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Transcript of Hematology 2012 Journeycake 444 9 (1)
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7/28/2019 Hematology 2012 Journeycake 444 9 (1)
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Childhood immune thrombocytopenia: role of rituximab,
recombinant thrombopoietin, andother new therapeutics
Janna M. Journeycake1
1Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX
Childhood immune thrombocytopenia (ITP) is often considered a benign hematologic disorder. However, 30% of
affected children will have a prolonged course and 5%-10% will develop chronic severe refractory disease. Until
recently, the only proven therapeutic option for chronic severe ITP was splenectomy, but newer alternatives are now
being studied. However, because immunosuppressive agents such as rituximab are not approved for use in ITP and
the thrombopoietin receptor agonists are not yet approved in children, the decision to use alternatives to splenectomy
needs to be considered carefully. This review describes the factors that should affect decisions to treat ITP at diagnosis
and compares the options for the occasional child in whom ITP does not resolve within the first year.
IntroductionChildhood immune thrombocytopenia (ITP) affects 4-6 of
100 000 children per year. In 2010, the International Working
Group proposed changes in the nomenclature and classification of
ITP. The disorder is now more appropriately called immune
thrombocytopenia rather than idiopathic thrombocytopenic purpura
and is defined as a platelet count 100 109/L not explained
by any other cause.1 Newly diagnosed ITP refers to the time from
onset of thrombocytopenia to 3 months later; whereas persistent
ITP is from 3-12 months after diagnosis. Chronic ITP is defined as
a platelet count that has been 100 109/L for longer than
12 months. Refractory ITP now refers to severe ITP that persists
after splenectomy. Before splenectomy, patients with ITP are
divided into responders and nonresponders to the different treatment
modalities.1 Presentation of ITP may be dramatic, with extensive
soft tissue bruising and mucosal hemorrhage, but it is more often aself-limiting condition. Approximately one-third of children will
have persistent/chronic ITP with ongoing thrombocytopenia more
than 6 months after diagnosis, and 5%-10% will develop severe,
chronic, and/or refractory disease.2 Other than splenectomy, there is
limited experience in the management of the child with a severe and
prolonged course of ITP. However, new agents are being explored
in children that may offer relief from bleeding symptoms, increase
quality of life, and allow for avoidance of splenectomy.
Treatment considerations for newly diagnosed ITPAlthough there are no new treatment options for newly diagnosed
ITP, changing trends in practice should be noted. Traditionally, drug
therapy is prescribed to raise the platelet count and prevent serious
and/or life-threatening bleeding, particularly intracranial hemor-
rhage (ICH) and other bleeding requiring transfusions. However,
such bleeding is uncommon in children. Neunert et al, for the
Intercontinental Cooperative ITP Study Group (ICIS), reported that
the rate of serious bleeding upon diagnosis of ITP in children with
platelet counts 20 109/L was only 3%. Among the group who
had minor or no bleeding at presentation, the rate of new serious
bleeding (ie, gastrointestinal, oral, or nasal) in the first 28 days was
only 0.6% irrespective of initial drug therapy.3 In addition, Psaila et
al specifically evaluated potential risk factors for ICH and demon-
strated that the majority of children who present with or develop
ICH have platelet counts 10-20 109/L, bleeding manifestations
beyond petechiae and ecchymoses (particularly hematuria), and a
high rate of reported head trauma.4
Since the early 1990s, the United Kingdom has adopted a minimal-
istic treatment approach to children with little or no bleeding at
diagnosis of ITP, with only 16% of children now receiving drug
therapy compared with 61% in 1995.5 The United States has not
experienced this same trend, but it is now recommended to consider
observation alone for patients without clinically significant bleeding
regardless of platelet count.6 The decision to treat should not be
based solely on platelet count, but also on the severity of the
associated bleeding, reliability of family for close follow-up, and
potential loss or gain of quality of life.
For the children who do require drug therapy, primary options
remain corticosteroids, IVIg, and anti-D Ig. The most recent change
in the use of these medications relates to anti-D Ig. Anti-D has been
given a black box warning by the US Food and Drug Administration
(FDA) for rare but serious and potentially life-threatening intra-
vascular hemolysis. Anti-D is still recommended as a safe and
effective first-line therapy for Rh children without splenectomy
who do not present with anemia, but it is no longer licensed or
available in some countries.6-9
Treatment options for nonresponders and/or patients
with chronic ITPIf a child has persistent severe bleeding symptoms that have not
responded to conventional-dose corticosteroids, IVIg, or anti-D or
has had persistent and marked thrombocytopenia for longer than
6-12 months, other considerations are necessary. The initial step is
to ensure that the diagnosis is correct.10 Table 1 shows alternative
causes of thrombocytopenia that may not respond to traditional
first-line ITP therapy. Second, treating physicians need to determine
whether the severity of symptoms warrants aggressive therapy.
