Fostamatinib Disodium Hexahydrate: A Novel Treatment for ... 1.pdf · n 1951 at the Barnes-Jewish Hospital in St. Louis, Missouri, Dr William J. Harrington injected himself with approxi-mately

THE AMERICAN JOURNAL OF MANAGED CARE® Supplement VOL. 25, NO. 19 S347

I n 1951 at the Barnes-Jewish Hospital in St. Louis, Missouri,

Dr William J. Harrington injected himself with approxi-

mately 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 symp-

toms 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 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 experi-

ence.6,7 In fact, neither the treatment guidelines from the American

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:S347-S358

For author information and disclosures, see end of text.

R E P O R T

Fostamatinib Disodium Hexahydrate: A Novel Treatment for

Adult Immune ThrombocytopeniaAli McBride, PharmD; Pratima Nayak, MD; Yuliya Kreychman, PharmD; Leslie Todd, BA;

Anne-Marie Duliege, MD, MS; Amit R. Mehta, MD

ABSTRACT

S348 NOVEMBER 2019 www.ajmc.com

R E P O R T

Society of Hematology (ASH)6 nor an international consensus docu-

ment7 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 IllnessHeterogeneity of Immune Thrombocytopenia ITP is an autoimmune disease that can arise apparently sponta-

neously (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’ dura-

tion).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 expe-

rience 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-threat-

ening 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 treat-

ment must be individualized because a safe platelet threshold for

maintaining adequate hemostasis in one patient may not be appro-

priate 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 ThrombocytopeniaThe classic understanding of ITP pathophysiology involves platelets

being coated by immunoglobulin G (IgG) antiplatelet auto-anti-

bodies. 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 ITPThe 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


FOSTAMATINIB DISODIUM HEXAHYDRATE: A NOVEL TREATMENT FOR ADULT ITP

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 activi-

ties, 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 broad-

ranging effects of ITP on patients’ lives.43,44

Epidemiology of Immune ThrombocytopeniaThe 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

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.

FIGURE 1. Pathophysiology of Immune Thrombocytopenia27-31


R E P O R T

Current Treatment Options and Unmet NeedsTreatment GoalsThe 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.6,7,49 Individual treatment targets for platelet counts vary

depending on the individual patient and the treatment. However,

30 x 109/L to 50 x 109/L is often used as a target to guide treatment

in patients who cannot achieve normal platelet counts.7

Treatment ChoicesPhysicians who treat patients with ITP have a variety of therapeutic

options available with guidance on disease management acces-

sible from 2 major clinical guidelines: the Evidence-Based Practice

Guideline for ITP published by ASH6 in 2011 and an International

Consensus Report published by an international working group of

experts in 2010.7 Both guidelines recommend using corticosteroids

as the standard initial therapy for ITP but caution against their

long-term use. They suggest intravenous immunoglobulin (IVIg)

and intravenous anti-D (IV anti-D) as alternative or complemen-

tary first-line treatments.6,7 However, there is no defined treatment

order among second-line therapies, which include rituximab (not

FDA-approved for ITP), thrombopoietin receptor agonists (TPO-

RAs), and splenectomy.6,7 These guidelines were written prior to

the approval of fostamatinib and are currently being updated.

A key difficulty in the management of ITP is that the durability

of response to both first- and second-line therapies is not sustained

in a high proportion of patients, and these treatment-refractory

patients often go on to receive additional lines of therapy.8,13

In order to better understand the sequencing of therapies for ITP,

we analyzed prescription claims data from a large clearing house

(Symphony Health PatientSource®, Phoenix, AZ), which collects data

from pharmacies and providers about insurance claims for prescrip-

tion payments across the United States.8 The ITP prescription claims

data for 7 years from 2009 to 2016 were included and represent

approximately 40,000 patients with 2,500,000 claims associated with

an ITP diagnosis code (Symphony Health, PatientSource®, 7 years

ending November 2016). Figure 2 shows the pattern of medications

prescribed for ITP for each line of therapy.8 During the first line of

therapy for ITP, 93% of patients in the analysis received steroids alone,

and other treatments were used by 1% to 2% of patients.8 During

subsequent lines of therapy, the use of steroids as a monotherapy

declined substantially, and the use of other medications or splenec-

tomy increased. Steroids continued to be used in combination with

other treatments, and 57% to 73% of patients continued to receive

steroids in subsequent lines of therapy. Overall, the sequencing of

therapy was highly variable, with an assortment of different treat-

ments being used and discontinued, with little discernible pattern.

While ASH has recommended consideration of splenectomy before

TPO-RA agonists, the International Consensus Report does not indi-

cate a preference for second-line treatment options for ITP, leaving

the decision in the hands of the medical practitioner. The treatment

of ITP continues to evolve with more options available to prevent or

delay the use of splenectomy.50 One retrospective analysis of treat-

ment options by year demonstrated that in the past decade, there was

a trend toward a reduction in the use of splenectomy as second-line

treatment, reflecting the availability and efficacy of new ITP thera-

pies as second-line treatment options in the management of ITP.50

Corticosteroids

Corticosteroids are the established first-line

treatment for most patients with ITP6-8 and

typically include oral prednisone, IV meth-

ylprednisolone, or high-dose (40 mg/day)

dexamethasone. Corticosteroids have been

shown to generate a rapid response in approxi-

mately two-thirds of patients.51

The detrimental effects of corticosteroids

often outweigh their benefits if they are used

for prolonged periods,7 and their efficacy often

wanes over time. For example, only 10% to

20% of patients achieve long-term remission

after 1 year of treatment with prednisone.51

For these reasons, guidelines recommend

rapidly tapering the dose of corticosteroids after

4 weeks in both responders and nonresponders.7

Adverse effects associated with pro-

longed corticosteroid use include diabetes,

FIGURE 2. Patterns of Treatment for Immune Thrombocytopenia8

IMM indicates immunomodulators.

Percentage of patients utilizing each treatment or combination of treatments during first and subsequent lines of therapy.

Data Source: Symphony Health, PatientSource®, 7 years ending November 2016.

