Fostamatinib Disodium Hexahydrate: a Novel Treatment for Adult

REPORT

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

n 1951 at the Barnes-Jewish Hospital in St. Louis, Missouri, ABSTRACT Dr William J. Harrington injected himself with approxi-

mately 1 pint of blood from a woman with a persistently low Immune thrombocytopenia (ITP) is an autoimmune disease associated blood platelet count, in an effort to prove that her symptoms with substantial heterogeneity and varying outcomes. Significant bleeding, Iwere associated with a factor in her blood that was causing platelet including intracranial hemorrhage, is a persistent risk for patients with destruction. After experiencing a generalized seizure, Harrington’s ITP, along with cardiovascular disease. ITP has also been associated with decreased patient functionality and quality of life. The primary goal of ITP platelet count decreased from 250 × 109/L to 10 × 109/L. Further, he therapy is to lower the risk of bleeding and associated complications by experienced gingival, nasal, and rectal bleeding, along with petechiae raising platelet counts to levels that provide adequate hemostasis with (tiny bruises). Harrington spent 3 days sleeping upright supported by minimal treatment-related toxicity. Current first-line treatments include pillows, to reduce intracerebral pressure and avoid experiencing an corticosteroids, as well as intravenous and anti-D immunoglobulin. intracranial hemorrhage, before making a full recovery. Incredibly, Despite the availability of several second-line options, the need for additional treatment options that can provide a stable, long-term after this ordeal, 7 individuals from his staff volunteered to undergo response with few adverse effects is critical and ongoing. Fostamatinib the same procedure to confirm the physician’s findings.1 disodium hexahydrate is an oral spleen tyrosine kinase inhibitor that Why is a low platelet count, known as thrombocytopenia, of produces a rapid, durable response in patients who have failed one such medical importance that volunteers were willing to risk their or other treatments. Additionally, fostamatinib is well tolerated, and health to uncover its underlying causes? The signs and symp- adverse effects can be actively mitigated through dose reduction, dose toms of thrombocytopenia vary in scope and severity, ranging interruption, or standard therapeutic approaches. from petechiae/bruising and oral cavity blood blisters, through Am J Manag Care. 2019;25:S347-S358 prolonged mucocutaneous bleeding (eg, epistaxis or menorrhagia), For author information and disclosures, see end of text. 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 visu- ally 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 reli- able 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

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Society of Hematology (ASH)6 nor an international consensus docu- utilization due to emergency treatment, hospital admissions, primary ment7 provide prescriptive recommendations regarding hierarchy, care visits, and specialist visits.16-18 Treatment decisions cannot be priority, or treatment order among second-line or later treatment based on platelet levels alone and should take into consideration options after patients have failed first-line corticosteroid therapy.6,7 patient risk factors such as advanced age, activity level, associated The absence of clinical consensus around the treatment sequence is comorbidities, and concurrent medications.7 This means that treat- clearly reflected among the fragmented practice patterns observed ment must be individualized because a safe platelet threshold for in the United States.8 ITP may last for decades, and there is no single maintaining adequate hemostasis in one patient may not be appro- treatment option that universally provides a response or is well priate for another. In practice, however, 30-50 x 109/L is often used tolerated in all patients. Consequently, many clinicians resort to as a general treatment or safety threshold that is applicable to the cycling their patients through various agents over time due to lack majority of patients.7 of efficacy, loss of response, or intolerability.7 Fostamatinib is an oral treatment for chronic ITP in adults and Pathophysiology of Immune Thrombocytopenia is the first treatment to target spleen tyrosine kinase (SYK), which The classic understanding of ITP pathophysiology involves platelets plays a key role in a known pathway of platelet destruction in ITP. being coated by immunoglobulin G (IgG) antiplatelet auto-anti- Fostamatinib was evaluated in two phase 3, randomized, double- bodies. This leads to the clearing of platelets from the bloodstream blind, placebo-controlled, 24-week trials, which led to approval of by macrophages, which are located primarily in the spleen and also fostamatinib for the treatment of adults with chronic ITP in April in the liver.13,19 However, there are other mechanisms of platelet 2018 by the FDA.9 These studies included patients who had previously destruction, as shown by the treatment failure of splenectomy had an insufficient response to at least 1 ITP treatment. Patients in 30% to 50% of adult patients with chronic ITP.7,20,21 Alternative who responded to fostamatinib showed rapid, durable increases mechanisms include complement-dependent platelet lysis22,23 and in functional platelet levels that led to improved clinical outcomes direct T-cell–mediated cytotoxicity of platelets.24-26 See Figure 1 for such as reduced bleeding events and a reduced need for rescue a visualization of the pathophysiology of ITP.27-31 medication.9 Fostamatinib has been shown to have a manageable In addition to increased platelet destruction, impaired platelet safety and tolerability profile.9-11 production may also contribute to the pathogenesis of ITP.32 Auto-antibodies in blood plasma can have inhibitory effects on Disease Overview, Epidemiology, and Burden megakaryocyte production and maturation.33,34 There may be a of Illness subset of patients with chronic ITP with fewer megakaryocytes than Heterogeneity of Immune Thrombocytopenia healthy controls, who have a lower platelet count because of defects ITP is an autoimmune disease that can arise apparently sponta- in megakaryocyte production and/or maturation35 (Figure 1).27-31 neously (primary ITP) or develop in response to an underlying The relative importance of these different mechanisms of platelet condition, such as infection with Helicobacter pylori, hepatitis C, destruction and impaired production can vary from patient to or HIV (secondary ITP).12 A principle of managing secondary ITP is patient, which may explain both the clinical heterogeneity of the to focus on treating the underlying condition, as this will usually disease36 and the differential responses to various treatments.20,37 resolve the thrombocytopenia.12 Primary ITP is characterized clinically by a low platelet count Burden of Chronic ITP (<100 x 109/L) in the absence of other causes or disorders that may be The main concern in patients with ITP is the risk of significant associated with thrombocytopenia, and it is therefore considered a bleeding, such as intracranial hemorrhage,38 which can be fatal.39 diagnosis of exclusion, with no currently available specific clinical The frequency of fatal hemorrhage varies in the literature, with some or laboratory parameters.6 The ITP International Consensus Report studies reporting a rate of about 1.6%.40 Since few patients experience characterizes ITP into 3 distinct phases based on disease duration: complete remission, this risk of bleeding can persist for decades. newly diagnosed ITP (<3 months following diagnosis); persistent ITP A systematic literature search in the year 2000 on the natural (3-12 months from diagnosis); and chronic ITP (>12 months’ dura- course of the disease in 1817 patients with ITP found that untreated tion).7 Patients with chronic ITP account for the majority of the total ITP could be associated with a marked reduction in life expectancy. population with ITP.13 Most adults with ITP will progress to chronic For example, a 30-year-old patient with ongoing ITP was estimated ITP, and it has been estimated that only a minority of patients expe- to have a loss of 20.4 years of life expectancy, while a 70-year-old rience a durable remission within 1 year of disease onset.14 was estimated to have a loss of 9.4 years.14 More recent studies show ITP is associated with increased rates of morbidity and mortality; an increase in mortality risk of 22% to 50% in patients hospitalized the disease symptoms can range from mild bruising to life-threat- with ITP.16,41 ITP is also associated with increased cardiovascular risk, ening bleeds.15 Consequently, ITP increases healthcare resource and patients with ITP have a 38% greater likelihood of developing