Unlike adults with ITP, many children with chronic disease will not
have major bleeding symptoms and will likely recover within an
additional 12-24 months. Therefore, continued observation may be
the only therapy indicated. The dilemma for pediatric hematologists
is to determine the best second-line therapy for the symptomatic
children, with the goals being increase of platelet count, resolution
of bleeding, and increased quality of life.
NOT SO BENIGN HEMATOLOGIC ISSUES IN CHILDREN
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The available treatments take into consideration all possible mecha-
nisms for thrombocytopenia in ITP. The primary cause for thrombo-
cytopenia is immune destruction of platelets in the reticuloendothe-
lial system, and splenectomy is a proven modality to achieve a
long-term improvement of platelet count.11 However, other ap-
proaches have been shown in small numbers of children to suppress
either B-cell or T-cell dysfunction and the resultant antiplatelet Ab
production.12 The best-studied medication is rituximab, as described
further below (see Rituximab). Finally, platelet production is
decreased in the BM of patients with ITP, likely due to Abs against
megakaryocytes.10,11,13 This supports the use of thrombopoietin(TPO) receptor agonists, as described more fully in a later section.
These next sections will discuss the mechanism of action and the
risks and benefits of these modalities.
Splenectomy
Mechanism of action and efficacySplenectomy remains the most predictable method for achieving a
durable response in ITP. Nearly 85% of patients undergoing
splenectomy will have an immediate platelet response and close to
70% will maintain them at 5 years. Splenectomy is successful
because it removes the primary site of platelet destruction and a site
of antiplatelet Ab production. Unfortunately, the ability to predict
response to splenectomy is not well defined. There are mixed results
in studies suggesting that prior response to corticosteroids and IVIg
may be predictive.14-16 There is also no reliable radionuclide
imaging test to recognize which patients may have sequestration of
platelets in the liver that would diminish the response to surgery. 17
If relapse occurs, it is generally within in the first 2 years after
splenectomy. At this point, the patient should have evaluation for
and removal of accessory spleen. If there is no spleen to remove,
then alternative therapies such as rituximab or TPO receptor
agonists should be considered, because they have been shown to be
equally efficacious in splenectomized and nonsplenectomized
patients.17
SafetyBefore splenectomy, it is important to determine that the patientdoes not have an underlying disease giving rise to secondary
ITP.6,7,10 For example, performing splenectomy in patients with
primary immunodeficiency may be deleterious. In children, addi-
tional considerations for delaying splenectomy include the particu-
larly high rates of spontaneous remission. Exceptions would include
emergency bleeding or severely diminished quality of life due to
unresponsive disease. Because children younger than 5 years of age
are more susceptible to overwhelming infection from encapsulated
organisms, it is recommended to delay splenectomy until after that
age.10 However, with the advent of more effective vaccines against
Haemophilus influenza, Neisseria meningitidis, and Streptococcus
pneumoniae and the use of prophylactic penicillin, the risk of death
from these organisms has been reduced substantially.6 Children
undergoing splenectomy should be vaccinated against all encapsu-
lated organisms 2 weeks before surgery if possible and receive
booster immunizations every 5 years. Prophylactic penicillin or an
equivalent antibiotic should be prescribed to all children 5 years
of age and to older children for at least 2 years after surgery because
that is the highest-risk period for overwhelming infection.10
Laparoscopic splenectomy is considered safe. However, bleeding ispossible, particularly if platelet counts are less than 20 109 at the
time of surgery. In 2 large pediatric case series on the outcome of
laparoscopic splenectomy (390 children, 83 with ITP), no deaths
were reported. Perioperative bleeding occurred in 1%-5%, and
conversion to open splenectomy occurred 1.7%-5%.18,19 Portal vein
thrombosis in the immediate postoperative period has also been
reported in children.17,18 In addition to the long-term risk of sepsis,
postsplenectomy patients have to be monitored for late thrombotic
events. Although the rate of venous thrombosis, atherosclerosis, and
pulmonary hypertension is unknown for patients undergoing splenec-
tomy specifically for ITP, these complications are well described
after splenectomy in other hematologic diseases such as hereditary
spherocytosis and thalassemia.7,17,20
Even though splenectomy is a relatively safe and effective treat-
ment for severe and nonresponsive ITP, it is an irreversible
procedure that places young children at high susceptibility for
complications for many years. Table 2 compares the risks and
benefits of the splenectomy to the newer agents described in the
following sections.