8%6%

11%

11%

24%

5%

11%

6%8%3%6%

39%

3%6%2%8%

10%

11%

8%7%

25%

5%6%5%6%

14%

11%

11%

9%6%

33%

6%6%7%

15%

9%

10%

9%

26%

7%

12%

9%

16%

14%

9%

93%

Steroid

Steroid + IMM/Chemo

Rituximab

IMM/Chemo

Rituximab + Steroid

Romiplostim

Romiplostim + Steroid

Eltrombopag + Steroid

Splenectomy

Splenectomy + Steroid

Eltrombopag

Second Third Fourth Fifth SixthFirst

1%

2%2%2%

2%1%2%

1%1%

2%3%2%

2%3%

Tota

l Pat

ient

s (%

)

Line of Therapy and Treatment Sharein a 5-year Window

Line of Therapy



osteoporosis, and hypertension.7,51,52 Moreover, short-term use of

corticosteroids in patients with ITP is associated with an increased

risk of serious infections.53

Intravenous Immunoglobulin

IVIg may be used as a first-line treatment for patients in whom

corticosteroids are contraindicated. Alternatively, IVIg can be used

alongside corticosteroids as there appear to be some synergistic

effects.7 IVIg is also used as a rescue therapy.7 The mechanism of action

of IVIg is not completely understood and may include inhibition of

Fc-receptor–mediated platelet phagocytosis, suppression of anti-

platelet antibody production, anti-idiotypic inhibition of antiplatelet

antibodies, or accelerated elimination of antiplatelet antibodies.54

Response rates with IVIg are similar to those with corticosteroids;

however, responses with IVIg are short-lived, with most patients

reverting to pretreatment platelet levels after 3 to 4 weeks.51 IVIg

infusions take several hours, and adverse effects may include head-

aches and, rarely, renal failure and thrombosis.7 Therefore, IVIg is

typically utilized as an adjunctive therapy in the management of

ITP and not as a monotherapy.

Anti-D Immunoglobulin

IV anti-D can be used as a first-line treatment in rhesus(D)-positive,

nonsplenectomized patients with ITP.6,7 IV anti-D can be infused

in a shorter time and patients may experience a longer treatment

response than with IVIg, with some individuals still responding at 26

months.55 Additional tests are required before IV anti-D can be used,

including blood group, direct antiglobulin test, and reticulocyte count.7

Adverse effects associated with the use of IV anti-D include

hemoglobinuria, hemolytic anemia, disseminated intravascular

coagulation, and renal failure.55

Treatment Choices: Second-Line and Third-LineRituximab

Rituximab (Rituxan; Biogen/Genentech) is a monoclonal antibody that

targets the CD20 antigen expressed on the surface of B cells. It is used

for the treatment of lymphoma at a dose of 100 mg/m2 or 375 mg/m2

IV weekly for 4 weeks.56 Although rituximab has not been approved

for the treatment of chronic ITP, it has become an off-label treatment

option that uses the same dosing schedule as that used for lymphoma

treatment. Rituximab depletes B lymphocytes, which are responsible

for antiplatelet antibody production. Overall responses were seen

in 40% to 63% of patients,57-60 although a recent small, randomized

controlled trial failed to demonstrate a statistically significant differ-

ence in response to rituximab versus placebo in patients treated

with concurrent corticosteroids.61 Fewer than 40% of patients who

responded to rituximab maintain a durable response at 1 year.59,60,62,63

Rituximab causes infusion reactions in approximately 18% of

patients with ITP, which can be fatal in a small minority of patients.59

Other potentially fatal adverse reactions include severe mucocu-

taneous reactions, hepatitis B virus reactivation, and progressive

multifocal leukoencephalopathy.56 Non-fatal adverse effects associ-

ated with rituximab for the treatment of ITP include first-infusion

fever/chills, rash or scratchiness in the throat, serum sickness, and

(very rarely) bronchospasm, retinal artery thrombosis, and infection.7

Thrombopoietin Receptor Agonists

TPO-RAs mimic the action of thrombopoietin by stimulating platelet

production through binding and activating the TPO receptor.64

Two TPO-RAs have been approved by the FDA for use in patients

with chronic ITP who have had an insufficient response to a prior

treatment: romiplostim (Nplate, Amgen), an Fc-peptide fusion

protein administered weekly as a subcutaneous injection,65 and

eltrombopag (Promacta, Novartis), a small nonpeptide molecule

administered orally on a daily basis.66

Overall response rates (a single platelet response of 50 x 109/L)

at any time during treatment ranged from 79% to 88% for romip-

lostim and 59% to 79% for eltrombopag.65-69 Durable response

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

30 months with romiplostim and 15 months with eltrombopag.65-69

Most patients take treatment breaks, and the average duration of

continuous therapy (defined as no treatment gap of >30 days) is

108 days with romiplostim and 110 to 131 days with eltrombopag.70,71

The most common reported adverse events are pain (arthralgia,

myalgia, extremity pain, abdominal pain, shoulder pain), dizzi-

ness, insomnia, dyspepsia, and paresthesia for romiplostim65 and

gastrointestinal disturbances (nausea, diarrhea, vomiting), upper

respiratory tract infection, urinary tract infection, increased alanine

aminotransferase, and myalgia for eltrombopag.66

TPO-RAs may cause fluctuations in platelet counts,72 and the

increased platelet counts could potentially cause thrombotic/throm-

boembolic complications, particularly portal vein thrombosis.65,66

Thromboembolic events have been reported in approximately 6%

of patients in clinical trials with TPO-RAs67,68 although frequencies

as high as 15% to 26% were reported in some cohorts.67 TPO-RAs are

also associated with an increased risk of progression of myelodys-

plastic syndromes to acute myeloid leukemia.65,66 The eltrombopag

prescribing information also has a boxed warning about the risk of

severe and potentially life-threatening hepatotoxicity.66

Splenectomy

Splenectomy is the surgical removal of the spleen, which is the

primary site of platelet destruction and also a site of auto-antibody

production. Approximately 80% of patients with ITP respond to

splenectomy, and 50% to 70% of patients maintain a long-term

response of more than 5 years.7,21 However, approximately one-

third of adult patients will relapse after splenectomy, often within


R E P O R T

2 years post surgery, which may be related to the different mecha-

nisms of platelet destruction and impaired platelet production

underpinning the disease.22,25,32

Splenectomy may be associated with surgical complications

that require prolonged hospitalization,73 as well as the long-term

risks for thrombosis and serious infections, which can be fatal.74-79

Furthermore, the presence of comorbidities in older patients can

contribute to increased surgery-related complications.21 The use

of splenectomy has decreased over the years, with the emergence

of new pharmacological treatments for ITP.50

Other Immunosuppressant TherapiesOff-label use of other immunosuppressant agents in patients with

chronic ITP (eg, alemtuzumab, azathioprine, cyclophosphamide,

cyclosporine, danazol, dapsone, and mycophenolate mofetil) is

sometimes considered, particularly as salvage therapy or in addition

to second-line agents.7 The safety and efficacy of these agents in

patients with chronic ITP have not been evaluated in well-designed

prospective clinical trials. They have shown some clinical activity

in small, uncontrolled studies in ITP, albeit often with a short

duration of response and/or less favorable safety profile.7,80-84 For

this reason, the use of these agents, either as monotherapy or in

combination therapy, is usually reserved for patients who do not

respond to standard-of-care treatments.

