Systematic Literature Review of Treatments Used for Adult Immune Thrombocytopenia (ITP) in the Second-line Setting

Abstract

Immune thrombocytopenia (ITP) is a rare platelet disorder that is often persistent or chronic in adults. Patient management is dependent upon physician judgment and patient preference, given both the rarity of the condition and a paucity of high‐quality clinical trial evidence to inform practice guidelines. A systematic literature review was conducted to provide an up‐to‐date summary of studies evaluating the safety and efficacy/effectiveness of therapies used to treat adults with primary ITP in the second‐line setting. Using comprehensive search strings, several medical research databases were queried. Final abstraction was performed on 186 articles. Most (75%) studies were observational in nature; nearly half were conducted in Europe. Splenectomy was the most commonly studied (n=83, 47%), followed by rituximab (n=49, 26%) and the thrombopoietin‐receptor agonists (TPO‐RAs) romiplostim (n=34, 18%) and eltrombopag (n=24, 13%). Twelve prospective, randomized controlled trials (RCTs) with a placebo or standard‐of‐care arm evaluating the safety and efficacy of either rituximab or a TPO‐RA were identified and described in detail. These trials provide important information on the safety and efficacy of these treatments, and in the absence of head‐to‐head data, offer insights on how these therapies compare with one another in treating adult ITP in the second‐line setting. This review confirms that for most second‐line ITP treatment options, there remains a lack of rigorous evidence derived from RCTs, and for many treatments, there is limited evidence of any kind. The need for additional research to guide treatment choices in this setting and greater use of standardized ITP terminology are highlighted.
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CRITICAL REVIEW
Systematic literature review of treatments used for adult
immune thrombocytopenia in the second-line setting
Lauren C. Bylsma
1
| Jon P. Fryzek
1
| Karynsa Cetin
2
| Fiona Callaghan
2
| Carla Bezold
1
|
Bhakti Mehta
3
| Jeffrey S. Wasser MD
4
1
EpidStat Institute, Ann Arbor, Michigan
2
Center for Observational Research, Amgen,
Inc., Thousand Oaks, California
3
Global Development, Amgen, Inc., Thousand
Oaks, California
4
Carole and Ray Neag Comprehensive Cancer
Center, University of Connecticut School of
Medicine, Farmington, Connecticut
Correspondence
Jeffrey S. Wasser, Division of Hematology and
Medical Oncology, University of Connecticut
School of Medicine, 263 Farmington Avenue,
Mail Stop 1628, Farmington, CT 06030.
Email: jwasser@uchc.edu
Funding information
This study was supported in part by research
funding from Amgen Inc to EpidStat Institute.
Abstract
Immune thrombocytopenia (ITP) is a rare platelet disorder that is often persistent or chronic in
adults. Patient management is dependent upon physician judgment and patient preference,
given both the rarity of the condition and a paucity of high-quality clinical trial evidence to
inform practice guidelines. A systematic literature review was conducted to provide an up-to-
date summary of studies evaluating the safety and efficacy/effectiveness of therapies used to
treat adults with primary ITP in the second-line setting. Using comprehensive search strings,
several medical research databases were queried. Final abstraction was performed on 186 arti-
cles. Most (75%) studies were observational in nature; nearly half were conducted in Europe.
Splenectomy was the most commonly studied (n = 83, 47%), followed by rituximab (n = 49,
26%) and the thrombopoietin-receptor agonists (TPO-RAs) romiplostim (n = 34, 18%) and
eltrombopag (n = 24, 13%). Twelve prospective, randomized controlled trials (RCTs) with a pla-
cebo or standard-of-care arm evaluating the safety and efficacy of either rituximab or a TPO-RA
were identified and described in detail. These trials provide important information on the safety
and efficacy of these treatments, and in the absence of head-to-head data, offer insights on
how these therapies compare with one another in treating adult ITP in the second-line setting.
This review confirms that for most second-line ITP treatment options, there remains a lack of
rigorous evidence derived from RCTs, and for many treatments, there is limited evidence of any
kind. The need for additional research to guide treatment choices in this setting and greater use
of standardized ITP terminology are highlighted.
1|INTRODUCTION
Primary immune thrombocytopenia (ITP) is a rare autoimmune disor-
der characterized by isolated thrombocytopenia that can lead to an
increased tendency to bleed.
1,2
Although it typically presents as a
subtle-onset, chronic syndrome in adults, with no forewarning symp-
toms or illness, clinical manifestations can range from minor bruising
to severe hemorrhaging.
3–5
The primary goal of treatment is to
achieve a safe platelet count (above which, a patient does not experi-
ence bleeding episodes), and this is determined on a case-by-case
basis.
3
Common first-line therapies include corticosteroids, intrave-
nous immunoglobulin (IVIg), and anti-D (Rho[D] immune globulin
intravenous).
6–8
Relapse or failure to respond to these may necessi-
tate second-line treatment, which can include splenectomy or a vari-
ety of medical therapies, most of which have not been approved by
regulatory authorities for the treatment of ITP but have been used
because of efficacy demonstrated in other autoimmune diseases or as
immune suppressants.
9
Splenectomy has historically been considered the second-line ther-
apy of choice in adult ITP.
10,11
A systematic review was previously con-
ducted to examine studies (published from 1966 to 2003) that assessed
the efficacy/effectiveness of medical treatments for adult patients with
ITP who have not responded to splenectomy. The review covered a total
of 90 studies representing 656 patients who were splenectomized, aged
Received: 8 June 2018 Revised: 17 September 2018 Accepted: 24 September 2018
DOI: 10.1002/ajh.25301
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.
118 wileyonlinelibrary.com/journal/ajh Am J Hematol. 2019;94:118–132.

>16 years, had ITP for >3 months, and a platelet count <50 ×10
9
/L.
12
Only one study
13
was a randomized controlled trial (RCT) but the ran-
domization was by dose of the same therapy; the remaining were cohort
studies or uncontrolled case series. A complete response (as defined in
each respective original report) was achieved in 14% of patients across
the 22 treatment types, with the largest numbers of responders reported
with cyclophosphamide (27% of 83 patients), rituximab (24% of
41 patients), and azathioprine (17% of 109 patients). Although partial
response was achieved in 40% of patients across these three therapies,
36% to 42% had no response. This review focused on the third-line set-
ting and beyond, but it demonstrated that at least at that time, there was
minimal evidence for the effectiveness of any medical treatment for ITP
patients with persistent, severe thrombocytopenia, highlighting the need
for RCTs to properly evaluate potentially effective treatments in this
setting.
Since the publication of this systematic review, the management of
ITP has evolved. Treatment decisions are less likely to be guided solely by
platelet counts and more likely to rely on a combination of platelet levels;
shared decision making between the physician and the patient; and patient
factors, such as insurance coverage, lifestyle, history of bleeding, occupa-
tion, comorbidities, and expectations.