Rituximab
Mechanism of actionRituximab depletes B cells by binding to the CD20 antigen surface
markers. By removing the autoreactive B-cell clones, autoimmunity
can be eradicated.21 In addition, rituximab has been shown to
increase numbers of T-regulatory cells and prevent the activity ofTh1-autoreactive cells specifically against GPIIb/IIIa.12 Although
it is not FDA approved for the treatment of ITP, we have more than
5 years of experience in the use of rituximab as a second-line option
and numerous additional reports of its safety and efficacy in
malignant and rheumatologic diseases.
EfficacyThere are no randomized trials for rituximab in children with ITP,
but in 4 cohort studies and 10 case reports, there is evidence that
children with chronic ITP have an overall response rate of 61%.21
The first long-term follow-up study for both adults and children with
ITP described an initial response rate of approximately 60%. 22 In
children, nearly 60% of the initial responders maintained plateletcounts 50 109/L for longer than 1 year and had a greater than
80% chance of maintaining the response at 2 years. An estimated
26% of children will have a 5-year durable response. One theory for
the lack of sustained response to rituximab is the persistence of
autoreactive B cells in the germinal centers and the BM.12 In
addition, the majority of plasma cells are preserved in patients
receiving anti-CD20 Ab therapy.12
The good initial response rate of 68% (33%-100%) in children with
primary ITP was confirmed by Liang et al in a systematic review of
children only.23 Patients with secondary ITP had an even better
response at 64%-100%. The median time to response was 3 weeks,
Table 1. Non-ITP causes of thrombocytopenia
Infectious (HIV, hepatitis C, Helicobacter pylori, CMV)
Systemic lupus erythematosus
Antiphospholipid syndrome
Autoimmune lymphoproliferative syndrome
Primary immunodeficiency (common variable immunodeficiency, IgA
deficiency)
Liver disease
BM failure syndromes
MalignancyInherited thrombocytopenia
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with a median duration of response of 12.8 months. Liang et al
pointed out that there is no standard dose for rituximab in
children. Although the most frequently administered dose remains
375 mg/m2 for 4 consecutive weeks, there are small series of
children who had similar response rates with a single dose of
375 mg/m2 or after lower doses regimens of 100 mg/dose for
4 weeks.23,24 Because late relapses are possible after achieving
remission with rituximab, ongoing follow-up is necessary.22 Re-
peated doses of rituximab can be considered for relapsed patients.
Several studies have investigated predictors of response to ritux-
imab. Patel et al determined that age, sex, prior duration of ITP, and
previous response to therapy did not predict response to rituximab.22
Although previous splenectomy did not affect the overall response
rates, those who had undergone the procedure tended to relapse
earlier. Children with only partial responses to alternative therapies
initially relapsed more frequently after rituximab than those with
complete responses.22 The most recent publication by Grace et al
found in a multivariate analysis that previous response to corticoste-
roids and history of secondary ITP predicted better response.25
Those investigators theorized that there is an overlapping biology of
response between glucocorticoids and rituximab in how they target
both the B-cell and T-cell arms of the immune system.
Although there are no randomized trials comparing rituximab with
splenectomy for long-term treatment of ITP, 2 randomized trials
explored rituximab use in adults before splenectomy. The first study
comparing rituximab dexamethasone to dexamethasone alone for
newly diagnosed ITP demonstrated a higher rate of sustained
responses in those receiving rituximab.