Unmet NeedsThe heterogeneous nature of ITP means that individual patient

responses to therapy vary both in magnitude and in duration.

A substantial proportion of patients have disease that either fails to

respond to therapy or shows an attenuated response over time. In

addition, serious adverse effects may limit the use of some thera-

pies in a proportion of patients. Consequently, many patients cycle

through a number of different therapies with no clear guidance on

which treatment to use after corticosteroids (Figure 28).7,51 Rather,

clinical judgment about the relative safety risks for each patient, often

taking patient preference and expected compliance into consideration,

frequently forms the basis of the decision as to which treatment is

selected. Thus, a need exists for a treatment that generates a durable

response and has manageable and moderate adverse effects.

Cost of DiseaseITP can cause increased healthcare resource utilization from emer-

gency treatment, hospital admissions, primary care visits, and

specialist visits.16-18 Bleeding-related episodes are the most clearly

defined cost; the average cost of a bleeding episode was estimated

to be $4703 in 201285 and $6022 in 2017.86 The average annual costs

for bleeding-related episodes alone are $8465 for patients with

platelet counts ≥50 × 109/L but rise to $34,473 for patients with

platelet counts <50 × 109/L.85

In examining the costs associated with ITP overall, patients

with the disease have longer average hospital stays (6.02 days for

patients with ITP vs 4.7 days for all conditions) than do those with

other disorders (according to data from the 2006-2012 time period).

Consequently, hospital stays associated with ITP are more costly

($16,594 for patients with ITP vs $11,200 for all conditions).16 One

study estimated that 45% of the costs associated with ITP are attrib-

utable to emergency department services, and 46% are related to

hospital admissions.17 Another study showed that patients with

ITP have more visits with primary care physicians and specialists;

in the month prior to completing the survey, 20% of 1002 patients

with ITP had primary care visits compared with 11% of 1031 age- and

gender-matched controls, and 28% had specialist visits compared

with 11% in controls.18

Cost of Current Treatment PathwayThe treatment of ITP is limited by the variable durability of treatment

response; more than half of all patients experience bleeding-related

episodes or require rescue medication.87 These bleeding episodes

are associated with expensive hospitalizations86 and rescue medi-

cations such as IVIg, which incur administration costs in addition

to the cost of drug acquisition.88,89

The adverse effects of treatments for ITP are also burdensome.

Corticosteroids are associated with multiple adverse effects, including

hypertension, bone fractures, metabolic syndrome, and peptic

ulcers,52 which, in turn, are associated with additional costs.90 IVIg

and IV anti-D are associated with rare but very costly adverse effects,

such as thrombosis and renal failure.7,55 Rituximab can cause fatal

infusion reactions, severe mucocutaneous reactions, and progres-

sive multifocal leukoencephalopathy.56 TPO-RAs are associated

with progression of myelodysplastic syndromes to acute myeloid

leukemia, thrombotic/thromboembolic complications, and, with

eltrombopag, hepatotoxicity.65,66

Fostamatinib for Chronic Immune ThrombocytopeniaFostamatinib disodium hexahydrate (Tavalisse®, Rigel) is the first-

in-class and only oral inhibitor of SYK that is indicated for the

treatment of thrombocytopenia in adult patients with chronic ITP

who have had an insufficient response to a previous treatment.91 In

ITP, Fcg receptors on macrophages bind to auto-antibodies on plate-

lets, activating a signaling cascade involving SYK that culminates

in macrophage-mediated platelet phagocytosis.29,92 The inhibition

of SYK signaling prevents platelet destruction by activated macro-

phages (Figure 1 27-31).13,29 Fostamatinib is the first treatment to target

a specific pathway in the pathophysiology of ITP.

Clinical BenefitsThe safety and efficacy of fostamatinib were evaluated in 2 double-

blind, randomized, placebo-controlled, phase 3 studies (FIT1 and



FIT2; NCT02076399 and NCT02076412, respectively) and an open-

label, extension (OLE) study (FIT3; NCT02077192). The FIT1 and

FIT2 studies were conducted in 150 adults with chronic ITP over

24 weeks, and the FIT3 study is ongoing.9,93

These were the first phase 3 studies that included ITP patients

with prior exposure to TPO-RAs. All patients had received at least

1 prior treatment: 93% had received corticosteroids, 47% had received

TPO-RAs, 34% had received rituximab, and 34% had undergone sple-

nectomy. At baseline, the median duration of disease was 8.5 years,

and all patients had at least 3 platelet counts of less than 30 × 109/L

including 2 measurements within the preceding 3 months.9,93

Fostamatinib was administered orally at a starting dose of

100 mg bid that could be increased to 150 mg bid (depending on

platelet counts and tolerability) after week 4. By the end of the study

period, 88% of patients had been titrated up to 150 mg bid. As an

oral treatment, fostamatinib is easy to administer and requires

minimal titration, reducing both the expenditure of clinical time

and the utilization of healthcare resources.93

Platelet ResponseThe primary endpoint of stable response was stringently defined as

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.

Combined results from the FIT1 and FIT2 studies showed a stable

response rate of 18% with fostamatinib versus 2% with placebo

(P = .0003; sensitivity analysis showed 17% versus 2%, P = .007), and

an overall response rate of 43% with fostamatinib versus 14% with

placebo (P = .0006) (Figure 3).9 Median postbaseline platelet counts

over 24 weeks were 95 x 109/L in stable responders, 49 x 109/L in

overall responders, 14 x 109/L in nonresponders, and 17.5 x 109/L with

placebo. Platelet responses to fostamatinib among responders were

generally rapid; responders achieved an initial platelet threshold

of ≥50 x 109/L at a median of 15 days.9 However, some patients had

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

period.93 The phase 3 results led to the approval of fostamatinib for

the treatment of adults with chronic ITP by the US FDA in April 2018.