9
Thrombopoietin-receptor agonists
(TPO-RAs), including eltrombopag and romiplostim, have also entered the
market after undergoing rigorous randomized trials in splenectomized and
non-splenectomized patients with persistent or chronic ITP.
14–16
Addition-
ally, the incidence of splenectomy has declined in recent years.
17,18
Despite these developments and trends, the International Consensus
Report on the management of primary ITP (released in 2010) lists medical
treatment options in the second-line setting in alphabetical order to avoid
indicating a preference for a specific treatment, highlighting the lack of suf-
ficient data to rank the treatments according to efficacy.
1
Similarly, shortly
after the publication of this report, the American Society of Hematology
(ASH) published practice guidelines for ITP, concluding that there is no evi-
dence to guide a sequence of treatment for patients who have recurrent
or persistent thrombocytopenia with bleeding after first-line treatment
with corticosteroids, IVIg, or anti-D.
19
Indeed, clinical decision-making on optimal second-line ITP treat-
ment is challenging and has been described as controversial.
20,21
The
lack of prescriptive clinical guidance in this setting highlights a gap in
the scientific literature regarding comparisons of safety and efficacy
across available treatments.
2,22
Given this and the changing treatment
landscape over the past decade, we sought to systematically review
published reports and provide an up-to-date summary of studies eval-
uating the safety and efficacy/effectiveness of therapies used to treat
primary ITP in adults in the second-line setting, with a particular focus
on RCTs that have been conducted.
2|METHODS
The scope of this review included both interventional and observational
studies that evaluated the safety, efficacy (from interventional designs),
and/or effectiveness (from observational designs) of therapies used to
treat primary ITP in adults in the second-line setting. We excluded stud-
ies in which the therapy of interest was used in the first-line setting, case
series with less than 20 patients, studies published in languages other
than English, and studies conducted in children, pregnant women, or
patients with secondary thrombocytopenia. The therapies of interest
were: splenectomy, azathioprine, cyclophosphamide, cyclosporine A,
danazol, dapsone, eltrombopag, mycophenolate mofetil, rituximab, romi-
plostim, and vinca alkaloids, as these are the second-line treatment
options provided in the International Consensus Report and the most
recent ASH guidelines on the management of primary ITP.
1,19
The out-
comes of interest covered several efficacy endpoints, including any
platelet-related change (eg, platelet response, duration of platelet
response, etc), rate of and/or time to splenectomy (in studies where sple-
nectomy was not the treatment of interest), rate of rescue medication
and/or other ITP therapy use, and rate of bleeding. In terms of safety
endpoints, we searched for data on the rates of clinically significant
bleeding, thrombotic/thromboembolic events, pulmonary hypertension,
infections, respiratory tract infections, neuropathy, leukopenia, hemor-
rhagic cystitis, fever, and other serious adverse drug reactions. We also
obtained data on mortality.
This review was conducted in accordance with the Preferred
Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)
guidelines.
23
Comprehensive literature searches were conducted by
several reviewers in October 2016 in the PubMed, EMBASE, Web of
Science, Cochrane Central Register of Controlled Trials, and the
Cochrane Database of Systematic Reviews databases using multiple
search strings to fully encompass all aspects of the inclusion criteria
(Supplemental Table 1). Bibliographies of relevant reviews and meta-
analyses were also searched for additional pertinent publications. The
flow diagram of study inclusion is presented in Figure 1. Study cita-
tions were downloaded into a database, and duplicates were removed
from the search results using automated de-duplication methods and
manual screening. Studies were reviewed for relevance at the levels
of title, abstract, and full text by two independent reviewers. Articles
designated as eligible for inclusion were abstracted into a database
and independent reviewers performed a quality control assessment
for accuracy on each abstracted study. Disagreements were resolved
by consensus adjudication. If more than one article from the same
study population was published, data from the publication with the
longest follow-up, most recent data, and/or most specifically relevant
population and/or outcomes were extracted. Data elements
abstracted included study design, population characteristics, treat-
ment description and dosage, and the aforementioned efficacy/effec-
tiveness and safety outcomes. Several measures to assess study bias
were also abstracted using the Cochrane Risk of Bias Tool,
24
including
evaluation of randomization, concealment, blinding, baseline compara-
bility, follow-up, selective reporting, and analysis.
Tabulated summaries were generated to explain basic characteristics
of the included studies. Results for placebo-controlled RCTs or standard-
of-care (SOC)-controlled RCTs were examined in detail, given their gen-
eral comparability in trial design and rigor. For these studies, for end-
points/outcomes common to at least two studies (complete platelet
response, overall platelet response, use of rescue therapies, and bleed-
ing), the study definition of that endpoint and the corresponding results
were described. Rate ratios and response ratios and 95% confidence
intervals (CIs) were calculated to compare rate/response of the outcome
of interest in patients receiving the therapy of interest and patients
receiving placebo or SOC for each outcome from each study. Forest
BYLSMA ET AL.119

plots for each endpoint/outcome were created to display the risk/
response ratios across individual studies and therapies. In addition to the
measures that were formally described in rate/response ratios and forest
plots, median duration of overall/complete platelet response from each
study was collected and described, when available. Analyses were per-
formed using R statistical software
25
and the “metafor”package.
26
Afor-
mal meta-analysis was not performed due to the small number of studies
for some treatments (n < 3).
3|RESULTS
Of nearly 300 000 publications identified through our comprehen-
sive literature searches, 186 reports met our inclusion criteria of
studies evaluating the safety and efficacy/effectiveness of the
second-line therapies of interest in adult primary ITP. An overview of
the basic characteristics of these studies is summarized in Table 1.
The majority (N = 139; 75%) of studies were observational in nature,
FIGURE 1 Flowchart of article selection for the systematic literature review. Comprehensive search strings were applied to the medical research
databases, and studies were reviewed for relevancy at the levels of title, abstract, and full text. [Color figure can be viewed at
wileyonlinelibrary.com]
120 BYLSMA ET AL.

with retrospective cohort studies being the most common (N = 104;
56% of total), followed by prospective cohort studies (N = 32; 17%
of total). A substantial proportion (47%) of the studies were con-
ducted solely in European countries, 14% were based on United
States (US) data alone, 12% were based on data from China and
Japan alone, and 3% were conducted solely in Australia. Of the ther-
apies included in our search, splenectomy was the most commonly
studied (N = 83; 47%), followed by rituximab (N = 49; 26%), romi-
plostim (N = 34; 18%), and eltrombopag (N = 24; 13%). All other
therapies were the focus of just 1% to 4% of the studies identified,
and just over 4% of the studies included a combination of at least
two of the therapies of interest.
