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Fostamatinib Disodium Hexahydrate: A Novel Treatment for Adult Immune Thrombocytopenia
Ali McBride, PharmD; Pratima Nayak, MD; Yuliya Kreychman, PharmD; Leslie Todd, BA; Anne-Marie Duliege, MD, MS; Amit R. Mehta, MD

Fostamatinib Disodium Hexahydrate: A Novel Treatment for Adult Immune Thrombocytopenia

Ali McBride, PharmD; Pratima Nayak, MD; Yuliya Kreychman, PharmD; Leslie Todd, BA; Anne-Marie Duliege, MD, MS; Amit R. Mehta, MD
Immune thrombocytopenia (ITP) is an autoimmune disease associated with substantial heterogeneity and varying outcomes. Significant bleeding, including intracranial hemorrhage, is a persistent risk for patients with ITP, along with cardiovascular disease. ITP has also been associated with decreased patient functionality and quality of life. The primary goal of ITP therapy is to lower the risk of bleeding and associated complications by raising platelet counts to levels that provide adequate hemostasis with minimal treatment-related toxicity. Current first-line treatments include corticosteroids, as well as intravenous and anti-D immunoglobulin. Despite the availability of several second-line options, the need for additional treatment options that can provide a stable, long-term response with few adverse effects is critical and ongoing. Fostamatinib disodium hexahydrate is an oral spleen tyrosine kinase inhibitor that produces a rapid, durable response in patients who have failed one or other treatments. Additionally, fostamatinib is well tolerated, and adverse effects can be actively mitigated through dose reduction, dose interruption, or standard therapeutic approaches.
Am J Manag Care. 2019;25:-S0
In 1951 at the Barnes-Jewish Hospital in St. Louis, Missouri, Dr William J. Harrington injected himself with approximately 1 pint of blood from a woman with a persistently low blood platelet count, in an effort to prove that her symptoms were associated with a factor in her blood that was causing platelet destruction. After experiencing a generalized seizure, Harrington’s platelet count decreased from 250 × 109/L to 10 × 109/L. Further, he experienced gingival, nasal, and rectal bleeding, along with petechiae (tiny bruises). Harrington spent 3 days sleeping upright supported by pillows, to reduce intracerebral pressure and avoid experiencing an intracranial hemorrhage, before making a full recovery. Incredibly, after this ordeal, 7 individuals from his staff volunteered to undergo the same procedure to confirm the physician’s findings.1

Why is a low platelet count, known as thrombocytopenia, of such medical importance that volunteers were willing to risk their health to uncover its underlying causes? The signs and symptoms of thrombocytopenia vary in scope and severity, ranging from petechiae/bruising and oral cavity blood blisters, through prolonged mucocutaneous bleeding (eg, epistaxis or menorrhagia), to intracranial hemorrhage that can lead to death in severe cases. The risk for bleeding is a constant source of concern for patients, leading to restriction of activities, impaired functionality, and decreased quality of life.2 The petechiae and bruising can be visually disturbing, leading to social isolation. Patients with immune thrombocytopenia (ITP) often suffer from depression and fatigue, which can be debilitating.3,4

Thrombocytopenia can be caused by many different factors. The factor that was transferred to Harrington from his patient’s blood was later discovered to be anti-platelet antibodies.5 Autoimmune platelet destruction, or ITP, is one of the most common forms of thrombocytopenia.

ITP is a heterogeneous disease that varies widely with respect to the degree and duration of response to treatment. Both approved and off-label treatment options are available, but there is no reliable method for predicting patient response, rendering the choice of therapy largely empiric and based on individual clinician experience.6,7 In fact, neither the treatment guidelines from the American Society of Hematology (ASH)6 nor an international consensus document7 provide prescriptive recommendations regarding hierarchy, priority, or treatment order among second-line or later treatment options after patients have failed first-line corticosteroid therapy.6,7 The absence of clinical consensus around the treatment sequence is clearly reflected among the fragmented practice patterns observed in the United States.8 ITP may last for decades, and there is no single treatment option that universally provides a response or is well tolerated in all patients. Consequently, many clinicians resort to cycling their patients through various agents over time due to lack of efficacy, loss of response, or intolerability.7

Fostamatinib is an oral treatment for chronic ITP in adults and is the first treatment to target spleen tyrosine kinase (SYK), which plays a key role in a known pathway of platelet destruction in ITP. Fostamatinib was evaluated in two phase 3, randomized, double-blind, placebo-controlled, 24-week trials, which led to approval of fostamatinib for the treatment of adults with chronic ITP in April 2018 by the FDA.9 These studies included patients who had previously had an insufficient response to at least 1 ITP treatment. Patients who responded to fostamatinib showed rapid, durable increases in functional platelet levels that led to improved clinical outcomes such as reduced bleeding events and a reduced need for rescue medication.9 Fostamatinib has been shown to have a manageable safety and tolerability profile.9-11

Disease Overview, Epidemiology, and Burden of Illness
Heterogeneity of Immune Thrombocytopenia
ITP is an autoimmune disease that can arise apparently spontaneously (primary ITP) or develop in response to an underlying condition, such as infection with Helicobacter pylori, hepatitis C, or HIV (secondary ITP).12 A principle of managing  secondary ITP is to focus on treating the underlying condition, as this will usually resolve the thrombocytopenia.12