Across the phase 3 studies and the open-label extension (OLE)

study, 146 patients were treated with fostamatinib, and 64 of 146

(44%) patients achieved an overall response, which included 43 of

101 (43%) patients from the fostamatinib arm and 21 of 44 (48%)

patients who were transitioned to fostamatinib from the placebo

arm of the phase 3 studies.93 The overall response to fostamatinib

was maintained over the course of treatment; median platelet

counts remained ≥50 x 109/L at all visits, with a median post-base-

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

FIGURE 3. Overall and Stable Responses to Treatment: FIT1, FIT29

Percentage of patients with an overall response (platelet count of ≥50 x 109/L during weeks 1 to 12) or stable response (platelet count of ≥50 x 109/L on ≥4 of 6 visits during weeks 14 through 24) to fostamatinib (100-150 mg BID) or placebo (FIT1 and FIT2 pooled analysis).

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 trials. Bussel J, Arnold DM, Grossbard E, et al; Am J Hematol. 93(7); 2018. Permission conveyed through Copyright Clearance Center, Inc.

0

10

20

30

40

50

60

n =

**37%

8%

Overall

*18%

0%Stable

*48%

21%

Overall

18%

4%

Stable

**43%

14%

Overall

**18%

2%

Stable

Pat

ient

s (%

)

ResponsesFostamatinibPlacebo

*P <.05

**P <.015125 5125 5024 5024 10149 10149

FIT1 FIT2 Pooled

FIGURE 4. Median Platelet Count in Overall Responders to Fostamatinib: FIT1, FIT2, FIT393

Shaded area indicates timepoints with less than 10 patients contributing data.

Republished with permission of Wiley Periodicals, Inc., from Long-term fosta-matinib 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.

1 column

0

10,000

70,000

30,000

90,000

110,000

50,000

130,000

0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128

53OVERALL

RESPONDER 62 53 46 40 40 34 56 29 22 18 14 11 4 4 3 163 56 47 47 37 34 36 30 26 21 20 11 11 4 4 2

Study Visit (Weeks)

Overall Responders

Med

ian

Pla

tele

t Cou

nt (/

μL)


R E P O R T

with a TPO-RA (Figure 5).93 The median dura-

tion of the first overall response to fostamatinib

was not reached and is estimated to be greater

than 28 months, based on the Kaplan-Meier

curve (Figure 6).93

While 17 patients achieved a stable response

to fostamatinib in the randomized studies,

10 of 44 (23%) placebo patients from the random-

ized studies achieved a stable response to

fostamatinib in the OLE study; thus, the total

number of stable responders was 27 of 146

(18%) patients in the fostamatinib exposure

population. Fostamatinib stable responders

generally had a durable long-term response,

and 18 of 27 (67%) patients maintained a stable

response for at least 1 year.93 Moreover, an addi-

tional 7 stable responders (26%) remained on

fostamatinib for more than 1 year because of

persistent clinical benefit, despite having 1 or

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

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.

Months Treated With Fostamatinib

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

TSTS

ST

TSTTST

ST

STS

SS

TSS

TSS

T

S

S

S

TS

TSSS

T

S

S

T

S

S

T

TS

S

T

T

T

T

T

T

ResponseTreatmentContinued responseContinued treatment

Duration of First Response (months)

Pat

ient

sa (%)

+ Censored

0

20

40

60

80

100

Number of subjects at risk

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

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

29

064

FIGURE 6. Kaplan-Meier Estimate of the Median Duration of First Response in Overall Responders: Fostamatinib Exposure Population: FIT1, FIT2, FIT393

aPlatelet Count ≥50,000/µL)

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.



more platelet counts drop below 50 x 109/L, and

5 of these patients regained their response. The

other 2 patients with a stable response had not

reached 12 months of therapy as of the data

cutoff date (April 2017). Overall, 93% of patients

who achieved a stable response continued to

respond and/or derive clinical benefit after

12 months of treatment, and the median dura-

tion of first stable response was not reached

and estimated to be greater than 28 months.93

Responses to fostamatinib were observed

among patients with long-standing ITP (average

time from diagnosis of 8.5 years), who were

heavily pre-treated (splenectomy, rituximab,

and/or TPO-RAs) and are considered difficult

to treat. Lower rates of response have been

observed in studies of rituximab and other

agents among heavily pretreated patients

with a longer ITP duration compared with

earlier stage patients.94,95 Fostamatinib was

also effective in 75% of patients with persis-

tent ITP (<12 months).93 Subgroup analyses

illustrate overall responses across subgroups

categorized by duration of ITP, prior TPO-RA

therapy, prior splenectomy, and baseline

platelet count (Figure 7), demonstrating that

fostamatinib can produce a platelet response

among diverse types of patients, including

those with and without multiple exposures

to prior ITP treatments and those with longer

and shorter durations of ITP.9

Control of Bleeding and Use of Rescue MedicationPatients who responded to fostamatinib demon-

strated good control of hemostasis. Moderate/

severe bleeding-related adverse events were

seen in 9% of overall responders and 10% of

nonresponders on fostamatinib compared with

16% of those on placebo (Table 1).9 Bleeding-

related serious adverse events did not occur

in any overall responders compared with 7%

among nonresponders and 10% in placebo-

treated patients.9 Rescue medication was used

by 16% of overall responders and 34% of nonre-

sponders to fostamatinib, compared with

45% of patients receiving placebo (Figure 8).9

In stable responders, 17% used rescue medica-

tion only in the first week, prior to achieving

-100 -75 -50 -25 0 25 50 75 100

FAVORS FOSTAMATINIB FAVORS PLACEBO

FIGURE 7. Subgroup Analysis of Overall Response: FIT1 and FIT2 Pooled Analysis9

TPO-RA indicates thrombopoietin receptor agonist.

Republished with permission of Wiley Periodicals, Inc., from Fostamatinib for the treatment of adult per-sistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Bussel J, Arnold DM, Grossbard E, et al; Am J Hematol. 93(7); 2018. Permission conveyed through Copyright Clearance Center, Inc.

