for support (Atkins et al., 2016). As this an aggressive procedure, patients need time to recover. Recovery from aHSCT can take between 3 to 6 months for most patients. For other patients recovery can take more than a year.

The cost of aHSCT depends on regulation and policy, so it varies per country. In the US, the price of aHSCT ranges from US$7,000 to $10,000 per treatment. Prices of other countries are usually higher, ranging from US$20,000 up to $100,000 (Knoepfler, 2015) A cost-effectiveness study in the United Kingdom has shown that the cost-effectiveness of aHSCT is expected to be around ?2,800 per additional gained quality-adjusted life year (Tappenden et al., 2010) This treatment is not covered by health insurance in the Netherlands (Nationaal MS Fonds, n.d.) In a meta-analysis of aHSCT for MS a proportion of patients maintaining no evidence of disease activity (NEDA) of 83% at 2 years and 67% at 5 years was found after the treatment (Rotstein et al., 2015). Direct comparison is limited, but these numbers imply that aHSCT is as effective or more effective than conventional drugs (Burman & Fox, 2012) The proportions are much higher than those reported for conventional drugs used to treat MS: The NEDA-rate for interferon-? and glatiramer acetate at the same period is about 15%. For natalizumab or alemtuzumab, only 32%-39% of the patients maintained NEDA at 2 years (Rotstein et al., 2015). In an open-label study, patients also improved in other functional measures and in quality of life (Hauser, 2015). A reduction in Brain T2 lesion volume as measured by magnetic resonance imaging was also found. However, aHSCT does not appear to be effective to treat progressive forms of MS. Instead aHSCT appears to be effective for treating RRMS, at least over several years of observation (Shroff, 2018).

Although aHSCT has positive effects, it can also cause side effects. Short term side effects include cytopenia, engraftment syndrome, transient alopecia, infection, fever and other toxicities common to other autologous transplantations (Burt et al., 2015). Long term side effects include secondary autoimmune conditions, for instance the reactivation of varicella-zoster virus, thyroiditis, Crohn's disease and rheumatoid arthritis (Muraro et al., 2017). The main concern limiting the use of aHSCT for MS is the risk of treatment related mortality (TRM) (Das et al., 2019). However, data of the European Society for Blood and Marrow Transplantation showed that the TRM rate has declined over the last two decades, despite the increased use of aHSCT for MS. This analysis shows that the TRM rate of 1995-2000 was 7.3%, the TRM rate of 2001- 2007 was 1.3% and the TRM rate of 2008-2016 was 0.7% (Muraro et al., 2017). In conclusion, the third-line treatments can be used to effectively treat MS. In spite of that, their use can be limited due to potential risk of adverse events. Some treatments have more severe adverse events than others. In addition to conventional therapy, off-label treatments and stem cell transplantation might be effective treatments for MS patients. However, some of these therapies only seem effective against RRMS and not the progressive types of MS. A careful evaluation of risks and benefits should be made with individual patients to examine which therapy would be the best option.

Symptomatic treatments

Besides pharmacological therapies, the non-pharmacological treatment of symptoms is an additional component of the management of MS. The aim of the symptomatic treatment is to improve quality of life by relieving symptoms that are affecting patients' abilities to carry out daily activities (Henze, Rieckmann & Toyka, 2006).

Non-pharmacological treatments

Physiotherapy and exercise

Physiotherapy is an important part of rehabilitation. In MS, physiotherapy is aimed at regaining motor skills to improve mobility (Kubsik-Gidlewska et al., 2017). To do so, physiotherapy is aimed at increasing muscle strength, lowering muscle tension, improving balance, increasing or maintaining the range of motion in the joints and preventing muscle atrophy. The daily rehabilitation of MS patients can include exercises to improve balance and coordination, but also breathing, stretching and relaxation (Kubsik-Gidlewska et al., 2017). Furthermore, rehabilitation can also include aerobic training and exercises that strengthen particular groups of muscles. Physical exercise has recently been introduced into the plan of physiotherapy for MS patients (Kubsik-Gidlewska et al., 2017). The advice for MS patients is to perform physical activities for 2-3 times a week for a maximum of 40 minutes.