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cardiovascular disease (ie, ischemic heart disease, stroke, transient a considerable effect on patients’ lives, hindering their ability to ischemic attack, and heart failure) compared with matched controls.42 carry out normal daily activities.3,4 ITP can substantially affect patients’ functionality and health- Formal measurement of the impact of ITP on patients’ QoL related quality of life (QoL). For example, a fear of bleeding associated has been performed using general instruments, including the with low platelet counts leads to patients limiting their daily activi- 36-Item Short Form Health Survey, EuroQoL-5D , and a validated ties, including decreased or no participation in outdoor activities disease-specific questionnaire called the ITP Patient Assessment and exercise. Patients may also tend to avoid air travel and crowds, Questionnaire, all of which have shown the significant and broad- in order to limit jostling and resultant bruising, which can be ranging effects of ITP on patients’ lives.43,44 extensive and emotionally damaging. Social stigma associated with bruising, due to suspicions about spousal or parental abuse, Epidemiology of Immune Thrombocytopenia means that patients may feel embarrassed and seek social isolation, The incidence of ITP in adults is estimated to be 1.6 to 3.9 cases per both of which can lead to depression when the disease is of longer 100,000/year and increases with age, reaching 4.6 cases per 100,000/ duration.3 Work absenteeism or tardiness due to bleeding episodes year for people over 60 years of age.45-47 Approximately 9% of patients (eg, extended nosebleeds, hospitalizations) can also contribute to achieve remission within 1 year of disease onset,6 meaning that significant anxiety among individuals with ITP. Fatigue is another most patients with newly diagnosed ITP go on to develop chronic significant component of morbidity that is often overlooked, ITP. The prevalence of adult ITP increases with age, with estimates despite being the most commonly reported symptom. Fatigue has ranging from 4 to 20 cases per 100,000 in the United States.46,48

FIGURE 1. Pathophysiology of Immune Thrombocytopenia27-31

CD40 indicates cluster of differentiation 40; CD8, cluster of differentiation 8; GPIIb/IIIa, glycoprotein IIb/IIIa; IL-2, interleukin-2; IL-6, interleukin-6; IFNγ, interferon gamma; SYK, spleen tyrosine kinase. Immune thrombocytopenia is a disease of platelet destruction via (A) SYK-mediated phagocytosis by macrophages, (B) removal of desialylated platelets by Kupffer cells, (C) complement-dependent destruction, and (D) cytotoxic T-cell killing. ITP can also be a disease of insufficient platelet production via (E) autoantibody-mediated impairment of megakaryocyte maturation. Adapted from references 27-31.

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Current Treatment Options and Unmet Needs In order to better understand the sequencing of therapies for ITP, Treatment Goals we analyzed prescription claims data from a large clearing house The primary goal of ITP therapy is to lower the risk of bleeding (Symphony Health PatientSource®, Phoenix, AZ), which collects data and associated complications by raising platelet counts to levels from pharmacies and providers about insurance claims for prescrip- that provide adequate hemostasis with minimal treatment-related tion payments across the United States.8 The ITP prescription claims toxicity.6,7,49 Individual treatment targets for platelet counts vary data for 7 years from 2009 to 2016 were included and represent depending on the individual patient and the treatment. However, approximately 40,000 patients with 2,500,000 claims associated with 30 x 109/L to 50 x 109/L is often used as a target to guide treatment an ITP diagnosis code (Symphony Health, PatientSource®, 7 years in patients who cannot achieve normal platelet counts.7 ending November 2016). Figure 2 shows the pattern of medications prescribed for ITP for each line of therapy.8 During the first line of Treatment Choices therapy for ITP, 93% of patients in the analysis received steroids alone, Physicians who treat patients with ITP have a variety of therapeutic and other treatments were used by 1% to 2% of patients.8 During options available with guidance on disease management acces- subsequent lines of therapy, the use of steroids as a monotherapy sible from 2 major clinical guidelines: the Evidence-Based Practice declined substantially, and the use of other medications or splenec- Guideline for ITP published by ASH6 in 2011 and an International tomy increased. Steroids continued to be used in combination with Consensus Report published by an international working group of other treatments, and 57% to 73% of patients continued to receive experts in 2010.7 Both guidelines recommend using corticosteroids steroids in subsequent lines of therapy. Overall, the sequencing of as the standard initial therapy for ITP but caution against their therapy was highly variable, with an assortment of different treat- long-term use. They suggest intravenous immunoglobulin (IVIg) ments being used and discontinued, with little discernible pattern. and intravenous anti-D (IV anti-D) as alternative or complemen- While ASH has recommended consideration of splenectomy before tary first-line treatments.6,7 However, there is no defined treatment TPO-RA agonists, the International Consensus Report does not indi- order among second-line therapies, which include rituximab (not cate a preference for second-line treatment options for ITP, leaving FDA-approved for ITP), thrombopoietin receptor agonists (TPO- the decision in the hands of the medical practitioner. The treatment RAs), and splenectomy.6,7 These guidelines were written prior to of ITP continues to evolve with more options available to prevent or the approval of fostamatinib and are currently being updated. delay the use of splenectomy.50 One retrospective analysis of treat- A key difficulty in the management of ITP is that the durability ment options by year demonstrated that in the past decade, there was of response to both first- and second-line therapies is not sustained a trend toward a reduction in the use of splenectomy as second-line in a high proportion of patients, and these treatment-refractory treatment, reflecting the availability and efficacy of new ITP thera- patients often go on to receive additional lines of therapy.8,13 pies as second-line treatment options in the management of ITP.50

Corticosteroids FIGURE 2. Patterns of Treatment for Immune Thrombocytopenia8 Corticosteroids are the established first-line 6-8 Line of Therapy and Treatment Share treatment for most patients with ITP and in a 5-year Window typically include oral prednisone, IV meth- 1% 2% 2% 1% 5% 2% 3% 2% Splenectomy + Steroid ylprednisolone, or high-dose (40 mg/day) 6% 2% 2% 1% 2% 6% 7% 3% 9% 2% 3% 9% 9% Splenectomy dexamethasone. Corticosteroids have been 8% 8% 10% Eltrombopag + Steroid 6% 11% 11% 14% shown to generate a rapid response in approxi- 9% Eltrombopag 11% 10% 11% mately two-thirds of patients.51 15% 16% Romiplostim + Steroid 8% The detrimental effects of corticosteroids 2% 14% Romiplostim 93% 24% 6% 7% 9% 6% 1% 3% 6% Rituximab + Steroid often outweigh their benefits if they are used 5% 6% 12% 7 11% 6% Rituximab for prolonged periods, and their efficacy often 5% 7% Total Patients (%) 11% 39% Steroid + IMM/Chemo wanes over time. For example, only 10% to 33% 26% 6% 25% IMM/Chemo 8% 20% of patients achieve long-term remission Steroid 51 First Second Third Fourth Fifth Sixth after 1 year of treatment with prednisone. Line of Therapy For these reasons, guidelines recommend rapidly tapering the dose of corticosteroids after IMM indicates immunomodulators. 4 weeks in both responders and nonresponders.7 Percentage of patients utilizing each treatment or combination of treatments during first and subsequent lines of therapy. Adverse effects associated with pro- Data Source: Symphony Health, PatientSource®, 7 years ending November 2016. longed corticosteroid use include diabetes,