For most of the treatments, including azathioprine, cyclophospha-
mide, cyclosporine, danazol, dapsone, mycophenolate mofetil,
vinblastine, and vincristine, there were limited studies of efficacy/
effectiveness and safety identified. Only 22 unique studies conducted
over the past four decades covered at least one of these eight thera-
pies, the majority (n = 16) of which were observational in nature. Of
note, cyclophosphamide and vincristine have not been studied in a
prospective, interventional manner, and the remaining 6 therapies are
supported by one such study each. However, the sole interventional
study of cyclosporine evaluated this therapy in combination with oral
dexamethasone and IV low-dose rituximab in a phase 2b study.
27
The
other five studies are briefly described here.
In a single-arm study of 53 adults with chronic ITP treated with
azathioprine, 45% of patients had a “complete remission”after receiv-
ing azathioprine (defined as platelet counts ≥150 ×10
9
/L for at least
3 months); median time to response was 4 months.
28
In an open-label
study of dapsone among 66 adults with chronic ITP, 30.3% showed a
partial response (platelet count >50 ×10
9
/L and at least twice the ini-
tial platelet count) and 19.7% demonstrated a complete response
(platelet count >150 ×10
9
/L); median time to obtain the maximal
platelet count response was 130 days.
29
Similarly, in a single-arm
study of mycophenolate mofetil administered among just 21 adults
with chronic ITP, 28.6% demonstrated a partial response (platelet
count 50 to <100 ×10
9
/L) and 23.8% demonstrated a complete
response (platelet count ≥100 ×10
9
/L) after 12 weeks of treat-
ment.
30
Vinblastine has been studied in a single interventional study
in which 42 patients with ITP, including 17 with chronic ITP, were ran-
domized to either receive vinblastine by IV slow infusions or vinblas-
tine by IV bolus injections, 8 of whom had failed at least one prior
therapy and thus were being treated in the second-line setting.
13
Of
these, 37.5% showed a complete response (platelet count
>150 ×10
9
/L), 12.5% a partial response (platelet count 100 to
150 ×10
9
/L), and 0 of 8 patients had a minor response (platelet count
>50 ×10
9
/L and at least a doubling of platelet counts from initial
levels), which was evaluated at 6 weeks after IV vinblastine adminis-
tered either through continuous infusion or bolus injection. Lastly, and
most recently, a multicenter, randomized trial was conducted to
assess the efficacy and safety of a recombinant human thrombopoie-
tin (rhTPO) in patients with persistent ITP who had failed glucocorti-
costeroid treatment.
31
A total of 140 eligible patients were
randomized to receive rhTPO + danazol or danazol alone, but only
short-term (2 weeks) response with danazol alone was assessed. At
2 weeks, 36.5% of 67 patients in the danazol-alone group had their
platelet count restored to normal (≥100 ×10
9
/L) and/or had a plate-
let count rise to at least 50 ×10
9
/L or increase by 30 ×10
9
/L above
baseline with no bleeding symptoms.
Among the remaining non-surgical therapies, we identified 12 pro-
spective RCTs with a placebo or SOC arm evaluating the safety and effi-
cacy of eltrombopag (5 studies
14,32–35
), rituximab (2 studies
36,37
), or
romiplostim (5 studies,
15,38–40
with one publication reporting on two
studies conducted in parallel
15
). (No head-to-head RCTs directly compar-
ing one second-line therapy of interest to another were found.) These
studies are summarized in more detail in Table 2, and study-specific defi-
nitions of the outcomes/endpoints common to at least two of the stud-
ies are provided in Table 3. Two studies were prospective phase
2, placebo-controlled RCTs (1 eltrombopag
32
and 1 romiplostim
38
); one
was a prospective SOC-controlled, open label RCT (romiplostim
39
); one
TABLE 1 Studies included in the systematic review of observational
and interventional studies reporting on the safety and efficacy/
effectiveness of therapies used in adult immune thrombocytopenia in
the second-line setting
Number of studies (%)
Study design
Retrospective cohort study 104 (55.9%)
Prospective cohort study 32 (17.2%)
Non-single-arm RCT 20 (10.8%)
Single-arm trial 18 (9.7%)
Case series 7 (3.8%)
Other observational study 3 (1.6%)
Other clinical study 2 (1.1%)
Case-control study 0 (0%)
Geographic region
European countries only 87 (46.8%)
All others 30 (16.1%)
United States only 26 (14.0%)
Global (involving at least 2 geographic
regions above)
15 (8.1%)
China only 13 (7.0%)
Japan only 10 (5.4%)
Australia only 5 (2.7%)
Therapy studied
a
Splenectomy only
b
83 (44.6%)
Rituximab only 49 (26.3%)
Romiplostim only 34 (18.3%)
Eltrombopag only 24 (12.9%)
Combination of at least 2 therapies
c
8 (4.3%)
Danazol only 7 (3.8%)
Vinca alkaloids only 6 (3.2%)
Cyclophosphamide only 6 (3.2%)
Azathioprine only 4 (2.2%)
Cyclosporine A only 4 (2.2%)
Mycophenolate mofetil only 3 (1.6%)
Dapsone only 2 (1.1%)
a
Not mutually exclusive as studies may contain multiple arms evaluating
different drugs.
b
Some studies included other therapies that were not of interest but all
studies included splenectomy.
c
More than one therapy of interest was included with/without other ther-
apies not of interest.