Patient Subgroup Difference (95% Cl)

All patients (N = 150) 28.29 (14.54, 42.04)

Baseline platelet count

>15,000/ µL (n = 82) 35.85 (16.40, 55.29)

≤15,000/ µL (n = 68) 20.26 (2.14, 38.39)

Prior splenectomy

Yes (n = 53) 13.62 (-8.81, 36.06)

No (n = 97) 35.92 (18.85, 52.99)

Prior rituximab

Yes (n = 48) 21.01 (-3.36, 45.38)

No (n = 102) 31.98 (15.34, 48.62)

Prior TPO-RA

Yes (n = 71) 22.78 (4.03, 41.54)

No (n = 79) 32.42 (12.50, 52.35)

Age

<65 years (n = 111) 30.68 (15.02, 46.33)

≥65 years (n = 39) 21.10 (-7.99, 50.20)

Sex

Male (n = 59) 26.97 (6.59, 47.36)

Female (n = 91) 29.23 (10.95, 47.52)

Duration of ITP at baseline

<8 year (n = 73) 34.0 (13.84, 54.16)

≥8 years (n = 77) 23.35 (4.86, 41.84)

-100 -75 -50 -25 0 25 50 75 100

FAVORS FOSTAMATINIB FAVORS PLACEBO

TABLE 1. Percentage of Overall Responders, Nonresponders, and Placebo Patients Who Had a Bleeding Episode in the Phase 3 Clinical Trials: FIT1 and FIT2 Pooled Analysis9

BLEEDING EPISODESAny %

Mild %

Moderate %

Severe %

Serious %

Fostamatinib overall responder (n = 43)

21 12 9 0 0

Fostamatinib non-responder (n = 58)

33 22 9 2 7

Placebo (n = 49) 35 18 10 6 10


a response. In contrast, nonresponders and placebo patients used

rescue medication throughout the study (up to week 24).9 Types

of rescue medication included IVIg, corticosteroids, and platelet

transfusion, as recommended by clinical guidelines.9

SafetyFostamatinib was generally well tolerated, with 10% of patients

discontinuing treatment with fostamatinib compared with 8%

receiving placebo in the phase 3 studies.93 The most common

adverse events reported with fostamatinib are consistent with

known kinase inhibitor class effects,96 including gastrointestinal

disorders, hypertension, and transaminase elevation (Table 2).9

No single “preferred term” adverse event led to discontinuation

of more than 1 patient in either treatment group.

Most adverse events were mild to moderate in severity and were

manageable with appropriate monitoring and standard therapeutic

approaches, including dose reductions or treatment interruptions.93

Overall, 31% of patients receiving fostamatinib compared to 17%

receiving placebo had a treatment modification: interruption (18%

vs 10%), reduction (9% vs 2%), or withdrawal (10% vs 8%). Serious

adverse events were reported in 13% of patients receiving fostama-

tinib and 21% of patients receiving placebo; severe adverse events

were reported in 16% of patients receiving fostamatinib and 15%

of patients receiving placebo. In the OLE study, adverse events led

to dose interruptions in 23% of patients and discontinuation due

to adverse events occurred in 16% of patients including 2 stable

responders. No new adverse events were detected with long-term

use of fostamatinib in the OLE study.93 The safety profile of fosta-

matinib in ITP clinical trials is consistent with the overall safety

profile observed in 3240 patients with rheumatoid arthritis.10,11,97

SummaryITP is a rare disease with significant symptoms that can lead to serious

medical complications or death. It is a heterogeneous disease in terms

of the clinical symptoms, underlying pathophysiology, and patient

responses to treatment, which makes management challenging.

There is no consensus on the optimal treatment strategy for ITP.

The therapeutic landscape for second-line treatments is fragmented,

with little guidance on which treatments to use or the order in

TABLE 2. Incidence of Common (≥5% of Patients) Adverse Events From the Phase 3 Clinical Trials: FIT1 and FIT2 Pooled Analysis9

Adverse Events

Fostamatinib (N = 102)

Placebo (N = 48)

Mild %

Moderate %

Severe %

TOTAL %

Mild %

Moderate %

Severe %

TOTAL%

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.

FIGURE 8. Percent of Overall Responders, Nonresponders, and Placebo Patients Who Used Rescue Medication: FIT1 and FIT2 Pooled Analysis9

Adapted from reference 9.

16%

0

10

20

30

40

50

FostamatinibOverall responder

(n = 43)

34%

FostamatinibNon-responder

(n = 58)

45%

Placebo(n = 49)

Pat

ient

s (%

)


which treatments should be used. Current treatment options have

shown unpredictable responses, uncertain durability, poor toler-

ability, and/or safety concerns. Therefore, 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 a novel agent that repre-

sents a novel class of treatment for ITP and produces a rapid, durable

response and efficacy in patients who have experienced failure with

a prior treatment. Fostamatinib is well tolerated, and adverse effects

can be actively mitigated through dose reduction, interruption, or

discontinuation. Fostamatinib is a convenient oral medication that can

be taken with or without food and is associated with fewer bleeding

events and a reduced need for rescue medication. Patients typically

respond in 15 days to fostamatinib and continue responding to treat-

ment for a median duration of response exceeding 28 months. n

AcknowledgmentsEditorial and medical writing support under the guidance of the authors was provided by James Williams, PhD (Apothecom, UK), and was funded by Rigel in accordance with Good Publication Practice (GPP3) guidelines (Ann Intern Med. 2015;163:461-464).