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osteoporosis, and hypertension.7,51,52 Moreover, short-term use of Other potentially fatal adverse reactions include severe mucocu- corticosteroids in patients with ITP is associated with an increased taneous reactions, hepatitis B virus reactivation, and progressive risk of serious infections.53 multifocal leukoencephalopathy.56 Non-fatal adverse effects associated with rituximab for the treatment of ITP include first-infusion Intravenous Immunoglobulin fever/chills, rash or scratchiness in the throat, serum sickness, and IVIg may be used as a first-line treatment for patients in whom (very rarely) bronchospasm, retinal artery thrombosis, and infection.7 corticosteroids are contraindicated. Alternatively, IVIg can be used alongside corticosteroids as there appear to be some synergistic Thrombopoietin Receptor Agonists effects.7 IVIg is also used as a rescue therapy.7 The mechanism of action TPO-RAs mimic the action of thrombopoietin by stimulating platelet of IVIg is not completely understood and may include inhibition of production through binding and activating the TPO receptor.64 Fc-receptor–mediated platelet phagocytosis, suppression of anti- Two TPO-RAs have been approved by the FDA for use in patients platelet antibody production, anti-idiotypic inhibition of antiplatelet with chronic ITP who have had an insufficient response to a prior antibodies, or accelerated elimination of antiplatelet antibodies.54 treatment: romiplostim (Nplate, Amgen), an Fc-peptide fusion Response rates with IVIg are similar to those with corticosteroids; protein administered weekly as a subcutaneous injection,65 and however, responses with IVIg are short-lived, with most patients eltrombopag (Promacta, Novartis), a small nonpeptide molecule reverting to pretreatment platelet levels after 3 to 4 weeks.51 IVIg administered orally on a daily basis.66 infusions take several hours, and adverse effects may include head- Overall response rates (a single platelet response of 50 x 109/L) aches and, rarely, renal failure and thrombosis.7 Therefore, IVIg is at any time during treatment ranged from 79% to 88% for romip- typically utilized as an adjunctive therapy in the management of lostim and 59% to 79% for eltrombopag.65-69 Durable response ITP and not as a monotherapy. rates ranged from 38% to 61% for romiplostim and 37% to 56% for eltrombopag.65,66 The mean duration of response was reported to be Anti-D Immunoglobulin 30 months with romiplostim and 15 months with eltrombopag.65-69 IV anti-D can be used as a first-line treatment in rhesus(D)-positive, Most patients take treatment breaks, and the average duration of nonsplenectomized patients with ITP.6,7 IV anti-D can be infused continuous therapy (defined as no treatment gap of >30 days) is in a shorter time and patients may experience a longer treatment 108 days with romiplostim and 110 to 131 days with eltrombopag.70,71 response than with IVIg, with some individuals still responding at 26 The most common reported adverse events are pain (arthralgia, months.55 Additional tests are required before IV anti-D can be used, myalgia, extremity pain, abdominal pain, shoulder pain), dizzi- including blood group, direct antiglobulin test, and reticulocyte count.7 ness, insomnia, dyspepsia, and paresthesia for romiplostim65 and Adverse effects associated with the use of IV anti-D include gastrointestinal disturbances (nausea, diarrhea, vomiting), upper hemoglobinuria, hemolytic anemia, disseminated intravascular respiratory tract infection, urinary tract infection, increased alanine coagulation, and renal failure.55 aminotransferase, and myalgia for eltrombopag.66 TPO-RAs may cause fluctuations in platelet counts,72 and the Treatment Choices: Second-Line and Third-Line increased platelet counts could potentially cause thrombotic/throm- Rituximab boembolic complications, particularly portal vein thrombosis.65,66 Rituximab (Rituxan; Biogen/Genentech) is a monoclonal antibody that Thromboembolic events have been reported in approximately 6% targets the CD20 antigen expressed on the surface of B cells. It is used of patients in clinical trials with TPO-RAs67,68 although frequencies for the treatment of lymphoma at a dose of 100 mg/m2 or 375 mg/m2 as high as 15% to 26% were reported in some cohorts.67 TPO-RAs are IV weekly for 4 weeks.56 Although rituximab has not been approved also associated with an increased risk of progression of myelodys- for the treatment of chronic ITP, it has become an off-label treatment plastic syndromes to acute myeloid leukemia.65,66 The eltrombopag option that uses the same dosing schedule as that used for lymphoma prescribing information also has a boxed warning about the risk of treatment. Rituximab depletes B lymphocytes, which are responsible severe and potentially life-threatening hepatotoxicity.66 for antiplatelet antibody production. Overall responses were seen in 40% to 63% of patients,57-60 although a recent small, randomized Splenectomy controlled trial failed to demonstrate a statistically significant differ- Splenectomy is the surgical removal of the spleen, which is the ence in response to rituximab versus placebo in patients treated primary site of platelet destruction and also a site of auto-antibody with concurrent corticosteroids.61 Fewer than 40% of patients who production. Approximately 80% of patients with ITP respond to responded to rituximab maintain a durable response at 1 year.59,60,62,63 splenectomy, and 50% to 70% of patients maintain a long-term Rituximab causes infusion reactions in approximately 18% of response of more than 5 years.7,21 However, approximately one- patients with ITP, which can be fatal in a small minority of patients.59 third of adult patients will relapse after splenectomy, often within