BYLSMA ET AL.121

TABLE 2 Study design and population of randomized clinical trials evaluating eltrombopag, rituximab, or romiplostim vs placebo or standard of care
Study Study design
Location and study
years
Study population
ITP Splenectomy status Demographic and clinical characteristics Sample size
Eltrombopag
Bussel
et al. (2007)
32
Prospective, multicenter, phase
2, randomized,
placebo-controlled,
double-blind
Worldwide
(44 clinical sites)
ITP for at least 6 months,
platelet count less than
30 ×10
9
/L at enrollment,
age 18 years or older
Non-splenectomized (53%)
and splenectomized (47%)
Placebo:
Median age 42 years, 55% female, ITP duration not reported,
48% had a platelet count no higher than 15 ×10
9
/L
Placebo: n = 29
Eltrombopag:
n = 30 (30 mg);
2005-2005
n = 30 (50 mg); and
n = 28 (75 mg)Eltrombopag 30 mg:
Median age 51 years, 53% female, ITP duration not reported,
50% had a platelet count no higher than 15 ×10
9
/L
Eltrombopag 50 mg:
Median age 45 years, 70% female, ITP duration not reported,
40% had a platelet count no higher than 15 ×10
9
/L
Eltrombopag 75 mg:
Median age 55 years, 71% female, ITP duration not reported,
54% had a platelet count no higher than 15 ×10
9
/L
Bussel
et al. (2009)
14
Prospective, multicenter, phase
3, randomized,
placebo-controlled,
double-blind
Worldwide
(63 clinical sites)
2006
ITP for at least 6 months,
pretreatment platelet
count less than 30 ×10
9
/
L, age 18 years or older
Non-splenectomized (61%)
and splenectomized (39%)
Placebo:
Median age 51 years, 71% female, ITP duration not reported,
45% had a platelet count no higher than 15 ×10
9
/L
Placebo: n = 38
Eltrombopag: n = 76
Eltrombopag:
Median age 47 years, 57% female, ITP duration not reported,
50% had a platelet count no higher than 15 ×10
9
/L
Cheng
et al. (2011)
33
Prospective, phase 3, randomized,
placebo-controlled,
double-blind
Worldwide
(75 clinical sites)
2006-2007
ITP for at least 6 months,
baseline platelet count less
than 30 ×10
9
/L, age
18 years or older
Non-splenectomized (64%)
and splenectomized (36%)
Placebo:
Median age 53 years, 69% female, ITP duration not reported,
median platelet count 16 ×10
9
/L
Placebo: n = 62
Eltrombopag: n = 135
Eltrombopag:
Median age 47 years, 69% female, ITP duration not reported,
median platelet count 16 ×10
9
/L
Tomiyama
et al. (2012)
34
Prospective, multicenter, phase
3, randomized,
placebo-controlled,
double-blind
Japan
2007-2008
ITP for at least 6 months,
platelet count less than
30 ×10
9
/L, age 20 years
or older
Non-splenectomized (30%)
and splenectomized (70%)
Placebo:
Median age 61 years, 88% female, ITP duration not reported,
median platelet count 9.5 ×10
9
/L
Placebo: n = 8
Eltrombopag: n = 15
Eltrombopag:
Median age 58 years, 53% female, ITP duration not reported,
median platelet count 21 ×10
9
/L
Yang et al. (2014)
35
Prospective, multicenter, phase
3, randomized,
placebo-controlled,
double-blind
China
2013-2014
Chronic ITP with a platelet
count less than 30 ×10
9
/
L, age 18 years or older
Non-splenectomized (84%)
and splenectomized (16%)
Limited data in abstract Placebo: n = 51
Eltrombopag: n = 104
Placebo:
Median age, gender, and median ITP duration not reported,
55% had platelet count no higher than 15 ×10
9
/L
Eltrombopag:
Median age, gender, and median ITP duration not reported,
52% had platelet count no higher than 15 ×10
9
/L
Rituxumab
Arnold
et al. (2012)
36
Prospective, pilot, randomized,
placebo-controlled
Canada
2006-2010
Newly diagnosed or relapsed
ITP with a platelet count
less than 30 ×10
9
/L, age
18 years or older
Non-splenectomized Placebo:
Median age 40 years, 59% female, median ITP duration
0.7 years, median platelet count 14 ×10
9
/L
Placebo: n = 27
Rituximab: n = 33
Rituximab:
Median age 40 years, 58% female, median ITP duration
0.3 years, median platelet count 15 ×10
9
/L
(Continues)
122 BYLSMA ET AL.

TABLE 2 (Continued)
Study Study design
Location and study
years
Study population
ITP Splenectomy status Demographic and clinical characteristics Sample size
Ghanima
et al. (2015)
37
Prospective, multicenter, phase
3, randomized,
placebo-controlled,
double-blind
Norway, Tunisia, and
France
2006-2011
ITP with a platelet count less
than 30 ×10
9
/L, age
18 years or older
Non-splenectomized Placebo:
Median age 46 years, 72% female, median ITP duration
1.0 year, median platelet count 21 ×10
9
/L
Placebo: n = 54
Rituximab: n = 55
Rituximab:
Median age 46 years, 73% female, median ITP duration
0.7 years, median platelet count 16 ×10
9
/L
Romiplostim
Bussel
et al. (2006)
31
Prospective, multicenter, phase
2, randomized,
placebo-controlled,
double-blind
United States
2003-2004
ITP according to ASH
guidelines for at least
3 months, mean platelet
count less than
30 ×10
9
/L for patients
not receiving
corticosteroids or a mean
platelet count less than
50 ×10
9
/L for patients
receiving corticosteroids,
age 18-65 years
Non-splenectomized (33%)
and splenectomized (67%)
All arms combined:
Median age 49 years, 71% female, median ITP duration
5.2 years, median platelet count 16 ×10
9
/L
Placebo: n = 4
Romiplostim: n = 17
Kuter
et al. (2008)
a15
Prospective, multicenter, phase
3, randomized,
placebo-controlled,
double-blind
United States and
Europe
2005-2006
ITP according to ASH
guidelines, mean platelet
count less than
30 ×10
9
/L during
screening, age 18 years or
older
Splenectomized Placebo:
Median age 56 years, 52% female, median ITP duration
8.5 years, median platelet count 15 ×10
9
/L
Placebo: n = 21
Romiplostim: n = 42
Romiplostim:
Median age 51 years, 64% female, median ITP duration
7.8 years, median platelet count 14 ×10
9
/L
Prospective, multicenter, phase
3, randomized,
placebo-controlled, double
blind
United States and
Europe
2005-2006
ITP according to ASH
guidelines, mean platelet
count less than
30 ×10
9
/L during
screening, age 18 years or
older
Non-splenectomized Placebo:
Median age 46 years, 76% female, median ITP duration
1.6 years, median platelet count 19 ×10
9
/L
Romiplostim:
Median age 52 years, 66% female, median ITP duration
2.2 years, median platelet count 19 ×10
9
/L
Placebo: n = 21
Romiplostim: n = 41
Kuter
et al. (2010)
32
Prospective, multicenter,
randomized, controlled, open
label
North America,
Europe, and
Australia
2006-2007
ITP according to ASH
guidelines, pre-treatment
platelet count less than
50 ×10
9
/L, age 18 years
or older
Non-splenectomized Standard of care:
Median age 57 years, 60% female, median ITP duration
2.3 years, median platelet count 27 ×10
9
/L
Standard of care: n = 77
Romiplostim: n = 157
Romiplostim:
Median age 58 years, 54% female, median ITP duration
2.1 years, median platelet count 33 ×10
9
/L
Shirasugi
et al. (2011)
40
Prospective, phase 3, randomized,
placebo-controlled, double
blind
Japan ITP diagnosed at least
6 months prior to
enrollment, mean platelet
count no higher than
30 ×10
9
/L during
screening, age 20 years or
older
Non-splenectomized (56%)
and splenectomized (44%)
Placebo:
Mean age 47 years, 83% female, mean ITP duration 7.6 years,
mean platelet count 16 ×10
9
/L
Placebo: n = 12
Romiplostim: n = 222007-2009
Romiplostim:
Mean age 59 years, 64% female, mean ITP duration 9.7 years,
mean platelet count 18 ×10
9
/L
Abbreviations: ASH, American Society of Hematology; ITP, immune thrombocytopenia; L, liter; mg, milligram.
a
Reported on two parallel studies.