26
The second trial comparedrituximab with placebo in patients nonresponsive to first-line
therapy. Interestingly, the placebo-controlled study demonstrated
no statistical difference in rate of treatment failures, and the overall
response rates for both groups was still close to the expected 60%. 27
These trials and a recent meta-analysis of adults who received
rituximab before splenectomy suggest that surgery could be delayed
and maybe avoided altogether for patients likely to go into
remission.28
SafetyThe most common adverse reaction to rituximab occurs at the first
infusion, after which fever, serum sickness, and hypotension have
Table 2. Comparison of second-line therapies for severe/nonresponsive chronic ITP
Splenectomy Rituximab Romiplostim Eltrombopag
FDA approved Accepted therapy No Adults only Adults only
Recommended age 5 y Any Possibly less effective in
younger children
Possibly less effective
in younger children
Administration Laparosco pic vs open
surgery
375 mg/m2 IV weekly 4
375mg/m2 IV 1
100mg weekly IV 4
1 g/kg subcutaneously
weekly; titrate dose
based on weekly
platelet count
(maximum dose,
10 g/kg)
50-75 mg by mouth
daily take on empty
stomach; titrates
dose based on
weekly platelet count
(maximum dose,
75 mg)
Initial response rate 70%-85% 60%-68% 80%-88% 50%
5-year response rate 60%-70% 26% Unknown Unknown
Onset of action Immediate Weeks Weeks Weeks
Predictors of response response to prior therapy;
demonstration of no
hepatic sequestration
Response to
corticosteroids;
secondary ITP
Unknown Unknown
Infection r isk High r isk; n eeds p revention
(vaccines/antibiotics);
higher risk in secondary
ITP?
Potential risk; B-cell
depletion for 3-6 mo;
lackof response to
immunizations;
hypogammaglobulinemia;
higher risk if pretreated
with immunosuppressive
agents and after multiple
doses
Low risk Low risk
Thrombosis risk Potential risk Low risk Possible risk Possible risk
Malignancy risk Low risk Potential risk Myelofibrosis Myelofibrosis
Liver disease risk Low risk Potential reactivation of
hepatitis
Low risk Transaminitis
Cataract risk Low risk Low risk Low risk Worsening of cataracts
Pretreatment plan Vaccinate against
encapsulated organisms
Baseline hepatitis status;
baseline Igs; up to date
on immunizations
Consider bone marrow
biopsy
Baseline liver function;
baseline eye
examination;
consider bone
marrow biopsy
Posttreatment plan Booster immunizations every
5 y; antibiotic prophylaxis
Yearly Igs;routine platelet
counts
Weekly platelet counts;
BM tests yearly for
fibrosis
Weekly platelet counts;
routine liver function
studies; BM tests
yearly for fibrosis;
routine eye
examinations
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been reported. Serum sickness occurs more frequently in children
than adults and slowing the infusion and premedication with
antihistamines or corticosteroids may minimize these side effects.21
The severity of reactions decreases with subsequent doses. 17,21-23
Infection is a concern after administration of any immunosup-
pressive agent. During the 3-6 months before reconstitution of
B cells, there have been reports in children of pneumonia, varicella,
meningoencephalitis, and reactivation of hepatitis C.23 Because
most plasma cells do not have CD20 on their surface, humoralimmunity should be spared and production of Igs maintained after
rituximab administration. However, there is a concern for hypo-
gammaglobulinemia, particularly after repeated treatments, which
has been reported in 1 child and 2 adults.22,23 Due to the risk of
hypogammaglobulinemia, it is recommended to check baseline Igs
before administration of rituximab and then yearly. If levels are
abnormal, supplemental IVIg is indicated.22 Because the majority of
vaccinations are given to young children, it is important to consider
how administration of rituximab will affect their immunogenicity.
Some experts recommend that vaccines be given before rituximab
or delayed until the B cells have recovered. 21
Neutropenia, progressive multifocal leukoencephalopathy, hemato-
logic malignancies, and acute respiratory distress syndrome have
also been described with rituximab use.21 Most reports of toxicity
are not in ITP patients, but in older adults and in young children
with autoimmune hemolytic anemia, combined variable immuno-
deficiency, and other disorders requiring additional immunosup-
pressive agents.21
Recombinant TPO and TPO receptor agonists
Mechanism of actionEndogenous TPO regulates platelet production by increasing the
number, ploidy, and maturation of BM megakaryocytes.13 TPO
is made in the liver, and its synthesis is consistent over time
unless there are reductions in the number of functioning hepato-
cytes. Because TPO is cleared by binding to platelet surface
receptors, when platelet production is reduced, less TPO is bound
and TPO levels increase. In ITP, there is only a small, if any,
increase in TPO.13
TPO receptor activation on megakaryocyte precursors leads to
increased number and maturation of cells and prevents apoptosis,
thereby increasing platelet production. This antiapoptotic effect of
TPO likely plays an important role in ITP, in which BM megakaryo-
cytes and precursors are increased in number but undergo apoptosis
mediated by antiplatelet IgG.13
In 1994, 5 institutions cloned and purified TPO, and in 1995, 2 first-
generation recombinant human TPO agents entered clinical trials.Recombinant human TPO was a full-length glycosylated protein
identical to endogenous TPO, and the second agent was a pegylated
recombinant human megakaryocyte growth and differentiating
factor identical to the first 163 amino acids of the native protein.