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2 years post surgery, which may be related to the different mecha- In examining the costs associated with ITP overall, patients nisms of platelet destruction and impaired platelet production with the disease have longer average hospital stays (6.02 days for underpinning the disease.22,25,32 patients with ITP vs 4.7 days for all conditions) than do those with Splenectomy may be associated with surgical complications other disorders (according to data from the 2006-2012 time period). that require prolonged hospitalization,73 as well as the long-term Consequently, hospital stays associated with ITP are more costly risks for thrombosis and serious infections, which can be fatal.74-79 ($16,594 for patients with ITP vs $11,200 for all conditions).16 One Furthermore, the presence of comorbidities in older patients can study estimated that 45% of the costs associated with ITP are attrib- contribute to increased surgery-related complications.21 The use utable to emergency department services, and 46% are related to of splenectomy has decreased over the years, with the emergence hospital admissions.17 Another study showed that patients with of new pharmacological treatments for ITP.50 ITP have more visits with primary care physicians and specialists; in the month prior to completing the survey, 20% of 1002 patients Other Immunosuppressant Therapies with ITP had primary care visits compared with 11% of 1031 age- and Off-label use of other immunosuppressant agents in patients with gender-matched controls, and 28% had specialist visits compared chronic ITP (eg, alemtuzumab, azathioprine, cyclophosphamide, with 11% in controls.18 cyclosporine, danazol, dapsone, and mycophenolate mofetil) is sometimes considered, particularly as salvage therapy or in addition Cost of Current Treatment Pathway to second-line agents.7 The safety and efficacy of these agents in The treatment of ITP is limited by the variable durability of treatment patients with chronic ITP have not been evaluated in well-designed response; more than half of all patients experience bleeding-related prospective clinical trials. They have shown some clinical activity episodes or require rescue medication.87 These bleeding episodes in small, uncontrolled studies in ITP, albeit often with a short are associated with expensive hospitalizations86 and rescue medi- duration of response and/or less favorable safety profile.7,80-84 For cations such as IVIg, which incur administration costs in addition this reason, the use of these agents, either as monotherapy or in to the cost of drug acquisition.88,89 combination therapy, is usually reserved for patients who do not The adverse effects of treatments for ITP are also burdensome. respond to standard-of-care treatments. Corticosteroids are associated with multiple adverse effects, including hypertension, bone fractures, metabolic syndrome, and peptic Unmet Needs ulcers,52 which, in turn, are associated with additional costs.90 IVIg The heterogeneous nature of ITP means that individual patient and IV anti-D are associated with rare but very costly adverse effects, responses to therapy vary both in magnitude and in duration. such as thrombosis and renal failure.7,55 Rituximab can cause fatal A substantial proportion of patients have disease that either fails to infusion reactions, severe mucocutaneous reactions, and progres- respond to therapy or shows an attenuated response over time. In sive multifocal leukoencephalopathy.56 TPO-RAs are associated addition, serious adverse effects may limit the use of some thera- with progression of myelodysplastic syndromes to acute myeloid pies in a proportion of patients. Consequently, many patients cycle leukemia, thrombotic/thromboembolic complications, and, with through a number of different therapies with no clear guidance on eltrombopag, hepatotoxicity.65,66 which treatment to use after corticosteroids (Figure 28).7,51 Rather, clinical judgment about the relative safety risks for each patient, often Fostamatinib for Chronic Immune Thrombocytopenia taking patient preference and expected compliance into consideration, Fostamatinib disodium hexahydrate (Tavalisse®, Rigel) is the first- frequently forms the basis of the decision as to which treatment is in-class and only oral inhibitor of SYK that is indicated for the selected. Thus, a need exists for a treatment that generates a durable treatment of thrombocytopenia in adult patients with chronic ITP response and has manageable and moderate adverse effects. who have had an insufficient response to a previous treatment.91 In ITP, Fcg receptors on macrophages bind to auto-antibodies on plate- Cost of Disease lets, activating a signaling cascade involving SYK that culminates ITP can cause increased healthcare resource utilization from emer- in macrophage-mediated platelet phagocytosis.29,92 The inhibition gency treatment, hospital admissions, primary care visits, and of SYK signaling prevents platelet destruction by activated macro- specialist visits.16-18 Bleeding-related episodes are the most clearly phages (Figure 1 27-31).13,29 Fostamatinib is the first treatment to target defined cost; the average cost of a bleeding episode was estimated a specific pathway in the pathophysiology of ITP. to be $4703 in 201285 and $6022 in 2017.86 The average annual costs for bleeding-related episodes alone are $8465 for patients with Clinical Benefits platelet counts ≥50 × 109/L but rise to $34,473 for patients with The safety and efficacy of fostamatinib were evaluated in 2 double- platelet counts <50 × 109/L.85 blind, randomized, placebo-controlled, phase 3 studies (FIT1 and

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FIT2; NCT02076399 and NCT02076412, respectively) and an open- FIGURE 3. Overall and Stable Responses to Treatment: FIT1, FIT29 label, extension (OLE) study (FIT3; NCT02077192). The FIT1 and FIT2 studies were conducted in 150 adults with chronic ITP over FIT1 FIT2 Pooled 60 9,93 24 weeks, and the FIT3 study is ongoing. * 50 48% ** These were the first phase 3 studies that included ITP patients 43% ** with prior exposure to TPO-RAs. All patients had received at least 40 37%

1 prior treatment: 93% had received corticosteroids, 47% had received 30 TPO-RAs, 34% had received rituximab, and 34% had undergone sple- * 21% ** 20 18% 18% 18% nectomy. At baseline, the median duration of disease was 8.5 years, Patients (%) 14% and all patients had at least 3 platelet counts of less than 30 × 109/L 10 8% 4% 2% 9,93 0% including 2 measurements within the preceding 3 months. 0 Overall Stable Overall Stable Overall Stable *P <.05 Fostamatinib was administered orally at a starting dose of n = 25 51 25 51 24 50 24 50 49 101 49 101 **P <.01 100 mg bid that could be increased to 150 mg bid (depending on Responses platelet counts and tolerability) after week 4. By the end of the study Placebo Fostamatinib period, 88% of patients had been titrated up to 150 mg bid. As an oral treatment, fostamatinib is easy to administer and requires Percentage of patients with an overall response (platelet count of ≥50 x 109/L minimal titration, reducing both the expenditure of clinical time during weeks 1 to 12) or stable response (platelet count of ≥50 x 109/L on ≥4 of 6 93 visits during weeks 14 through 24) to fostamatinib (100-150 mg BID) or placebo and the utilization of healthcare resources. (FIT1 and FIT2 pooled analysis). Republished with permission of Wiley Periodicals, Inc., from Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Platelet Response results of two phase 3,randomized, placebo-controlled trials. Bussel J, Arnold The primary endpoint of stable response was stringently defined as DM, Grossbard E, et al; Am J Hematol. 93(7); 2018. Permission conveyed through Copyright Clearance Center, Inc. a platelet count of ≥50 x 109/L on at least 4 of 6 visits during weeks 14 through 24. Overall response was defined as a platelet count of ≥50 x 109/L during weeks 1 to 12 and was a post hoc analysis. 1 column Combined results from the FIT1 and FIT2 studies showed a stable FIGURE 4. Median Platelet Count in Overall Responders to response rate of 18% with fostamatinib versus 2% with placebo Fostamatinib: FIT1, FIT2, FIT393 (P = .0003; sensitivity analysis showed 17% versus 2%, P = .007), and an overall response rate of 43% with fostamatinib versus 14% with Overall Responders placebo (P = .0006) (Figure 3).9 Median postbaseline platelet counts 130,000 9 9 over 24 weeks were 95 x 10 /L in stable responders, 49 x 10 /L in 110,000 overall responders, 14 x 109/L in nonresponders, and 17.5 x 109/L with 90,000 placebo. Platelet responses to fostamatinib among responders were

generally rapid; responders achieved an initial platelet threshold 70,000 of ≥50 x 109/L at a median of 15 days.9 However, some patients had 50,000 a slower but steady increase in platelet counts that exceeded 50 x 109/L during weeks 2 to 12 or after the initial 12-week treatment 30,000 period.93 The phase 3 results led to the approval of fostamatinib for Median Platelet Count (/ μ L) 10,000 the treatment of adults with chronic ITP by the US FDA in April 2018. 0 Across the phase 3 studies and the open-label extension (OLE) 0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 study, 146 patients were treated with fostamatinib, and 64 of 146 Study Visit (Weeks) OVERALL (44%) patients achieved an overall response, which included 43 of RESPONDER 53 63 62 56 53 47 46 47 40 37 40 34 34 36 56 30 29 26 22 21 18 20 14 11 11 11 4 4 4 4 3 2 1 101 (43%) patients from the fostamatinib arm and 21 of 44 (48%) patients who were transitioned to fostamatinib from the placebo Shaded area indicates timepoints with less than 10 patients contributing data. arm of the phase 3 studies.93 The overall response to fostamatinib Republished with permission of Wiley Periodicals, Inc., from Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase was maintained over the course of treatment; median platelet 3 clinical trial program. Bussel JB, Arnold DM, Boxer MA, et al. Am J Hematol. counts remained ≥50 x 109/L at all visits, with a median post-base- 94(5), 2019. Permission conveyed through Copyright Clearance Center, Inc. line platelet count of 63 x 109/L (Figure 4).93 The majority of overall responders maintained their response for the duration of time on fostamatinib, including those patients who had failed prior therapy

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FIGURE 5. Durability of Response to Fostamatinib: FIT1, FIT2, and FIT393

S T S T S T S T T S T T S T S S T S S S T S S T S T S S S S S T S S

S T S T S S T T S T

S T

T T T T Response Treatment Continued response T Continued treatment

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

Months Treated With Fostamatinib

Each lane shows one patient; overall response is shown in blue. Arrow at the end of each lane indicates continuation of response (blue) or treatment (gray). S, stable responder; T, failed prior therapy with thrombopoietin receptor agonist. Note: End of response defined as two platelet counts <30,000/μL at least 4 weeks apart (or use of rescue therapy). Republished with permission of Wiley Periodicals, Inc., from Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program. Bussel JB, Arnold DM, Boxer MA, et al. Am J Hematol. 94(5), 2019. Permission conveyed through Copyright Clearance Center, Inc.