BYLSMA ET AL.123

TABLE 3 Study endpoint definitions used in randomized clinical trials evaluating eltrombopag, rituximab, or romiplostim vs placebo or standard of care
Study Therapy studied Bleeding Overall response Complete response Rescue therapy
Duration of platelet
response
Eltrombopag
Bussel
et al. (2007)
36
Eltrombopag vs
placebo
Bleeding symptoms at day 43 of any grade
according to the WHO bleeding scale (grade
0: No bleeding, grade 1: Petechiae, grade 2:
Mild blood loss, grade 3: Gross blood loss,
grade 4: Debilitating blood loss)
Platelet count of at least
50 ×10
9
/L on day 43
Not reported Not reported Not reported
Bussel
et al. (2009)
18
Eltrombopag
versus placebo
Definition #1: Bleeding symptoms at day 43 of
any grade according to the WHO bleeding
scale (grade 0: No bleeding, grade 1:
Petechiae, grade 2: Mild blood loss, grade 3:
Gross blood loss, grade 4: Debilitating blood
loss)
Platelet count of at least
50 ×10
9
/L on day 43
Platelet count of at least
50 ×10
9
/L and at least
twice the baseline value at
any point during treatment
Not reported Not reported
Definition #2: Bleeding symptoms of any
grade according to the WHO bleeding scale
at any point during treatment
Definition #3: Bleeding of any type as an
adverse event throughout treatment
Cheng
et al. (2011)
37
Eltrombopag
versus placebo
Definition #1: Bleeding symptoms of any grade
according to the WHO bleeding scale (grade
0: No bleeding, grade 1: Petechiae, grade 2:
Mild blood loss, grade 3: Gross blood loss,
grade 4: Debilitating blood loss)
Platelet count of
50-400 ×10
9
/L at any
assessment
Definition #1: Platelet count
of 50 to 400 ×10
9
/L at
75% or more of
assessments
New treatment for chronic ITP,
an increased dose of baseline
treatment, platelet
transfusion, or splenectomy
Mean maximum weeks
of continuous
response during the
6-month treatment
period
Definition #2: Durable
response defined as
achieving a platelet count
of 50-400 ×10
9
/L in at
least 6 of the last 8 weeks
of treatment and never
receiving rescue treatment
Definition #2: Bleeding symptoms of grade
2 or higher according to the WHO bleeding
scale (grade 2: Mild blood loss, grade 3:
Gross blood loss, grade 4: Debilitating blood
loss)
Definition #3: Bleeding of any type as an
adverse event throughout treatment
Definition #4: Serious bleeding as an adverse
event throughout treatment
Tomiyama
et al. (2012)
38
Eltrombopag vs
placebo
Bleeding symptoms of any grade (but only
reported in the eltrombopag arm)
Platelet count of
50-400 ×10
9
/L at
6 weeks
Platelet count of
50-400 ×10
9
/L at 4 or
more assessments
between week 2 and week
6
Not reported Not reported
Yang
et al. (2014)
39
Eltrombopag
versus placebo
Not reported Platelet count of
50-250 ×10
9
/L at
6 weeks
Not reported Not reported Not reported
Rituximab
Arnold
et al. (2012)
34
Rituximab versus
placebo
Grade 2 or higher bleeding events according to
the ITP bleeding score
Platelet count of at least
30 ×10
9
/L plus at least a
doubling of the platelet
count from baseline at
6 months
Platelet count of at least
100 ×10
9
/L at 6 months
Not explicitly defined but
consisted of the following in
the results: Prednisone,
dexamethasone, rhesus
immune globulin, azathioprine,
Not reported
(Continues)
124 BYLSMA ET AL.

TABLE 3 (Continued)
Study Therapy studied Bleeding Overall response Complete response Rescue therapy
Duration of platelet
response
danazol, romiplostim, and
platelet transfusion
Ghanima
et al. (2015)
35
Rituximab versus
placebo
Grade 2 or 3 bleeding events according to the
WHO bleeding scale (grade 2: Mild blood
loss, grade 3: Gross blood loss).
Platelet count of at least
30 ×10
9
/L after week
4 from first study drug
administration plus at least
a doubling of the platelet
count from baseline
Platelet count of at least
100 ×10
9
/L after week
4 from first study drug
administration plus at least
a doubling of the platelet
count from baseline
Not reported Median time to relapse
after achieving an
overall or complete
platelet response
following treatment
Romiplostim
Bussel
et al. (2006)
31
Romiplostim
versus placebo
Bleeding as a serious adverse event Platelet count of
50-450 ×10
9
/L and at
least a doubling of platelet
count from baseline
Not reported Not reported Not reported
Kuter
et al. (2008)
19
Romiplostim
versus placebo
Grade 3 or higher bleeding events (those rated
as severe [grade 3], life-threatening [grade 4],
or fatal [grade 5]).
Durable + transient rates of
platelet response, where:
Durable platelet
response = weekly
platelet response of at
least 50 ×10
9
/L during at
least 6 weeks of the last
8 weeks of treatment
Increased dose of concurrent ITP
therapy or use of any new
drug to increase platelet
counts
Not reported
Durable = weekly platelet
response of at least
50 ×10
9
/L during at
least 6 weeks of the last
8 weeks of treatment
Transient = weekly platelet
response of at least
50 ×10
9
/L during at least
4 weeks without a durable
platelet response from
week 2 to week 25
Kuter
et al. (2010)
32
Romiplostim
versus standard
of care
Definition #1: Grade 2 or higher bleeding
events (those rated as moderately severe
[grade 2], severe [grade 3], life-threatening
[grade 4], or fatal [grade 5])
Definition #2: Grade 3 or higher bleeding
events (those rated as severe [grade 3],
life-threatening [grade 4], or fatal [grade 5])
Platelet count greater than
50 ×10
9
/L at any
scheduled visit
Not reported Not reported Not reported
Shirasugi
et al. (2011)
33
Romiplostim
versus placebo
Definition #1: Bleeding symptoms defined as
purpura/petechiae, epistaxis, oral bleeding,
menorrhagia, bruising, intracranial bleeding,
gastrointestinal bleeding, and/or other
bleeding symptoms at week 13
Platelet count of at least
50 ×10
9
/L and at least a
doubling of platelet count
from baseline
Not reported Any medication administered to
raise platelet counts, including
IVIg, platelet transfusions,
corticosteroids, and an
increase in dose or frequency
of a concomitant oral
corticosteroid, azathioprine,
and/or danazol
Median duration of
platelet response
during the 12-week
treatment period
Definition #2: Grade 3 or higher bleeding
events (those rated as severe [grade 3],
life-threatening [grade 4], or fatal [grade 5])
Abbreviations: ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin; L, liter; WHO, World Health Organization.
BYLSMA ET AL.125

was a prospective placebo-controlled pilot RCT (rituximab
36
); and the
remaining eight studies were prospective phase 3, placebo-controlled
RCTs (4 eltrombopag,
14,33–35
1 rituximab,
37
and 3 romiplostim
39,40
).