Both products had half-lives of 40 hours and increased platelet
counts in humans. Unfortunately, several subjects developed Abs to
endogenous TPO and subsequently new thrombocytopenia.13
Since then, 2 new TPO receptor agonists (romiplostim and eltrom-
bopag) have been studied extensively and are approved for the
treatment of chronic ITP in adults who have had an insufficient
response to corticosteroids, IVIg, and splenectomy.
EfficacyRomiplostim is a TPO mimetic formed from 4 14amino acid
peptides. The 4 chains increase its stability and effectiveness over
single-chain peptides. Because it has no homology to TPO, the risk
of immunogenicity seen with early agents is diminished. Only one
report of a transient neutralizing Ab against romiplostim itself has
been reported.29 In early animal and human studies, the response to
romiplostim was found to be dose dependent, and the effect begins
on day 5 and diminishes by day 28 after a single subcutaneous dose.
Romiplostim has been FDA approved since 2008, and the majority
of patients have had a very good response with an initial dose of
1 g/kg given subcutaneously each week.30,31 Nearly all patients
receiving romiplostim were able to discontinue or dose reduce other
immunosuppressive therapies and required fewer rescue treat-
ments. An open-label study of romiplostim in nonsplenectomized
patients demonstrated a reduced incidence of treatment failure,
which was defined as platelet count 20 109/L, bleeding events,
or need for splenectomy.30
In children, there has been one randomized clinical trial of
romiplostim and 3 recent case series. The trial was a phase 1/2 study
in children diagnosed with ITP for at least 6 months.32 The primary
outcome was safety, but efficacy was assessed as well. Outcome
measures included the total number of weeks the patients had a
platelet count 50 109/L, number of bleeding events with scores
of grade 2 or higher on the Buchanan and Adix scoring system, and
the percentage of patients with platelet count higher than 50 109/L
or greater than 20 109/L from baseline for 2 consecutive weeks.
Twenty-two children were enrolled (5 received placebo and 17 romi-
plostim).32 Romiplostim increased platelet count in 88% of pa-
tients and platelet counts were maintained at 50 109/L for a
median of 7 weeks in the treatment group and 0 weeks in placebo
group. The average weekly dose was between 1 and 10 g/kg. The
2 nonresponders in the treatment group had had prior splenectomy.
Twenty of the original 22 children are in the open-label continuation
study that is ongoing. A second report from this trial studied
health-related quality of life in the 22 enrolled children by using the
Kids ITP Tools quality of life scores. The results of this pilot study
suggest that using romiplostim decreased the parental burden from
the disease.33 Improvement in health-related quality of life has also
been demonstrated in adults taking TPO agonists.34 Three more
recent case series also demonstrated some efficacy of off-label use
of romiplostim in children with acute and chronic ITP, but the
response was variable, with younger children having a less robust
response.35-37
Eltrombopag is a small, nonpeptide TPO mimetic that has no
homology to endogenous TPO so it is not immunogenic. It binds to
the transmembrane region of the TPO receptor rather than the
TPO-binding site. Therefore eltrombopag does not compete withendogenous TPO and any effect it has is additive.38 Pharmaco-
kinetics are linear and dose dependent, with the half-life being
21-30 hours. It is orally administered with the starting dose of
50 mg daily.13 Polyvalent cations such as calcium, aluminum,
magnesium, and zinc also reduce the absorption of eltrombopag, so
this drug cannot be given within 4 hours of any foods or medications
containing these minerals.13 This dietary limitation may diminish its
utility in children even though it is given by the preferred oral route
rather than as an injection.