FIGURE 6. Kaplan-Meier Estimate of the Median Duration of First Response in Overall with a TPO-RA (Figure 5).93 The median dura- 93 Responders: Fostamatinib Exposure Population: FIT1, FIT2, FIT3 tion of the first overall response to fostamatinib

100 was not reached and is estimated to be greater

+ Censored than 28 months, based on the Kaplan-Meier curve (Figure 6).93 80 While 17 patients achieved a stable response to fostamatinib in the randomized studies, 60 (%) a 10 of 44 (23%) placebo patients from the randomized studies achieved a stable response to 40 fostamatinib in the OLE study; thus, the total Patients number of stable responders was 27 of 146 20 (18%) patients in the fostamatinib exposure Number of subjects at risk population. Fostamatinib stable responders 64 56 50 45 41 39 37 34 33 31 31 29 27 26 24 23 21 17 15 13 11 10 5 4 4 3 3 2 1 0 0 generally had a durable long-term response, 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 and 18 of 27 (67%) patients maintained a stable Duration of First Response (months) response for at least 1 year.93 Moreover, an addi- aPlatelet Count ≥50,000/µL) tional 7 stable responders (26%) remained on Republished with permission of Wiley Periodicals, Inc., from Long-term fostamatinib treatment of adults fostamatinib for more than 1 year because of with immune thrombocytopenia during the phase 3 clinical trial program. Bussel JB, Arnold DM, Boxer MA, et al. Am J Hematol. 94(5), 2019. Permission conveyed through Copyright Clearance Center, Inc. persistent clinical benefit, despite having 1 or

S354 NOVEMBER 2019 www.ajmc.com FOSTAMATINIB DISODIUM HEXAHYDRATE: A NOVEL TREATMENT FOR ADULT ITP more platelet counts drop below 50 x 109/L, and FIGURE 7. Subgroup Analysis of Overall Response: FIT1 and FIT2 Pooled Analysis9 5 of these patients regained their response. The other 2 patients with a stable response had not Patient Subgroup Difference (95% Cl) reached 12 months of therapy as of the data All patients (N = 150) 28.29 (14.54, 42.04) cutoff date (April 2017). Overall, 93% of patients Baseline platelet count who achieved a stable response continued to >15,000/ µL (n = 82) 35.85 (16.40, 55.29) respond and/or derive clinical benefit after ≤15,000/ µL (n = 68) 20.26 (2.14, 38.39) 12 months of treatment, and the median dura- Prior splenectomy tion of first stable response was not reached Yes (n = 53) 13.62 (-8.81, 36.06) and estimated to be greater than 28 months.93 No (n = 97) 35.92 (18.85, 52.99) Responses to fostamatinib were observed Prior rituximab among patients with long-standing ITP (average Yes (n = 48) 21.01 (-3.36, 45.38) time from diagnosis of 8.5 years), who were No (n = 102) 31.98 (15.34, 48.62) heavily pre-treated (splenectomy, rituximab, and/or TPO-RAs) and are considered difficult Prior TPO-RA to treat. Lower rates of response have been Yes (n = 71) 22.78 (4.03, 41.54) observed in studies of rituximab and other No (n = 79) 32.42 (12.50, 52.35) agents among heavily pretreated patients Age with a longer ITP duration compared with <65 years (n = 111) 30.68 (15.02, 46.33) 94,95 earlier stage patients. Fostamatinib was ≥65 years (n = 39) 21.10 (-7.99, 50.20) also effective in 75% of patients with persis- Sex tent ITP (<12 months).93 Subgroup analyses Male (n = 59) 26.97 (6.59, 47.36) illustrate overall responses across subgroups Female (n = 91) 29.23 (10.95, 47.52) categorized by duration of ITP, prior TPO-RA Duration of ITP at baseline therapy, prior splenectomy, and baseline <8 year (n = 73) 34.0 (13.84, 54.16) platelet count (Figure 7), demonstrating that fostamatinib can produce a platelet response ≥8 years (n = 77) 23.35 (4.86, 41.84) among diverse types of patients, including -100 -75 -50 -25 0 25 50 75 100

those with and without multiple exposures -100FAVORS-75 -50PLACEBO-25 0 FAVORS25 50 FOSTAMATINIB75 100

to prior ITP treatments and those with longer FAVORS PLACEBO FAVORS FOSTAMATINIB and shorter durations of ITP.9 TPO-RA indicates thrombopoietin receptor agonist. Republished with permission of Wiley Periodicals, Inc., from Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled Control of Bleeding and Use of trials. Bussel J, Arnold DM, Grossbard E, et al; Am J Hematol. 93(7); 2018. Permission conveyed through Rescue Medication Copyright Clearance Center, Inc. Patients who responded to fostamatinib demonstrated good control of hemostasis. Moderate/ TABLE 1. Percentage of Overall Responders, Nonresponders, and Placebo Patients severe bleeding-related adverse events were Who Had a Bleeding Episode in the Phase 3 Clinical Trials: FIT1 and FIT2 seen in 9% of overall responders and 10% of Pooled Analysis9 nonresponders on fostamatinib compared with Any Mild Moderate Severe Serious 16% of those on placebo (Table 1).9 Bleeding- BLEEDING EPISODES % % % % % related serious adverse events did not occur Fostamatinib overall 21 12 9 0 0 in any overall responders compared with 7% responder (n = 43) among nonresponders and 10% in placebo- Fostamatinib 33 22 9 2 7 treated patients.9 Rescue medication was used non-responder (n = 58) by 16% of overall responders and 34% of nonre- Placebo (n = 49) 35 18 10 6 10 sponders to fostamatinib, compared with 45% of patients receiving placebo (Figure 8).9 In stable responders, 17% used rescue medication only in the first week, prior to achieving

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 25, NO. 19 S355 a response. In contrast, nonresponders and placebo patients used disorders, hypertension, and transaminase elevation (Table 2).9 rescue medication throughout the study (up to week 24).9 Types No single “preferred term” adverse event led to discontinuation of rescue medication included IVIg, corticosteroids, and platelet of more than 1 patient in either treatment group. transfusion, as recommended by clinical guidelines.9 Most adverse events were mild to moderate in severity and were manageable with appropriate monitoring and standard therapeutic Safety approaches, including dose reductions or treatment interruptions.93 Fostamatinib was generally well tolerated, with 10% of patients Overall, 31% of patients receiving fostamatinib compared to 17% discontinuing treatment with fostamatinib compared with 8% receiving placebo had a treatment modification: interruption (18% receiving placebo in the phase 3 studies.93 The most common vs 10%), reduction (9% vs 2%), or withdrawal (10% vs 8%). Serious adverse events reported with fostamatinib are consistent with adverse events were reported in 13% of patients receiving fostama- known kinase inhibitor class effects,96 including gastrointestinal tinib and 21% of patients receiving placebo; severe adverse events were reported in 16% of patients receiving fostamatinib and 15% FIGURE 8. Percent of Overall Responders, Nonresponders, and of patients receiving placebo. In the OLE study, adverse events led Placebo Patients Who Used Rescue Medication: FIT1 and FIT2 to dose interruptions in 23% of patients and discontinuation due 9 Pooled Analysis to adverse events occurred in 16% of patients including 2 stable