All 12 RCTs reported on some measure of overall platelet
response, with studies of TPO-RAs using a definition centered on a
platelet count threshold of ≥50 ×10
9
/L and rituximab studies utilizing
a lower threshold of ≥30 ×10
9
/L (Table 3). Across TPO-RA studies,
which enrolled both splenectomized and non-splenectomized
patients, the overall platelet response tended to be higher in patients
receiving eltrombopag or romiplostim compared with patients in the
respective placebo/SOC arms (Figure 2). The calculated response ratio
comparing the rate of overall platelet response in eltrombopag vs pla-
cebo patients ranged from 1.40 (95% CI: 0.27-7.18) to 13.24 (95% CI:
1.98-88.62).
14,32–35
For studies of romiplostim, the response ratio ran-
ged from 1.50 (95% CI: 0.22-10.22) to 34.28 (95% CI:
2.20-533.41).
15,38–40
The two studies comparing rituximab to placebo
in non-splenectomized patients were generally null, demonstrating no
significant effect of intervention. The response ratio comparing the
overall platelet response in rituximab vs placebo patients was 0.86
(95% CI: 0.60-1.22) calculated from the Arnold et al. study
36
and 1.09
(95% CI: 0.85-1.40) calculated from the Ghanima et al. study
37
(Figure 2).
Complete platelet response was evaluated in seven tri-
als.
14,15,33,34,36,37
The definition of this measure varied considerably
across these studies, but most required a demonstrated minimum plate-
let count (eg, 50 or 100 ×10
9
/L) over a specified period of time
(Table 3). Across all three treatments evaluated, response rates tended to
be higher in patients receiving one of the treatments vs those in patients
receiving placebo or SOC (Figure 3). Similar to the data around overall
platelet response, the differences in complete platelet response between
treated and placebo/SOC patients were greatest among studies of
eltrombopag (rate ratios ranging from 4.32 [95% CI: 1.87-9.98] to 6.60
[95% CI: 0.41-105.81])
14,33,34
and romiplostim (rate ratios: 12.80 [95%
CI: 1.86-88.07] and 16.88 [95% CI: 1.06-268.42]).
15
Duration of response during the active, blinded treatment period
was reported in three of the 12 RCTs (Table 3).
33,37,40
In a trial of
eltrombopag administered daily for 6 months, the maximum continu-
ous response was a median of 8.1 weeks among eltrombopag patients
and 0 weeks among placebo patients.
33,41
A study of rituximab exam-
ined the median time to relapse after achieving overall or complete
platelet response following four weekly infusions of rituximab.
37
Median time to relapse over a 78-week observation period in patients
who achieved overall response was 36 weeks (IQR: 13-not reached)
in the rituximab group and 7 weeks (IQR: 5-69 weeks) in the placebo
group (P= 0.014). Similarly, median time to relapse in patients who
achieved complete response was 76 weeks (IQR: 31-not reached) and
49 weeks, respectively (P= 0.19). In a study of romiplostim given
weekly for a 12-week period, the median duration of platelet
response (interquartile range [IQR]) was 11 weeks (9-12) in the romi-
plostim group and 0 weeks (0-0) in the placebo group (P< 0.0001).
40
Rates of rescue therapy use were reported in four of the
12 trials,
15,33,36,40
and rescue therapy was generally defined as any
new treatment measure (or increase in dose of current treatment)
aimed at increasing platelet counts (Table 3). The rates of rescue ther-
apy use in patients receiving a therapy of interest vs patients receiving
placebo or SOC were consistently lower in the treatment arms across
the studies, corresponding to a range of rate ratios of 0.28 (95% CI:
0.13-0.59) in a study of romiplostim
15
to 0.67 (95% CI: 0.41-1.08) in a
study of rituximab
36
(Figure 4).
Bleeding was assessed in 10 of the 12 studies and was treated as
a measure of both efficacy and safety.
14,15,32,33,36–40
The assessment
of symptoms and events of bleeding varied across the studies, utilizing
a combination of the World Health Organization scale of bleeding, the
Adverse Events Reporting System of bleeding events by grade, and
the ITP bleeding score (Table 3). In general, bleeding rates in patients
FIGURE 2 Overall platelet response in trials of eltrombopag, rituximab, or romiplostim. Calculated response ratios comparing the overall platelet
response of patients receiving eltrombopag, rituximab, or romiplostim vs that in patients receiving placebo or standard of care
126 BYLSMA ET AL.

receiving one of the TPO-RAs romiplostim or eltrombopag (among
both splenectomized and non-splenectomized patients) tended to be
lower than those in the placebo or SOC arm (Figure 5), although none
of the individual results were significant. For studies of eltrombopag,
bleeding was up to 89% less likely in eltrombopag patients vs those
receiving placebo,
14,32,33
but in one study, the rate ratio was 1.16
(95% CI: 0.35-3.89),
32
indicating similar rates of bleeding in the
eltrombopag and placebo arms. In trials of romiplostim, the occur-
rence of bleeding events or symptoms was 25% to 81% less likely in
romiplostim patients vs those receiving placebo/SOC (range of rate
ratios: 0.19 [95% CI: 0.01-3.75] to 0.75 [95% CI: 0.39-1.42]).
15,38–40
Both rituximab trials that reported rates of bleeding were conducted
in non-splenectomized patients and observed slightly lower but similar
bleeding rates between patients receiving rituximab and placebo
36,37
(Figure 5).
No studies represented prospective RCTs with splenectomy and
a placebo or SOC arm, but surgical splenectomy has been well-studied
and still represents an important treatment option for ITP patients in
the second-line setting. Among the 83 studies evaluating splenec-
tomy, the reported rates of complete response rates ranged from
37.3%
42
to 100%
43
with a median complete response rate of 70.5%
across studies. The median partial response rate was 13.5% (range
FIGURE 3 Complete platelet response in trials of eltrombopag, rituximab, or romiplostim. Calculated response ratios comparing the complete
platelet response of patients receiving eltrombopag, rituximab, or romiplostim vs that in patients receiving placebo or standard of care
FIGURE 4 Rescue therapy use in trials of eltrombopag, rituximab, or romiplostim. Calculated rate ratios comparing the rate of rescue therapy use
among patients receiving eltrombopag, rituximab, or romiplostim vs that in patients receiving placebo or standard of care
BYLSMA ET AL.127

0%
43
to 88%
44
) and the overall response rates ranged from 63.4%
45
to 100%
43,46–49
, with a median of 86.5%. The median duration of
response was reported in five studies, ranging from 29.5 months
50
to
120 months
51
with a median of 81 months. The rate of relapse ran-
ged from 0%
52
to 81.8%
53
with a median rate of 20%, and the median
rate of significant bleeding was 4.76% (range 0%
54
to 28.1%
55
). Mor-
tality rates ranged from 0% among multiple studies to 28.8%
56
(over a
median follow-up time of 18 years) (median 2% across studies).