However, exercising can be strenuous, as MS patients can be susceptible to exercise-related fatigue, heat intolerance and falling (Halabchi et al., 2017). There are some concerns about the worsening of fatigue in MS patients when exercising, but evidence shows that regular exercise training can reduce fatigue amongst MS patients. MS patients that are heat intolerant are advised to avoid exercising during the hottest times of the day or when they are fatigued. Furthermore, special attention is needed when designing an exercise plan for patients that are vulnerable to falling (Halabchi et al., 2017). The costs for physiotherapy for MS patients in the Netherlands can be reimbursed by health insurance, because MS is on the list for chronic diseases (Zorgwijzer, n.d.).

According to meta-analyses and systematic reviews exercise can improve aerobic and muscular fitness, walking, balance, depressive symptoms and fatigue in MS patients (Halabchi et al., 2017) Research has shown that physical activity increases quality of life and lowers the degree of disability in patients with MS (Halabchi et al., 2017).

Cognitive therapy

As mentioned in the introduction, cognitive dysfunction is a core symptom of MS. There is a lack of effective pharmacological therapies for treating cognitive impairment in MS (Nasios et al., 2018). For that reason, the effect of cognitive rehabilitation and noninvasive brain stimulation techniques such as repetitive Transcranial Magnetic Stimulation (rTMS) on MS patients became a topic of interest.

Cognitive rehabilitation therapy (CRT)

CRT is provided by speech therapists, neuropsychologists or occupational therapists (Larocca & King, n.d.) In order to treat cognitive dysfunction, patients are trained in compensating for cognitive changes. CRT usually involves one or more sessions of an hour per week for several months. The assignments and activities that participants have to do are depending on individual needs and can include compensatory strategy training or psychoeducation (Larocca & King, n.d.). Compensatory strategy training will train the participant in the use of techniques that compensate for deficits, including methods like writing in notebooks or sticking notes on the refrigerator to help with memory. Participants will complete homework assignments about their own cognitive problems and will apply learned strategies in daily life situations. The efficacy of cognitive intervention was compared with a control intervention group by Brissart et al., (2013). The results showed a small benefit in the treatment group mainly in memory and verbal fluency, but some improvements were also found in the control group. Mattioli et al (2010) showed that an intensive cognitive rehabilitation program had positive effects on information processing, attention and decision making.

CRT can cause distress if participants have high expectancies of their performance on cognitive assignments, but do not perform as well as they think they should. However, the chance of experiencing distress as a side effect of CRT is considered very unlikely, and any distress that CRT causes is likely to be mild (Lincoln et al., 2015).

Repetitive Transcranial Magnetic Stimulation (rTMS)

Transcranial magnetic stimulation (TMS) is neurostimulation and neuromodulating and uses magnetic stimulation of electric fields in the brain. (Rossi et al, 2009) Quick pulses are created through a coil of wire (The London Psychiatry Centre, n.d.). By doing so a pulsed magnetic field is created. The electrical brain activity will be influenced by this magnetic field. To focus on specific parts of the brain, the coil of wire is placed on the patient's scalp. The magnetic field can penetrate the skull safe and painless. When this stimulation is given at regular intervals it is called rTMS (The London Psychiatry Centre, n.d.). When TMS is applied repetitively, the pulses can modulate cortical excitability. This therapy is often used for depressive disorders, in which the price for a daily session is $200-300. The length of treatment is usually 4 to 6 weeks and the price tag for this period can range from $5,000-$10,000 (Raeburn, 2016).Recently Hulst et al., (2017) published a study on the therapeutic use of rTMS on cognition in MS patients. The effects of rTMS of the right dorsolateral prefrontal cortex on working memory performance was studied, while measuring task-related brain activation and task-related brain connectivity in patients with MS. For MS patients the task-related frontal activation at baseline was higher compared to healthy controls. This disappeared after rTMS. Functional connectivity between parts of the brain increased in patients after rTMS when compared to sham stimulation. These results indicate that rTMS can induce changes in network efficiency in the brain of MS patients. For that reason rTMS could have a potential role in cognitive rehabilitation in MS. The most common adverse events of rTMS are headache, discomfort in the stimulated area and nausea (Durmaz, Ate? & ?enol, 2015). The most serious side effect of rTMS is epileptic seizure. However, in a growing number of MS patients that are treated with rTMS, no major safety or side effects were found (Nasios et al., 2018).