Primary ITP is characterized clinically by a low platelet count (<100 x 109/L) in the absence of other causes or disorders that may be associated with thrombocytopenia, and it is therefore considered a diagnosis of exclusion, with no currently available specific clinical or laboratory parameters.6 The ITP International Consensus Report characterizes ITP into 3 distinct phases based on disease duration: newly diagnosed ITP (<3 months following diagnosis); persistent ITP (3-12 months from diagnosis); and chronic ITP (>12 months’ duration).7 Patients with chronic ITP account for  the majority of the total population with ITP.13 Most adults with ITP will progress to chronic ITP, and it has been estimated that only a minority of patients experience a durable remission within 1 year of disease onset.14

ITP is associated with increased rates of morbidity and mortality; the disease symptoms can range from mild bruising to life-threatening bleeds.15 Consequently, ITP increases healthcare resource utilization due to emergency treatment, hospital admissions, primary care visits, and specialist visits.16-18 Treatment decisions cannot be based on platelet levels alone and should take into consideration patient risk factors such as advanced age, activity level, associated comorbidities, and concurrent medications.7 This means that treatment must be individualized because a safe platelet threshold for maintaining adequate hemostasis in one patient may not be appropriate for another. In practice, however, 30-50 x 109/L is often used as a general treatment or safety threshold that is applicable to the majority of patients.7

Pathophysiology of Immune Thrombocytopenia
The classic understanding of ITP pathophysiology involves platelets being coated by immunoglobulin G (IgG) antiplatelet auto-antibodies. This leads to the clearing of platelets from the bloodstream by macrophages, which are located primarily in the spleen and also in the liver.13,19 However, there are other mechanisms of platelet destruction, as shown by the treatment failure of splenectomy in 30% to 50% of adult patients with chronic ITP.7,20,21 Alternative mechanisms include complement-dependent platelet lysis22,23  and direct T-cell–mediated cytotoxicity of platelets.24-26 See Figure 1 for a visualization of the pathophysiology of ITP.27-31

In addition to increased platelet destruction, impaired platelet production may also contribute to the pathogenesis of ITP.32 Auto-antibodies in blood plasma can have inhibitory effects on megakaryocyte production and maturation.33,34 There may be a subset of patients with chronic ITP with fewer megakaryocytes than healthy controls, who have a lower platelet count because of defects in megakaryocyte production and/or maturation35 (Figure 1).27-31

The relative importance of these different mechanisms of platelet destruction and impaired production can vary from patient to patient, which may explain both the clinical heterogeneity of the disease36 and the differential responses to various treatments.20,37

Burden of Chronic ITP
The main concern in patients with ITP is the risk of significant bleeding, such as intracranial hemorrhage,38 which can be fatal.39 The frequency of fatal hemorrhage varies in the literature, with some studies reporting a rate of about 1.6%.40 Since few patients experience complete remission, this risk of bleeding can persist for decades.  

A systematic literature search in the year 2000 on the natural course of the disease in 1817 patients with ITP found that untreated ITP could be associated with a marked reduction in life expectancy. For example, a 30-year-old patient with ongoing ITP was estimated to have a loss of 20.4 years of life expectancy, while a 70-year-old was estimated to have a loss of 9.4 years.14 More recent studies show an increase in mortality risk of 22% to 50% in patients hospitalized with ITP.16,41 ITP is also associated with increased cardiovascular risk, and patients with ITP have a 38% greater likelihood of developing cardiovascular disease (ie, ischemic heart disease, stroke, transient ischemic attack, and heart failure) compared with matched controls.42

ITP can substantially affect patients’ functionality and health-related quality of life (QoL). For example, a fear of bleeding associated with low platelet counts leads to patients limiting their daily activities, including decreased or no participation in outdoor activities and exercise. Patients may also tend to avoid air travel and crowds, in order to limit jostling and resultant bruising, which can be extensive and emotionally damaging. Social stigma associated with bruising, due to suspicions about spousal or parental abuse, means that patients may feel embarrassed and seek social isolation, both of which can lead to depression when the disease is of longer duration.3 Work absenteeism or tardiness due to bleeding episodes (eg, extended nosebleeds, hospitalizations) can also contribute to significant anxiety among individuals with ITP. Fatigue is another significant component of morbidity that is often overlooked, despite being the most commonly reported symptom. Fatigue has a considerable effect on patients’ lives, hindering their ability to carry out normal daily activities.3,4

Formal measurement of the impact of ITP on patients’ QoL has been performed using general instruments, including the 36-Item Short Form Health Survey, EuroQoL-5D , and a validated disease-specific questionnaire called the ITP Patient Assessment Questionnaire, all of which have shown the significant and broadranging effects of ITP on patients’ lives.43,44

Epidemiology of Immune Thrombocytopenia
The incidence of ITP in adults is estimated to be 1.6 to 3.9 cases per 100,000/year and increases with age, reaching 4.6 cases per 100,000/year for people over 60 years of age.45-47 Approximately 9% of patients achieve remission within 1 year of disease onset,6 meaning that most patients with newly diagnosed ITP go on to develop chronic ITP. The prevalence of adult ITP increases with age, with estimates ranging from 4 to 20 cases per 100,000 in the United States.46,48

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