4|DISCUSSION
This systematic review identified published reports of interventional
and observational studies that have evaluated the efficacy/effective-
ness and safety of therapies used to treat adults with primary ITP in
the second-line setting. All therapies of interest were represented in
the studies identified, and the majority of studies were observational
(and primarily retrospective) in nature.
For the majority of non-surgical treatments, including azathio-
prine, cyclophosphamide, cyclosporine, danazol, dapsone, mycophe-
nolate mofetil, vinblastine, and vincristine, there were limited
published reports of any kind. Just over 11% of all 186 reports meet-
ing our inclusion criteria focused on at least one of these agents, and
only 5 studies (<3% of total) investigated one of these agents as a
monotherapy in a prospective, interventional manner. Of note, four of
these studies were conducted over two decades ago. Therefore, it is
not surprising that although these agents may have promise in treat-
ing ITP and are therefore listed as potential second-line treatments in
the International Consensus Report on the management of primary
ITP,
1
the 2011 ASH practice guidelines for ITP do not specify these
agents in their formal recommendations, stating that research on
these therapies is “inadequate to allow evidence-based recommenda-
tions on appropriate indications or timing.”
19
Our recent review of the
literature suggests that this is still the case.
Although no head-to-head RCTs directly comparing one second-
line therapy of interest to another were found, we identified 12 pro-
spective RCTs with a placebo or SOC arm evaluating the safety and
efficacy of either eltrombopag (5 studies), rituximab (2 studies), or
romiplostim (5 studies). Among endpoints/outcomes of interest, at
least two of these studies measured and reported some form of over-
all platelet response (all 12 studies), complete platelet response
(7 studies), use of rescue therapies (4 studies), and occurrence of
bleeding symptoms or events (10 studies). There are an insufficient
number of studies for each outcome to conduct a meta-analysis. The
rate or risk ratios calculated from each trial provide important infor-
mation on the safety and efficacy of the treatment studied and offer
insights on how these therapies compare with one another in treating
adult ITP in the second-line setting.
In terms of efficacy, the most compelling evidence stems from
the trials of eltrombopag
14,32–35
and romiplostim.
15,38–40
Without
exception, across the 10 studies, patients treated with one of these
therapies tended to have higher rates of overall and complete platelet
responses compared with patients receiving placebo or SOC. Bleeding
and use of rescue therapies were also generally lower in patients
receiving one of these TPO-RA agents. Importantly, longer-term,
open-label studies of these treatments have demonstrated that effi-
cacy is maintained and that the treatments are safe and well-tolerated
over longer periods of exposure.
57,58
In a study of patients treated
with eltrombopag for up to 3 years, platelet counts of ≥50 ×10
9
/L
and a doubling of platelet counts from baseline were maintained for a
median of 73 weeks over 104 weeks of treatment (n = 147) and
109 weeks over 156 weeks of treatment (n = 32) with no new or
increased risk of safety issues.
58
In a study of 291 patients treated
with romiplostim for up to 5 years (representing 614 patient-years of
exposure), the median percentage of time on study with a platelet
count ≥50 ×10
9
/L was 92% (IQR: 62-100), with a low rate of bleed-
ing and infrequent need for rescue therapy.
57
Most patients (63%)
FIGURE 5 Bleeding in trials of eltrombopag, rituximab, or romiplostim. Calculated rate ratios comparing the rate of bleeding in patients receiving
eltrombopag, rituximab, or romiplostim vs that in patients receiving placebo or standard of care
128 BYLSMA ET AL.

responded after just one dose of romiplostim, and the proportion of
patients with a platelet ≥50 ×10
9
/L remained between 62% and 78%
through week 212. Eltrombopag and romiplostim are both agents that
interact with the TPO receptor to trigger platelet production and are
indicated for the treatment of thrombocytopenia in the second-line
setting and beyond in patients with chronic ITP who have had an
insufficient response to corticosteroids, immunoglobulins, or
splenectomy.
59–62
Results from the two rituximab studies, which were both con-
ducted exclusively in non-splenectomized patients, provided less con-
clusive results.
36,37
In the Canadian pilot study of rituximab plus
standard of care vs placebo conducted by Arnold et al.,
36
no differ-
ence between rituximab and placebo groups were observed after
6 months with respect to the composite outcome of platelet response,
significant bleeding, or rescue treatment. In the more recent study of
rituximab vs placebo in the second-line treatment of adult ITP patients
in Norway, Tunisia, or France, Ghanima et al.
37
also did not detect a
difference in the rates of treatment failure (a composite endpoint of
splenectomy or meeting criteria for splenectomy), response, or
relapse. However, authors noted that a small benefit with rituximab
cannot be ruled out based on the longer duration of response with
rituximab that was observed in those who achieved an overall
response (but not in those who achieved a complete response) and
the numerically higher response rates observed with rituximab. This
assertion is supported by data from a study of 72 adults with chronic
ITP who were treated with the standard dose of rituximab of 4 weekly
infusions and had demonstrated initial response to rituximab, defined
as a documented ongoing platelet count of ≥50 ×10
9
/L for 1 year
after the first infusion without additional ITP treatment.
57
After a
median follow-up of 3.8 years, 64% of these adults maintained their
response to rituximab. Authors used these data, in combination with
data from published reports, to estimate that the 1-year and 5-year
response rates for adults treated with rituximab are 38% and 21%,
respectively. Importantly, rituximab, an anti-CD20 antibody, is cur-
rently not approved for the treatment of ITP but is widely used in this
setting.
63
However, as Ghanima et al.
37
point out, their placebo-
controlled study of rituximab emphasizes the need for additional RCTs
to assess the efficacy and safety of treatment in this setting before
implementation and cautions against relying on evidence from uncon-
trolled studies.
Although not formally studied as a treatment arm in any prospec-
tive RCT, splenectomy is widely covered in the literature. Importantly,
it is still generally recommended as the standard therapy for patients
with chronic ITP, given the high probability of durable platelet
response.
1,11,19
However, this invasive surgical procedure is not with-
out risk; perioperative and short-term and long-term postoperative
complications, such as infections, thromboembolic events, and
increased risk of certain malignancies including buccal, esophageal,
colon, liver, pancreatic, lung, prostate, and hematopoietic cancers have
been observed.
64,65
Additionally, there is currently no ability to reli-
ably predict who will respond, and there is evidence that a portion of
non-splenectomized patients will experience late remissions either
spontaneously or with continuing medical treatment.
22,66,67
Due to
these issues and because of the availability of medical alternatives,
splenectomy may not be the “go-to”treatment it once was for
patients requiring second-line therapy,
21
as evidenced by recent tem-
poral trends in the uptake of splenectomy.