50 responders. No new adverse events were detected with long-term 45% use of fostamatinib in the OLE study.93 The safety profile of fosta- 40 matinib in ITP clinical trials is consistent with the overall safety 34% profile observed in 3240 patients with rheumatoid arthritis.10,11,97 30 Summary 20 16%

Patients (%) ITP is a rare disease with significant symptoms that can lead to serious

10 medical complications or death. It is a heterogeneous disease in terms of the clinical symptoms, underlying pathophysiology, and patient 0 responses to treatment, which makes management challenging. Fostamatinib Fostamatinib Placebo Overall responder Non-responder (n = 49) There is no consensus on the optimal treatment strategy for ITP. (n = 43) (n = 58) The therapeutic landscape for second-line treatments is fragmented, with little guidance on which treatments to use or the order in Adapted from reference 9.

TABLE 2. Incidence of Common (≥5% of Patients) Adverse Events From the Phase 3 Clinical Trials: FIT1 and FIT2 Pooled Analysis9 Fostamatinib Placebo (N = 102) (N = 48) Mild Moderate Severe TOTAL Mild Moderate Severe TOTAL Adverse Events % % % % % % % % Diarrhea 21 10 1 31 13 2 0 15 Hypertension 17 9 2 28 10 0 2 13 Nausea 16 3 0 19 8 0 0 8 Dizziness 8 2 1 11 6 2 0 8 ALT increased 5 6 0 11 0 0 0 0 AST increased 5 4 0 9 0 0 0 0 Respiratory infection 7 4 0 11 6 0 0 6 Rash 8 1 0 9 2 0 0 2 Abdominal pain 5 1 0 6 2 0 0 2 Fatigue 4 2 0 6 0 2 0 2 Chest pain 2 3 1 6 2 0 0 2 Neutropenia 3 2 1 6 0 0 0 0

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.