REFERENCES1. Stasi R, Newland AC. ITP: a historical perspective. Br J Haematol. 2011;153(4):437-450. doi: 10.1111/j.1365-2141.2010.08562.x. 2. McMillan R, Bussel JB, George JN, Lalla D, Nichol JL. Self-reported health-related quality of life in adults with chronic immune thrombocytopenic purpura. Am J Hematol. 2008;83(2):150-154. doi: 10.1002/ajh.20992.3. Mathias SD, Gao SK, Miller KL, et al. Impact of chronic Immune Thrombocytopenic Purpura (ITP) on health-related quality of life: a conceptual model starting with the patient perspective. Health Qual Life Outcomes. 2008;6:13. doi: 10.1186/1477-7525-6-13.4. Newton JL, Reese JA, Watson SI, et al. Fatigue in adult patients with primary immune thrombocytope-nia. Eur J Haematol. 2011;86(5):420-429. doi: 10.1111/j.1600-0609.2011.01587.x.5. Shulman NR, Marder VJ, Weinrach RS. Similarities between known antiplatelet antibodies and the factor responsible for thrombocytopenia in idiopathic purpura. physiologic, serologic and isotopic studies. Ann N Y Acad Sci. 1965;124(2):499-542.6. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence- based practice guideline for immune thrombocytopenia. Blood. 2011;117(16):4190-4207. doi: 10.1182/blood-2010-08-302984.7. Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186. doi: 10.1182/blood-2009-06-225565.8. PatientSource®. Symphony Health website. prahs.com/product/patientsource/. Accessed October 10, 2019.9. Bussel J, Arnold DM, Grossbard E, et al. Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: results of two phase 3, randomized, placebo-controlled trials. Am J Hematol. 2018;93(7):921-930. doi: 10.1002/ajh.25125.10. Weinblatt ME, Kavanaugh A, Burgos-Vargas R, et al. Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58(11):3309-3318. doi: 10.1002/art.23992.11. Weinblatt ME, Kavanaugh A, Genovese MC, Musser TK, Grossbard EB, Magilavy DB. An oral spleen tyrosine kinase (Syk) inhibitor for rheumatoid arthritis. N Engl J Med. 2010;363(14):1303-1312. doi: 10.1056/NEJMoa1000500. 12. Liebman HA, Stasi R. Secondary immune thrombocytopenic purpura. Curr Opin Hematol. 2007;14(5):557-573. doi: 10.1097/MOH.0b013e3282ab9904.13. Kistangari G, McCrae KR. Immune thrombocytopenia. Hematol Oncol Clin North Am. 2013;27(3):495-520. doi: 10.1016/j.hoc.2013.03.001.14. Cohen YC, Djulbegovic B, Shamai-Lubovitz O, Mozes B. The bleeding risk and natural history of idiopathic thrombocytopenic purpura in patients with persistent low platelet counts. Arch Intern Med. 2000;160(11):1630-1638.15. Picozzi VJ, Roeske WR, Creger WP. Fate of therapy failures in adult idiopathic thrombocytopenic purpura. Am J Med. 1980;69(5):690-694.16. An R, Wang PP. Length of stay, hospitalization cost, and in-hospital mortality in US adult inpa-tients with immune thrombocytopenic purpura, 2006-2012. Vasc Health Risk Manag. 2017;13:15-21. doi: 10.2147/VHRM.S123631.17. Saleh MN, Fisher M, Grotzinger KM. Analysis of the impact and burden of illness of adult chronic ITP in the US. Curr Med Res Opin. 2009;25(12):2961-2969. doi: 10.1185/03007990903362388.18. Tarantino MD, Mathias SD, Snyder CF, Isitt JJ, Gernsheimer T, Young J. Impact of ITP on physician vis-its and workplace productivity. Curr Med Res Opin. 2010;26(2):319-28. doi: 10.1185/03007990903451298.

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 patients with 268 splenectomies. Br J Haematol. 1997;97(3):547-50. doi: 10.1046/j.1365-2141.1997.832723.x.20. Guan Y, Wang S, Xue F, et al. Long-term results of splenectomy in adult chronic immune thrombocy-topenia. Eur J Haematol. 2017 Mar;98(3):235-241. doi: 10.1111/ejh.12821.21. 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. 22. Cines DB, Schreiber AD. Effect of anti-P1A1 antibody on human platelets. I. the role of complement. Blood. 1979;53(4):567-577.23. Unterberger U, Eichelberger B1, Ulz A, Panzer S. Antibodies against complement-regulatory proteins on 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 suppl):S13-S15. doi: 10.1053/j.seminhematol.2016.04.005.25. 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/nm921.26. Zhao C, Li X, Zhang F, Wang L, Peng J, Hou M. Increased cytotoxic T-lymphocyte-mediated cytotoxic-ity predominant in patients with idiopathic thrombocytopenic purpura without platelet autoantibodies. Haematologica. 2008;93(9):1428-1430. doi: 10.3324/haematol.12889.27. 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 clearance and a therapeutic target in immune thrombocytopenia. Nat Commun. 2015;6:7737. doi: 10.1038/ncomms8737.29. Newland A, Lee EJ, McDonald V, Bussel JB. Fostamatinib for persistent/chronic adult immune throm-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. doi: 10.1182/blood-2008-02-139402. 31. Peerschke EI, Andemariam B, Yin W, Bussel JB. Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura. Br J Haematol. 2010;148(4):638-645. doi: 10.1111/j.1365-2141.2009.07995.x. 32. Ballem PJ, Segal GM, Stratton JR, Gernsheimer T, Adamson JW, Slichter SJ. Mechanisms of thrombo-cytopenia in chronic autoimmune thrombocytopenic purpura. Evidence of both impaired platelet produc-tion and increased platelet clearance. J Clin Invest. 1987;80(1):33-40. doi: 10.1172/JCI113060.33. 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. doi: 10.1182/blood-2002-05-1475.34. McMillan R, Wang L, Tomer A, Nichol J, Pistillo J. Suppression of in vitro megakaryocyte produc-tion by antiplatelet autoantibodies from adult patients with chronic ITP. Blood. 2004;103(4):1364-1369. doi: 10.1182/blood-2003-08-2672.35. Rivière E, Viallard JF, Guy A. Intrinsically impaired platelet production in some patients with persis-tent or chronic immune thrombocytopenia. Br J Haematol. 2015;170(3)408-415. doi: 10.1111/bjh.13444. 36. Cines DB, Bussel JB, Liebman HA, Luning Prak ET. The ITP syndrome: pathogenic and clinical diver-sity. Blood. 2009;113(26):6511-6521. doi: 10.1182/blood-2009-01-129155. 37. Peng J, Ma SH, Liu J, et al. Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost. 2014;12(4):497-504. doi: 10.1111/jth.12524.38. Lee MS, Kim WC. Intracranial hemorrhage associated with idiopathic thrombocytopenic purpura: report of seven patients and a meta-analysis. Neurology. 1998;50(4):1160-1163.39. Portielje JE, Westendorp RG, Kluin-Nelemans HC, Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001;97(9):2549-2554. 40. Neylon AJ, Saunders PW, Howard MR, Proctor SJ, Taylor PR; Northern Region Haematology Group. Clinically significant newly presenting autoimmune thrombocytopenic purpura in adults: a prospective study of a population-based cohort of 245 patients. Br J Haematol. 2003;122(6):966-974.41. Danese MD, Lindquist K, Gleeson M, Deuson R, Mikhael J. Cost and mortality associated with hospitalizations in patients with immune thrombocytopenic purpura. Am J Hematol. 2009;84(10):631-635. doi: 10.1002/ajh.21500.42. Chandan JS, Thomas T, Lee S, et al. The association between idiopathic thrombocytopenic purpura and cardiovascular disease: a retrospective cohort study. J Thromb Haemost. 2018;16(3):474-480. doi: 10.1111/jth.13940.43. Snyder CF, Mathias SD, Cella D, Isitt JJ, Wu AW, Young J. Health-related quality of life of immune thrombocytopenic purpura patients: results from a web-based survey. Curr Med Res Opin. 2008;24(10):2767-2776. doi: 10.1185/03007990802377461.44. Mathias SD, Bussel JB, George JN, McMillan R, Okano GJ, Nichol JL. A disease-specific measure of health-related quality of life for use in adults with immune thrombocytopenic purpura: its development and validation. Health Qual Life Outcomes. 2007;29(5):11. doi: 10.1186/1477-7525-5-11.45. Frederiksen H, Schmidt K. The incidence of idiopathic thrombocytopenic purpura in adults increases with age. Blood. 1999;94(3):909-913.46. Fogarty PF. Chronic immune thrombocytopenia in adults: epidemiology and clinical presentation. Hematol Oncol Clin North Am. 2009;23(6):1213-1221. doi: 10.1016/j.hoc.2009.08.004.47. Terrell DR, Beebe LA, Vesely SK, et al. The incidence of immune thrombocytopenic purpura in children and adults: a critical review of published reports. Am J Hematol. 2010;85(3):174-180. doi: 10.1002/ajh.21616.48. Segal JB, Powe NR. Prevalence of immune thrombocytopenia: analyses of administrative data. J Thromb Haemost. 2006;4(11):2377-2383. doi: 10.1111/j.1538-7836.2006.02147.x.49. Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international work-ing group. Blood. 2009;113(11):2386-2393. doi: 10.1182/blood-2008-07-162503.50. Palandri F, Polverelli N, Sollazzo D, et al. Have splenectomy rate and main outcomes of ITP changed after the introduction of new treatments? a monocentric study in the outpatient setting during 35 years. Am J Hematol. 2016;91(4):E267-E272. doi: 10.1002/ajh.24310.


