Diagnosis and Management of Immune Thrombocytopenia inthe Era of Thrombopoietin Mimetics

Howard A. Liebman1 and Vinod Pullarkat1

1Keck School of Medicine, University of Southern California, Los Angeles, CA

The recognition of that patients with Immune Thrombocytopenia (ITP) have functional thrombopoietin deficiency anddecreased platelet production due to immune-mediated megakaryocytic injury has challenged the traditional view ofthis disease as predominantly a disorder of antibody-mediated platelet destruction. The therapy of chronic refractoryITP has been transformed by the approval of the thrombopoietin minetics, romiplostim and eltrombopag, which haveshown remarkable efficacy in randomized trials. The use of these agents earlier in the disease course after failure ofcorticosteroid therapy remains controversial. In this article, we review the current data on the efficacy and safety ofthrombopoietin receptor agonists and discuss other therapies as well as diagnostic work up of ITP.

IntroductionImmune thrombocytopenia (ITP) is a heterogeneous autoimmunedisorder characterized by thrombocytopenia with or without muco-cutaneous bleeding manifestations. Because of its complex patho-physiology and its association with a variety of other disorders, ITPis best characterized as a syndrome sharing the common clinicalphenotype of immune-mediated thrombocytopenia.1

Definition and epidemiologyITP is an acquired disorder characterized by isolated thrombocyto-penia with a peripheral blood platelet count � 100 � 109/L in theabsence of any obvious initiating or underlying cause.2 Therefore,the diagnosis of ITP is one of exclusion and is based principally onpatient history, physical examination, complete blood count, andreview of the peripheral blood smear.3

The recent ITP international working group consensus report hasdivided the disorder into three phases: newly diagnosed ITP(� 3 months), persistent ITP (3 months-1 year), and chronic ITP(� 1 year).2 ITP can be further characterized as being either primary(idiopathic) or secondary to several associated disorders such asimmunodeficiency diseases, autoimmune-rheumatologic disorders,lymphoproliferative diseases, and certain chronic infections.2 It isestimated that � 20% of ITP cases in the United States aresecondary to other disorders.1 However, the incidence of secondaryITP worldwide may vary greatly, particularly in populations with ahigh incidence of HIV, hepatitis C, or Helicobacter pylori infection.

The incidence of newly diagnosed ITP in adults ranges from1.6-3.9 per 100 000 persons per year.4 Recent studies have found anincreased incidence and prevalence with advancing age.4 Thefemale-to-male ratio ranges from 1.2-1.9, with the female predomi-nance more evident among young to middle-age adults.4

Diagnostic approach to patients with suspected ITPA presumptive diagnosis of ITP is made by a careful history,physical examination, complete blood count, and review of theblood smear.3,5 Response to initial treatment with corticosteroids,intravenous immunoglobulin (IVIg), or anti-RhD supports thediagnosis and confirms the immune nature of the thrombocytopenia.However, additional investigation is necessary to exclude secondary

ITP and to provide additional information to assist with patientmanagement.

A complete blood count should reveal isolated thrombocytopeniawith normal white and red blood cell numbers. Anemia may exist ifthere has been significant acute or chronic blood loss or concomitantimmune hemolytic anemia (Evan syndrome). A careful review ofthe peripheral blood smear is mandatory to exclude other causes ofthrombocytopenia. Abnormalities in erythrocyte or leukocyte mor-phology may suggest an underlying BM disorder such as myelodys-plastic syndrome or a congenital cause of thrombocytopenia. Thepresence of a MYH9-related disorder may be suggested by leuko-cyte inclusion bodies. Many congenital thrombocytopenic disordersare associated with very large platelets (macrothrombocytopenia),which may also be reflected in an abnormally high mean plateletvolume. Increased numbers of small lymphocytes or lymphocyteswith granular inclusions may suggest a diagnosis of chroniclymphocytic leukemia or large granular lymphocytic leukemia withsecondary ITP. Pseudo-thrombocytopenia due to platelet clumpingshould be excluded, and if platelet clumping is seen on the bloodsmear, a repeat platelet count using a blood sample collected incitrate or heparin rather than EDTA should be performed. Thrombo-cytopenia resulting from thrombotic thrombocytopenic purpura orhemolytic uremic syndrome must be considered if the blood smearshows significant numbers of schistocytes.