S356 NOVEMBER 2019 www.ajmc.com which treatments should be used. Current treatment options have 19. Najean Y, Rain J, Billotey C. The site of destruction of autologous 111In-labelled platelets and the efficiency of splenectomy in children and adults with idiopathic thrombocytopenic purpura: a study of 578 shown unpredictable responses, uncertain durability, poor toler- patients with 268 splenectomies. Br J Haematol. 1997;97(3):547-50. doi: 10.1046/j.1365-2141.1997.832723.x. ability, and/or safety concerns. Therefore, the need for additional 20. Guan Y, Wang S, Xue F, et al. Long-term results of splenectomy in adult chronic immune thrombocytopenia. Eur J Haematol. 2017 Mar;98(3):235-241. doi: 10.1111/ejh.12821. treatment options that can provide a stable, long-term response 21. Chaturvedi S, Arnold DM, McCrae KR. Splenectomy for immune thrombocytopenia: down but not out. Blood. 2018;131(11):1172-1182. doi: 10.1182/blood-2017-09-742353. with few adverse effects is critical and ongoing. 22. Cines DB, Schreiber AD. Effect of anti-P1A1 antibody on human platelets. I. the role of complement. Fostamatinib disodium hexahydrate is a novel agent that repre- Blood. 1979;53(4):567-577. 23. Unterberger U, Eichelberger B1, Ulz A, Panzer S. Antibodies against complement-regulatory proteins on sents a novel class of treatment for ITP and produces a rapid, durable platelets in immune thrombocytopenia. Platelets. 2017;28(4):409-413. doi: 10.1080/09537104.2016.1235686. 24. Wei Y, Hou M . T cells in the pathogenesis of immune thrombocytopenia. Semin Hematol. 2016;53(1 response and efficacy in patients who have experienced failure with suppl):S13-S15. doi: 10.1053/j.seminhematol.2016.04.005. a prior treatment. Fostamatinib is well tolerated, and adverse effects 25. Olsson B, Andersson PO, Jernås M, et al. T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura. Nat Med. 2003;9(9):1123-1124. doi: 10.1038/nm921. can be actively mitigated through dose reduction, interruption, or 26. Zhao C, Li X, Zhang F, Wang L, Peng J, Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxic- discontinuation. Fostamatinib is a convenient oral medication that can ity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica. 2008;93(9):1428-1430. doi: 10.3324/haematol.12889. be taken with or without food and is associated with fewer bleeding 27. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13):995-1008. 28. Li J, van der Wal DE, Zhu G, et al. Desialylation is a mechanism of Fc-independent platelet events and a reduced need for rescue medication. Patients typically clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015;6:7737. respond in 15 days to fostamatinib and continue responding to treat- doi: 10.1038/ncomms8737. 29. Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune throm- ment for a median duration of response exceeding 28 months. n bocytopenia. Immunotherapy. 2018;10(1):9-25. doi: 10.2217/imt-2017-0097. 30. Olsson B, Ridell B, Carlsson L, Jacobsson S, Wadenvik H. Recruitment of T cells into bone marrow of ITP patients possibly due to elevated expression of VLA-4 and CX3CR1. Blood. 2008;112(4):1078-1084. Acknowledgments doi: 10.1182/blood-2008-02-139402. Editorial and medical writing support under the guidance of the authors 31. Peerschke EI, Andemariam B, Yin W, Bussel JB. Complement activation on platelets correlates with was provided by James Williams, PhD (Apothecom, UK), and was funded by a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura. Br J Rigel in accordance with Good Publication Practice (GPP3) guidelines (Ann Haematol. 2010;148(4):638-645. doi: 10.1111/j.1365-2141.2009.07995.x. Intern Med. 2015;163:461-464). 32. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombocytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet production and increased platelet clearance. J Clin Invest. 1987;80(1):33-40. doi: 10.1172/JCI113060. REFERENCES 33. Chang M, Nakagawa PA, Williams SA, et al. Immune thrombocytopenic purpura (ITP) plasma and purified ITP monoclonal autoantibodies inhibit megakaryocytopoiesis in vitro. Blood. 2003;102(3):887-895. 1. Stasi R, Newland AC. ITP: a historical perspective. Br J Haematol. 2011;153(4):437-450. doi: 10.1182/blood-2002-05-1475. doi: 10.1111/j.1365-2141.2010.08562.x. 34. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte produc- 2. McMillan R, Bussel JB, George JN, Lalla D, Nichol JL. Self-reported health-related quality of life in adults tion by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004;103(4):1364-1369. with chronic immune thrombocytopenic purpura. Am J Hematol. 2008;83(2):150-154. doi: 10.1002/ajh.20992. doi: 10.1182/blood-2003-08-2672. 3. Mathias SD, Gao SK, Miller KL, et al. Impact of chronic Immune Thrombocytopenic Purpura (ITP) on 35. Rivière E, Viallard JF, Guy A. Intrinsically impaired platelet production in some patients with persis- health-related quality of life: a conceptual model starting with the patient perspective. Health Qual Life tent or chronic immune thrombocytopenia. Br J Haematol. 2015;170(3)408-415. doi: 10.1111/bjh.13444. Outcomes. 2008;6:13. doi: 10.1186/1477-7525-6-13. 36. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diver- 4. Newton JL, Reese JA, Watson SI, et al. Fatigue in adult patients with primary immune thrombocytope- sity. Blood. 2009;113(26):6511-6521. doi: 10.1182/blood-2009-01-129155. nia. Eur J Haematol. 2011;86(5):420-429. doi: 10.1111/j.1600-0609.2011.01587.x. 37. Peng J, Ma SH, Liu J, et al. Association of autoantibody specificity and response to intravenous 5. Shulman NR, Marder VJ, Weinrach RS. Similarities between known antiplatelet antibodies and the immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost. factor responsible for thrombocytopenia in idiopathic purpura. physiologic, serologic and isotopic studies. 2014;12(4):497-504. doi: 10.1111/jth.12524. Ann N Y Acad Sci. 1965;124(2):499-542. 38. Lee MS, Kim WC. Intracranial hemorrhage associated with idiopathic thrombocytopenic purpura: 6. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence- report of seven patients and a meta-analysis. Neurology. 1998;50(4):1160-1163. based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. doi: 10.1182/ 39. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with blood-2010-08-302984. idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549-2554. 7. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management 40. Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR; Northern Region Haematology Group. of primary immune thrombocytopenia. Blood. 2010;115(2):168-186. doi: 10.1182/blood-2009-06-225565. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective 8. PatientSource®. Symphony Health website. prahs.com/product/patientsource/. Accessed study of a population-based cohort of 245 patients. Br J Haematol. 2003;122(6):966-974. October 10, 2019. 41. Danese MD, Lindquist K, Gleeson M, Deuson R, Mikhael J. Cost and mortality associated with 9. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic hospitalizations in patients with immune thrombocytopenic purpura. Am J Hematol. 2009;84(10):631-635. immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. doi: 10.1002/ajh.21500. 2018;93(7):921-930. doi: 10.1002/ajh.25125. 42. Chandan JS, Thomas T, Lee S, et al. The association between idiopathic thrombocytopenic purpura 10. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, et al. Treatment of rheumatoid arthritis with a Syk and cardiovascular disease: a retrospective cohort study. J Thromb Haemost. 2018;16(3):474-480. kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58(11):3309- doi: 10.1111/jth.13940. 3318. doi: 10.1002/art.23992. 43. Snyder CF, Mathias SD, Cella D, Isitt JJ, Wu AW, Young J. Health-related quality of life of 11. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral immune thrombocytopenic purpura patients: results from a web-based survey. Curr Med Res Opin. spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363(14):1303-1312. 2008;24(10):2767-2776. doi: 10.1185/03007990802377461. doi: 10.1056/NEJMoa1000500. 44. Mathias SD, Bussel JB, George JN, McMillan R, Okano GJ, Nichol JL. A disease-specific measure of 12. Liebman HA, Stasi R. Secondary immune thrombocytopenic purpura. Curr Opin Hematol. health-related quality of life for use in adults with immune thrombocytopenic purpura: its development 2007;14(5):557-573. doi: 10.1097/MOH.0b013e3282ab9904. and validation. Health Qual Life Outcomes. 2007;29(5):11. doi: 10.1186/1477-7525-5-11. 13. Kistangari G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495- 45. Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increases 520. doi: 10.1016/j.hoc.2013.03.001. with age. Blood. 1999;94(3):909-913. 14. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history 46. Fogarty PF. Chronic immune thrombocytopenia in adults: epidemiology and clinical presentation. of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Hematol Oncol Clin North Am. 2009;23(6):1213-1221. doi: 10.1016/j.hoc.2009.08.004. Med. 2000;160(11):1630-1638. 47. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children 15. Picozzi VJ, Roeske WR, Creger WP. Fate of therapy failures in adult idiopathic thrombocytopenic and adults: a critical review of published reports. Am J Hematol. 2010;85(3):174-180. doi: 10.1002/ajh.21616. purpura. Am J Med. 1980;69(5):690-694. 48. Segal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. 16. An R, Wang PP. Length of stay, hospitalization cost, and in-hospital mortality in US adult inpa- J Thromb Haemost. 2006;4(11):2377-2383. doi: 10.1111/j.1538-7836.2006.02147.x. tients with immune thrombocytopenic purpura, 2006-2012. Vasc Health Risk Manag. 2017;13:15-21. 49. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome doi: 10.2147/VHRM.S123631. criteria in immune thrombocytopenic purpura of adults and children: report from an international work- 17. Saleh MN, Fisher M, Grotzinger KM. Analysis of the impact and burden of illness of adult chronic ITP ing group. Blood. 2009;113(11):2386-2393. doi: 10.1182/blood-2008-07-162503. in the US. Curr Med Res Opin. 2009;25(12):2961-2969. doi: 10.1185/03007990903362388. 50. Palandri F, Polverelli N, Sollazzo D, et al. Have splenectomy rate and main outcomes of ITP changed 18. Tarantino MD, Mathias SD, Snyder CF, Isitt JJ, Gernsheimer T, Young J. Impact of ITP on physician vis- after the introduction of new treatments? a monocentric study in the outpatient setting during 35 years. its and workplace productivity. Curr Med Res Opin. 2010;26(2):319-28. doi: 10.1185/03007990903451298. Am J Hematol. 2016;91(4):E267-E272. doi: 10.1002/ajh.24310.