51. British Committee for Standards in Haematology General Haematology Task Force. Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol. 2003;120(4):574-596.52. Rice JB, White AG, Scarpati LM, Wan G, Nelson WW. Long-term systemic corticosteroid exposure: a systematic literature review. Clin Ther. 2017;39(11):2216-2229. doi: 10.1016/j.clinthera.2017.09.011. 53. Moulis G, Lapeyre-Mestre M, Palmaro A, Sailler L. Infections in non-splenectomized persistent or chronic primary immune thrombocytopenia adults: risk factors and vaccination effect. J Thromb Haemost. 2017;15(4):785-791. doi: 10.1111/jth.13622.54. Hansen RJ, Balthasar JP. Mechanisms of IVIG action in immune thrombocytopenic purpura. Clin Lab. 2004;50(3-4):133-140.55. Cheung E, Liebman H. Anti-RhD immunoglobulin in the treatment of immune thrombocytopenia. Biologics. 2009;3:57-62.56. Rituxan [prescribing information]. San Fransisco, CA: Genentech; 1997. 57. Cooper N, Stasi R, Cunningham-Rundles S, et al. The efficacy and safety of B-cell depletion with anti-CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura. Br J Haematol. 2004;125(2):232-239. doi: 10.1111/j.1365-2141.2004.04889.x.58. Stasi R, Stipa E, Forte V, Meo P, Amadori S. Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenic purpura. Blood. 2002;99(10):3872-3873.59. Arnold DM, Dentali F, Crowther MA, et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med. 2007;146(1):25-33.60. Godeau B, Porcher R, Fain O, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112(4):999-1004. doi: 10.1182/blood-2008-01-131029. 61. Ghanima W, Khelif A, Waage A, et al. RITP study group. Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9978):1653-1661. doi: 10.1016/S0140-6736(14)61495-1. 62. Marangon M, Vianelli N, Palandri F, et al. Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long-term response. Eur J Haematol. 2017;98(4):371-377. doi: 10.1111/ejh.12839.63. Reboursiere E, Fouques H, Maigne G, et al. Rituximab salvage therapy in adults with immune thrombocytopenia: retrospective study on efficacy and safety profiles. Int J Hematol. 2016;104(1):85-91. doi: 10.1007/s12185-016-1992-4. 64. Kaushansky K. Thrombopoietin: the primary regulator of megakaryocyte and platelet production. Thromb Haemost. 1995;74(1):521-525.65. NPLATE [prescribing information]. Thousand Oaks, CA: Amgen; 201766. Promacta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018 67. Kuter DJ, Bussel JB, Newland A, et al. Long-term treatment with romiplostim in patients with chronic immune thrombocytopenia: safety and efficacy. Br J Haematol. 2013;161(3):411-423. doi: 10.1111/bjh.12260. 68. Wong RSM, Saleh MN, Khelif A, et al. Safety and efficacy of long-term treatment of chronic/persistent ITP with eltrombopag: final results of the EXTEND study. Blood. 2017;130(23):2527-2536. doi: 10.1182/blood-2017-04-748707. 69. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag for management of chronic immune thrombocy-topenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 2011;377(9763):393-402. doi: 10.1016/S0140-6736(10)60959-2. 70. Lokhandwala T, Bhor M, Stafkey-Mailey D, et al. Comparison of treatment characteristics between patients diagnosed with immune thrombocytopenia (ITP) and treated with thrombopoietin receptor ago-nists (TPO-RA). J Clin Oncol. 2017;35(15 suppl):e18314. doi: 10.1200/JCO.2017.35.15_suppl.e18314.71. Stafkey-Mailey D, Roy A, Tasneem L. Evaluation of treatment patterns among patients with newly diagnosed, persistent, and chronic immune thrombocytopenia (ITP) treated with eltrombopag in real world setting in the US. Blood. 2017;130(suppl 1):2078.72. Rodeghiero F, Ruggeri M. Treatment of immune thrombocytopenia in adults: the role of thrombopoi-etin-receptor agonists. Semin Hematol. 2015;52(1):16-24. doi: 10.1053/j.seminhematol.2014.10.006. 73. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocy-topenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104(9):2623-2634. doi: 10.1182/blood-2004-03-1168.staf.74. McMillan R, Durette C. Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood. 2004;104(4):956-960. doi: 10.1182/blood-2003-11-3908. 75. Naouri A, Feghali B, Chabal J, et al. Results of splenectomy for idiopathic thrombocytopenic purpura. review of 72 cases. Acta Haematol. 1993;89(4):200-203. doi: 10.1159/000204523.