17,18
For example, in a study
conducted in Denmark, the 1-year cumulative incidence of splenec-
tomy among patients with ITP for a duration of at least 6 months
decreased in recent years, from 10% for those diagnosed in 1996
through 2001 to 3% for those diagnosed in 2008 through 2012.
18
With fewer patients undergoing splenectomy in the second-line set-
ting, there is a need to further investigate the potential for medical
treatments to delay or obviate the need for splenectomy.
Drawing specific treatment recommendations from this review is
challenging. There was a paucity of data for several of the therapies of
interest, namely azathioprine, cyclophosphamide, danazol, dapsone,
mycophenolate mofetil, and vinca alkaloids, making it difficult to
assess the relative value of these treatments in this setting. Small sam-
ple size and rarity of events also resulted in a lack of precision for
some outcomes. Additionally, comparability of data across the studies
was somewhat limited by a lack of consistency in the outcomes mea-
sured and varying outcome definitions. Although recommendations
on standard terminology, definitions, and outcome criteria in ITP were
developed by an International Working Group nearly a decade ago,
68
they have not been widely adopted, even in the clinical trial setting.
For example, while some studies reported complete, partial, or overall
response, others reported rates of remission and relapse or pre-
treatment and post-treatment median platelet counts. Even when the
same measure was assessed in multiple studies, the definition of that
measure was not uniform across investigations. This was particularly
evident in the use of bleeding scales across studies, as not all scales
were validated for use in ITP and some were designed to report toxic-
ity of chemotherapeutic agents. Of note, the International Working
Group did not recommend a specific bleeding scale for use in clinical
trials or cohort studies. Also, data availability on safety outcomes was
particularly problematic, as it depended on the study design (eg, RCT
vs retrospective cohort study), data source (eg, RCT vs electronic
health record data), and therapy being investigated (eg, splenectomy
vs romiplostim). Future reviews of this nature and interpretation of
the data for clinical utility and potential drug development would ben-
efit greatly from uniform use of the previously established standard-
ized terminology and extension of standardized terminology to
severity of bleeding in ITP.
Despite these limitations, this systematic review of the literature
provides a comprehensive and updated view of the evidence around
the safety and efficacy/effectiveness of second-line treatments for
adult primary ITP based on nearly 200 studies conducted in several
populations worldwide. It confirms that a gap remains: outside of the
TPO-RAs eltrombopag and romiplostim, the majority of treatment
options for managing recurrent or persistent thrombocytopenia are
still without rigorous evidence from RCTs to demonstrate safety and
efficacy in this setting, and many treatments have limited supportive
evidence of any kind. These findings are echoed in a recent review,
although not systematic in nature but based on extensive clinical
experience, where Lambert and Gernsheimer
10
conclude that for the
second-line treatment of adult ITP patients with persistently low
platelet counts and bleeding, evidence to date supports medical alter-
natives to splenectomy, specifically in the context of both TPO-RAs,
BYLSMA ET AL.129

which are now backed by long-term follow-up data on efficacy and
safety.
69,70
It is worth noting that since the publication of the most recent
International Consensus Report and ASH guidelines on the manage-
ment of primary ITP,
1,19
fostamatinib, a spleen tyrosine kinase (Syk)
inhibitor, was approved in April 2018 by the US Food and Drug
Administration for the treatment of chronic ITP in adults who have
had an insufficient response to prior therapy. This was based on two
parallel phase 3 placebo-controlled RCTs conducted in Australia,
Europe, and North America that studied a total of 150 patients with
persistent or chronic ITP, of whom 101 received fostamatinib.
71
In the
pooled analysis of the two studies, 18% of patients who received fos-
tamatinib achieved a stable response by week 24 (vs 2% in the pla-
cebo group, P= 0.0003), defined as platelet counts ≥50 ×10
9
/L
without rescue medication on at least 4 of the 6 clinic visits occurring
every 2 weeks during weeks 14 through 24. Overall response, defined
as at least one platelet count ≥50 ×10
9
/L within the first 12 weeks,
was assessed as a post hoc endpoint and was achieved in 43% of fos-
tamatinib patients (vs 14% in the placebo group, P= 0.0006). Of note,
these studies included patients with long-standing ITP (median dura-
tion of 8.5 years), a median of 3 unique prior ITP treatments, and an
average baseline platelet count <20 ×10
9
/L. This may represent a
promising new treatment for ITP with a unique mechanism of action,
but additional research is needed to further assess its long-term clini-
cal efficacy and safety and identify those most likely to respond. It
remains to be seen if and how this therapy will be incorporated into
future ITP management guidelines.
Ideally, more randomized and controlled clinical studies would be
conducted to properly assess the risk: benefit profile of any existing
or new treatment by itself or against other options in this setting.
Alternatively, given the rarity of both ITP and any potential adverse
events associated with a given therapy, well-designed non-
interventional studies using large population-based sources of data,
such as those from administrative claims databases, electronic health
record databases, or disease-specific or treatment-specific registries,
could offer valuable evidence on the real-world effectiveness and
safety and comparative effectiveness and safety of available treat-
ments.
72
In the absence of such studies, clinical expertise, patient
preference and shared decision making will continue to be the primary
drivers of treatment decisions rather than high-quality clinical trial evi-
dence or robust observational studies.
ACKNOWLEDGMENT
This study was supported in part by research funding from Amgen Inc
to EpidStat Institute.
CONFLICT OF INTERESTS
LCB and JPF are employees of EpidStat Institute and CB consults for
EpidStat Institute. EpidStat Institute received funding from Amgen Inc
for this research and from Amgen Inc, Merck, Genentech, Sanofi, and
AstraZeneca for other research.
KC, FC, and BM are employees of Amgen Inc and own stock in
Amgen Inc.
JSW receives research support from Amgen and is a consultant
and advisory board member for Amgen. JSW has consulted for Novar-
tis and is on the Speakers Bureau for Novartis. JSW also receives
research funding from Merck, Incyte, and Pfizer.
AUTHOR CONTRIBUTIONS
LCB, JPF, KC, FC, CB, BM, and JSW contributed to the design and
execution of the systematic literature review, including data collection
and organization. FC performed the statistical analysis of the data.
LCB, JPF, KC, FC, CB, BM, and JSW assisted in analyzing and inter-
preting the data. LCB developed the first draft of the manuscript, and
JPF, KC, FC, CB, BM, and JSW made significant contributions to the
final version of the manuscript.
ORCID
Lauren C. Bylsma https://orcid.org/0000-0002-3091-6090
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Sup-
porting Information section at the end of the article.
How to cite this article: Bylsma LC, Fryzek JP, Cetin K, et al.
Systematic literature review of treatments used for adult
immune thrombocytopenia in the second-line setting. Am
J Hematol. 2019;94:118–132. https://doi.org/10.1002/ajh.
25301
132 BYLSMA ET AL.