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 25, NO. 19 S357 51. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for 76. Schwartz J, Leber MD, Gillis S, Giunta A, Eldor A, Bussel JB. Long term follow-up after the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in splenectomy performed for immune thrombocytopenic purpura (ITP). Am J Hematol. 2003;72(2):94-98. pregnancy. Br J Haematol. 2003;120(4):574-596. doi: 10.1002/ajh.10253. 52. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: a 77. Thai LH, Mahévas M, Roudot-Thoraval F, et al. Long-term complications of splenectomy in adult systematic literature review. Clin Ther. 2017;39(11):2216-2229. doi: 10.1016/j.clinthera.2017.09.011. immune thrombocytopenia. Medicine (Baltimore). 2016;95(48):e5098. doi: 10.1097/MD.0000000000005098. 53. Moulis G, Lapeyre-Mestre M, Palmaro A, Sailler L. Infections in non-splenectomized persistent or 78. Vianelli N, Galli M, de Vivo A, et al. Gruppo Italiano per lo Studio delle Malattie Ematologiche chronic primary immune thrombocytopenia adults: risk factors and vaccination effect. J Thromb Haemost. dell’Adulto. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results 2017;15(4):785-791. doi: 10.1111/jth.13622. of 402 cases. Haematologica. 2005;90(1):72-77. 54. Hansen RJ, Balthasar JP. Mechanisms of IVIG action in immune thrombocytopenic purpura. Clin Lab. 79. Zheng D, Huang CS, Huang SB, Zheng CX. Laparoscopic splenectomy for primary immune 2004;50(3-4):133-140. thrombocytopenia: current status and challenges. World J Gastrointest Endosc. 2016;8(17):610-615. 55. Cheung E, Liebman H. Anti-RhD immunoglobulin in the treatment of immune thrombocytopenia. doi: 10.4253/wjge.v8.i17.610. Biologics. 2009;3:57-62. 80. Gómez-Almaguer D, Solano-Genesta M, Tarín-Arzaga L, et al. Low-dose rituximab and alemtuzumab 56. Rituxan [prescribing information]. San Fransisco, CA: Genentech; 1997. combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood. 2010;116(23):4783- 57. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with 4785. doi: 10.1182/blood-2010-06-291831. anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol. 81. Oo T, Hill QA. Disappointing response to dapsone as second line therapy for primary ITP: a case 2004;125(2):232-239. doi: 10.1111/j.1365-2141.2004.04889.x. series. Ann Hematol. 2015;94(6):1053-1054. doi: 10.1007/s00277-014-2285-8. 58. Stasi R, Stipa E, Forte V, Meo P, Amadori S. Variable patterns of response to rituximab treatment in 82. Park YH, Yi HG, Lee MH, Kim CS, Lim JH. Clinical efficacy and tolerability of vincristine in splenecto- adults with chronic idiopathic thrombocytopenic purpura. Blood. 2002;99(10):3872-3873. mized patients with refractory or relapsed immune thrombocytopenia: a retrospective single-center study. 59. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for Int J Hematol. 2016;103(2):180-188. doi: 10.1007/s12185-015-1903-0. adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33. 83. Taylor A, Neave L, Solanki S, et al. Mycophenolate mofetil therapy for severe immune thrombocyto 60. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates penia. Br J Haematol. 2015;171(4):625-630. doi: 10.1111/bjh.13622. with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. 84. Cuker A, Cines DB, Neunert CE. Controversies in the treatment of immune thrombocytopenia. Blood. 2008;112(4):999-1004. doi: 10.1182/blood-2008-01-131029. Curr Opin Hematol. 2016;23(5):479-485. doi: 10.1097/MOH.0000000000000270. 61. Ghanima W, Khelif A, Waage A, et al. RITP study group. Rituximab as second-line treatment for adult 85. Northridge K, Danese M, Deuson R. Determining the cost of a bleeding-related episode in primary immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled adult chronic immune thrombocytopenia (ITP) in the United States. Value in Health. 2013;16(3):A1-A298. trial. Lancet. 2015;385(9978):1653-1661. doi: 10.1016/S0140-6736(14)61495-1. doi: 10.1016/j.jval.2013.03.559. 62. Marangon M, Vianelli N, Palandri F, et al. Rituximab in immune thrombocytopenia: gender, age, and 86. Lin J, Zhang X, Li X, et al. Cost of bleeding-related episodes in adult patients with primary immune response as predictors of long-term response. Eur J Haematol. 2017;98(4):371-377. doi: 10.1111/ejh.12839. thrombocytopenia: a population-based retrospective cohort study of administrative claims data for com- 63. Reboursiere E, Fouques H, Maigne G, et al. Rituximab salvage therapy in adults with immune mercial payers in the United States. Clin Ther. 2017;39(3):603-609.e1. doi: 10.1016/j.clinthera.2017.01.023. thrombocytopenia: retrospective study on efficacy and safety profiles. Int J Hematol. 2016;104(1):85-91. 87. Altomare I, Cetin K, Wetten S, Wasser JS. Rate of bleeding-related episodes in adult patients with doi: 10.1007/s12185-016-1992-4. primary immune thrombocytopenia: a retrospective cohort study using a large administrative medical 64. Kaushansky K. Thrombopoietin: the primary regulator of megakaryocyte and platelet production. claims database in the US. Clin Epidemiol. 2016;8:231-9. doi:10.2147/CLEP.S105888. Thromb Haemost. 1995;74(1):521-525. 88. Winters JL, Brown D, Hazard E, Chainani A, Andrzejewski C. Cost-minimization analysis of the direct 65. NPLATE [prescribing information]. Thousand Oaks, CA: Amgen; 2017 costs of TPE and IVIg in the treatment of Guillain-Barré syndrome. BMC Health Serv Res. 2011;11:101. 66. Promacta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018 doi: 10.1186/1472-6963-11-101. 67. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic 89. Blackhouse G, Gaebel K, Xie F, et al. Cost-utility of intravenous immunoglobulin (IVIG) compared with immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161(3):411-423. doi: 10.1111/bjh.12260. corticosteroids for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in Canada. 68. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/ Cost Eff Resour Alloc. 2010;8:14. doi: 10.1186/1478-7547-8-14. persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527-2536. 90. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and doi: 10.1182/blood-2017-04-748707. the economic implications of steroid use. Respir Med. 2009;103(7):975-994. doi: 10.1016/j.rmed.2009.01.003. 69. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocy- 91. Tavalisse [prescribing information]. San Fransisco, CA: Rigel Pharmaceuticals Inc; 2018. topenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377(9763):393-402. doi: 10.1016/ 92. Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological S0140-6736(10)60959-2. functions. Nat Rev Immunol. 2010;10(6):387-402. doi: 10.1038/nri2765. 70. Lokhandwala T, Bhor M, Stafkey-Mailey D, et al. Comparison of treatment characteristics between 93. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treat- patients diagnosed with immune thrombocytopenia (ITP) and treated with thrombopoietin receptor ago- ment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161-2171. nists (TPO-RA). J Clin Oncol. 2017;35(15 suppl):e18314. doi: 10.1200/JCO.2017.35.15_suppl.e18314. doi: 10.1182/blood-2008-04-150078. 71. Stafkey-Mailey D, Roy A, Tasneem L. Evaluation of treatment patterns among patients with newly 94. Peñalver FJ, Jiménez-Yuste V, Almagro M, et al. Multi-institutional retrospective Spanish study diagnosed, persistent, and chronic immune thrombocytopenia (ITP) treated with eltrombopag in real group on the use of rituximab in refractory ITP. rituximab in the management of chronic immune throm- world setting in the US. Blood. 2017;130(suppl 1):2078. bocytopenic purpura: an effective and safe therapeutic alternative in refractory patients. Ann Hematol. 72. Rodeghiero F, Ruggeri M. Treatment of immune thrombocytopenia in adults: the role of thrombopoi- 2006;85(6):400-406. etin-receptor agonists. Semin Hematol. 2015;52(1):16-24. doi: 10.1053/j.seminhematol.2014.10.006. 95. Boruchov DM, Gururangan S, Driscoll MC, Bussel JB. Multiagent induction and maintenance therapy 73. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocy- for patients with refractory immune thrombocytopenic purpura (ITP). Blood. 2007;110(10):3526-3531. topenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, doi: 10.1182/blood-2007-01-065763. and surgical complications. Blood. 2004;104(9):2623-2634. doi: 10.1182/blood-2004-03-1168.staf. 96. Gomez-Puerta JA, Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr 74. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Top Med Chem. 2013;13(6):760-773. doi: 10.2174/15680266113139990094. Blood. 2004;104(4):956-960. doi: 10.1182/blood-2003-11-3908. 97. Kunwar S, Devkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the 75. Naouri A, Feghali B, Chabal J, et al. Results of splenectomy for idiopathic thrombocytopenic purpura. treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. review of 72 cases. Acta Haematol. 1993;89(4):200-203. doi: 10.1159/000204523. 2016;36(8):1077-1087. doi: 10.1007/s00296-016-3482-7.

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