76. Schwartz J, Leber MD, Gillis S, Giunta A, Eldor A, Bussel JB. Long term follow-up after splenectomy performed for immune thrombocytopenic purpura (ITP). Am J Hematol. 2003;72(2):94-98. doi: 10.1002/ajh.10253. 77. Thai LH, Mahévas M, Roudot-Thoraval F, et al. Long-term complications of splenectomy in adult immune thrombocytopenia. Medicine (Baltimore). 2016;95(48):e5098. doi: 10.1097/MD.0000000000005098. 78. Vianelli N, Galli M, de Vivo A, et al. Gruppo Italiano per lo Studio delle Malattie Ematologiche dell’Adulto. Efficacy and safety of splenectomy in immune thrombocytopenic purpura: long-term results of 402 cases. Haematologica. 2005;90(1):72-77.79. Zheng D, Huang CS, Huang SB, Zheng CX. Laparoscopic splenectomy for primary immune thrombocytopenia: current status and challenges. World J Gastrointest Endosc. 2016;8(17):610-615. doi: 10.4253/wjge.v8.i17.610.80. Gómez-Almaguer D, Solano-Genesta M, Tarín-Arzaga L, et al. Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood. 2010;116(23):4783-4785. doi: 10.1182/blood-2010-06-291831. 81. Oo T, Hill QA. Disappointing response to dapsone as second line therapy for primary ITP: a case series. Ann Hematol. 2015;94(6):1053-1054. doi: 10.1007/s00277-014-2285-8. 82. Park YH, Yi HG, Lee MH, Kim CS, Lim JH. Clinical efficacy and tolerability of vincristine in splenecto-mized patients with refractory or relapsed immune thrombocytopenia: a retrospective single-center study. Int J Hematol. 2016;103(2):180-188. doi: 10.1007/s12185-015-1903-0. 83. Taylor A, Neave L, Solanki S, et al. Mycophenolate mofetil therapy for severe immune thrombocyto penia. Br J Haematol. 2015;171(4):625-630. doi: 10.1111/bjh.13622. 84. Cuker A, Cines DB, Neunert CE. Controversies in the treatment of immune thrombocytopenia.Curr Opin Hematol. 2016;23(5):479-485. doi: 10.1097/MOH.0000000000000270.85. Northridge K, Danese M, Deuson R. Determining the cost of a bleeding-related episode in primary adult chronic immune thrombocytopenia (ITP) in the United States. Value in Health. 2013;16(3):A1-A298. doi: 10.1016/j.jval.2013.03.559.86. Lin J, Zhang X, Li X, et al. Cost of bleeding-related episodes in adult patients with primary immune thrombocytopenia: a population-based retrospective cohort study of administrative claims data for com-mercial payers in the United States. Clin Ther. 2017;39(3):603-609.e1. doi: 10.1016/j.clinthera.2017.01.023. 87. Altomare I, Cetin K, Wetten S, Wasser JS. Rate of bleeding-related episodes in adult patients with primary immune thrombocytopenia: a retrospective cohort study using a large administrative medical claims database in the US. Clin Epidemiol. 2016;8:231-9. doi:10.2147/CLEP.S105888.88. Winters JL, Brown D, Hazard E, Chainani A, Andrzejewski C. Cost-minimization analysis of the direct costs of TPE and IVIg in the treatment of Guillain-Barré syndrome. BMC Health Serv Res. 2011;11:101. doi: 10.1186/1472-6963-11-101.89. Blackhouse G, Gaebel K, Xie F, et al. Cost-utility of intravenous immunoglobulin (IVIG) compared with corticosteroids for the treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) in Canada. Cost Eff Resour Alloc. 2010;8:14. doi: 10.1186/1478-7547-8-14.90. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med. 2009;103(7):975-994. doi: 10.1016/j.rmed.2009.01.003. 91. Tavalisse [prescribing information]. San Fransisco, CA: Rigel Pharmaceuticals Inc; 2018.92. Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10(6):387-402. doi: 10.1038/nri2765.93. Bussel JB, Kuter DJ, Pullarkat V, Lyons RM, Guo M, Nichol JL. Safety and efficacy of long-term treat-ment with romiplostim in thrombocytopenic patients with chronic ITP. Blood. 2009;113(10):2161-2171. doi: 10.1182/blood-2008-04-150078.94. Peñalver FJ, Jiménez-Yuste V, Almagro M, et al. Multi-institutional retrospective Spanish study group on the use of rituximab in refractory ITP. rituximab in the management of chronic immune throm-bocytopenic purpura: an effective and safe therapeutic alternative in refractory patients. Ann Hematol. 2006;85(6):400-406. 95. Boruchov DM, Gururangan S, Driscoll MC, Bussel JB. Multiagent induction and maintenance therapy for patients with refractory immune thrombocytopenic purpura (ITP). Blood. 2007;110(10):3526-3531. doi: 10.1182/blood-2007-01-065763.96. Gomez-Puerta JA, Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 2013;13(6):760-773. doi: 10.2174/15680266113139990094.97. Kunwar S, Devkota AR, Ghimire DK. Fostamatinib, an oral spleen tyrosine kinase inhibitor, in the treatment of rheumatoid arthritis: a meta-analysis of randomized controlled trials. Rheumatol Int. 2016;36(8):1077-1087. doi: 10.1007/s00296-016-3482-7.

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