There are 2 randomized placebo-controlled phase 3 trials demonstrat-
ing efficacy. The RAISE trial in adults demonstrated an increased
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platelet count and decreased need for rescue treatment compared
with placebo. This effect was seen regardless of splenectomy
status.38 The other trial demonstrated a 59% response rate for
platelet counts 50 109/L at 6 weeks compared with 16% in the
placebo group.31 In the open-label expansion study, 86% of patients
achieved a platelet count 50 109/L, which remained in the
target range for more than 50% of the time on medication.12 The
second trial, PETIT, a randomized clinical trial of eltrombopag in
children, is currently in progress. The initial results in 15 patients
divided among 3 age cohorts were presented at the EuropeanHematology Association in June 2012. Fifty percent of children
with bleeding symptoms at the start of the study had a reduction of
events. The results suggest that children may require higher median
doses than adults at 70-75 mg in all age groups. 39
SafetyAfter more than 5 years of collecting data on patients receiving
romiplostim and eltrombopag, it can be seen that TPO receptor
agonists are well tolerated and reduce the need for rescue therapy
and ongoing immunosuppression. Adverse events during administra-
tion include headache, nasopharyngitis, and fatigue with romiplos-
tim and nausea and vomiting with eltrombopag.12
In the open-label extension studies, thromboembolic events were
reported with both agents. Although it is difficult to assess the
strength of the prothrombotic nature of these agents due to the
uncontrolled design of these extension studies, thrombosis is a
major concern with their long-term use. There did not appear to
be a correlation between platelet count increase and thrombosis, but
it is recommended that the target platelet range be limited to
50-100 109/L to minimize risk.12
There is also concern for myelofibrosis formation after prolonged
stimulation of megakaryocytes with TPO receptor agonists. This
was demonstrated clearly in mouse models, and there are reports of
reversible BM reticulin deposits in patients on romiplostim.12 In a
recent study of BM biopsies, Bioicchi et al demonstrated an increase
from baseline in cellularity and megakaryocyte hyperplasia in all
patients. In addition, there was a significant increase in reticulin
(grade MF-1) seen in the BM at a mean duration of 2.7 years on
therapy with TPO receptor agonists.40 Fortunately, there was no
collagen present, the BM function remained normal, and no patient
had chromosomal or molecular abnormalities identified. However,
because the TPO agents likely stimulate the same pathways that can
lead to myeloproliferative neoplasms, including the JAK2 pathway,
monitoring for BM changes is likely needed until there is more
definitive information about the risk of transformation to malignancy.
With eltrombopag specifically, there is a concern for liver toxicity
and dose reduction is required for use with hepatic insufficiency.12,13
Fortunately, the transaminitis resolves with discontinuation. An-other side effect that has been observed in animal studies of
eltrombopag and also reported in humans was the development
or worsening of cataracts and lens changes.13,30,31 Neither TPO
agent should be given to pregnant or nursing teens or adults becaue
it is likely to be transmitted to the fetus or milk through FcRn
receptors.12 Finally, the main concern for the practical use of TPO
receptor agonists is the indefinite duration of treatment required and
the need to see patients frequently to titrate the dose. Relapse rates
are high in patients who have interruption of therapy.12
The off-label use of TPO agents will likely benefit those children
with ITP hoping to delay or avoid splenectomy. These agents are
also a potential bridge for treating nonresponding symptomatic
children while awaiting spontaneous remission, although studies
in such settings have not been performed. In addition, these agents
will not replace corticosteroids or IVIg as initial therapy or rescue
medications because it takes an average of 2 weeks to see a
response.
Other agentsThere are multiple studies of other immunosuppressive agents
used in chronic refractory ITP in both children and adults. Although
they are not new, these agents include azathioprine, cyclophos-
phamide, danazol, dapsone, cyclosporine, sirolimus, and myco-
phenolate mofetil. These have been used as single agents or in
combination. However, the published evidence for their efficacy,
particularly in children, is controversial and limited and their use
should be reserved for patients refractory to all other therapies,
including splenectomy.10,12
ConclusionChildhood ITP is generally a self-limiting, benign hematologic
condition in which drug therapy may not be needed. However, we
have multiple options to consider for those children with severe
bleeding at presentation or those who develop prolonged symp-tomatic disease. Each has a unique side effect profile and the
final decision regarding which modality to choose will depend on
family/patient preference, quality of life, and evidence of durable
response. The new TPO agents are a promising alternative to
conventional therapies that need to be further explored in children
with problematic ITP.
DisclosuresConflict-of-interest disclosure: The author declares no competing
financial interests. Off-label drug use: Recombinant TPO and
rituximab in children.
CorrespondenceJanna M. Journeycake, MD, MSCS, Department of Pediatrics,
University of Texas Southwestern Medical Center at Dallas, 5323
Harry Hines Blvd, Dallas, TX 75390-9063; Phone: 214-456-8556;
e-mail: [email protected].
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