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

444 American Society of Hematology


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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

Hematology 2012 445


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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

Hematology 2012 447


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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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