The international working group on ITP recommended severaladditional laboratory tests to further assist in the diagnosis andmanagement of patients with primary ITP5 (Table 1). BM examina-tion has been recommended in patients refractory to ITP therapy orin those who relapse after an initial remission, patients withsystemic symptoms or atypical physical findings, and patientsbefore splenectomy.5 A BM aspirate and biopsy should be per-formed in patients older than 60 years and should include cytoge-netic studies and flow cytometry.5

Clinical presentation and natural history of ITP inadultsAdult patients with ITP are more likely to manifest disease with achronic course. Overall, �15% of patients remit within 1 year afterdisease onset, but rare late remissions occur, even among patientswho have failed splenectomy.6,7 Bleeding manifestations are the

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most common presenting symptoms in patients with ITP, but theincreased use of automated blood counts results in the frequentidentification of asymptomatic patients or patients with minimalbleeding. Therefore, it is uncertain whether there is a period of mildto moderate thrombocytopenia in adults before the development ofsevere thrombocytopenia with bleeding. In a study of 217 healthysubjects with incidentally discovered thrombocytopenia and plateletcounts between 100 � 109/L and 150 � 109/L, the 10-year probabil-ity of developing ITP as defined by platelet counts � 100 � 109/Lwas 6.9% (95% confidence interval: 4.0%-12.0%). The 10-yearprobability of developing autoimmune disorders other than ITP was12% (95% confidence interval: 6.9%-20.8%).8

Mucocutaneous bleeding, including petechiae, purpura, epistaxis,and gum bleeding, is the most common initial manifestation of ITP.Complications of internal bleeding or fatal intracranial hemorrhageare rare and more often occur in older individuals with additionalcomorbidities.6,7 Symptomatic bleeding is to a degree related to theplatelet count, with nearly all major bleeding occurring with plateletcounts � 30 � 109/L. Only in patients with hepatitis C–relatedthrombocytopenia does major bleeding appear to occur with somefrequency at higher platelet counts.9

The risk of bleeding and fatal hemorrhage in adults with severechronic ITP, defined as a platelet count of � 30 � 109/L at least1 year after diagnosis, was analyzed in a pooled analysis ofpublished clinical series comprising 1800 patients.10 The annualincidence of fatal hemorrhage was 1.6-3.9 cases per 100 patientyears, with a lower risk in patients � 40 years of age (0.4% peryear) compared with patients � 60 years of age (13% per year).10

The risk of nonfatal hemorrhage was estimated to be 3% per year inpatients � 40 years of age and 71% per year for patients � 60 yearsof age. However, it should be noted that this case series dated from1954 to 1991 and therefore did not include patients treated withnewer agents (eg, rituximab and thrombopoietin [TPO] receptoragonists) or managed with laparoscopic splenectomy.

Clinical presentation and natural history of ITP inchildrenThe peak age of presentation of ITP in children is between 5 and6 years, with 70% of cases presenting between ages of 1 and10 years.11 Approximately 50%-60% of children will have a febrileillness that preceded the discovery of thrombocytopenia. Numerousviral infections, including rubella, varicella, mumps, rubeola, andEBV, as well as immunizations with measles-mumps-rubella vac-

cine, have been associated with the subsequent development of ITPin children.1,11,12

Signs of mucocutaneous bleeding most often occur without othersystemic symptoms, and the child frequently does not appear ill.12

Bleeding manifestations vary from little or none to the typicalfindings of purpura, petechiae, epistaxis, and menorrhagia in olderfemales.12 Most children present with platelet counts � 20 � 109/L.13 In a study of 863 children with newly diagnosed ITP, none ormild bleeding manifestations were reported in 77% of patients,moderate bleeding occurred in 20%, and severe bleeding in 3%.13

Life-threatening bleeding is rare and the estimated risk of intracra-nial hemorrhage is between 0.1% and 0.5% in newly diagnosedcases.11-13 Approximately 65%-70% of children remit by 6 monthsand another 15%-20% by 12 months.11,12 The 5%-10% of childrenwho develop chronic ITP tend to be older, are more often female,and usually present with a higher platelet count.12

Pathophysiology of ITPAssays specific for auto-antibodies directed against specific platelet-specific glycoproteins can detect antibodies in 40%-80% of patientswith clinical ITP.14 However, the absence of detectable antibodiesdoes not rule out a diagnosis of ITP, because many patients withoutdetectable antibodies respond to traditional ITP therapies, andantibodies may occur in patients with liver disease and otherconditions without clinical ITP. The antigenic target for theseantiplatelet auto-antibodies are the ubiquitous platelet glycoproteinssuch as platelet GPIIb/IIIa in nearly 2/3 of patients, platelet GPIb/IXin approximately 1/5 of patients, and in the remaining patients,antibodies are directed against both of these platelet glycoproteincomplexes or other platelet antigens.

Dendritic cells from patients with ITP have up-regulated costimula-tory molecules enhancing auto-reactive T- and B-cell responsesagainst platelets.15 The ongoing process of macrophage-mediatedplatelet destruction and further presentation of new platelet proteinsto T and B lymphocytes contributes to the epitope spreadingobserved over time in patients with ITP, and may contribute to amore refractory disease in patients with ITP of longer duration.1

ITP patients may have significant defects in immune self-tolerance.1,15 Autoreactive cytotoxic CD8-expressing T-lymphocyteclones capable of directly damaging platelets and possibly mega-karyocytes have also been demonstrated16 and are likely to prolifer-ate under the influence of similar Th lymphocytes. Quantitative and

Table 1. International ITP Working Group consensus recommendations for the diagnosis of ITP in children and adults

Basic initial evaluation Additional studies of potential value Studies of unproven benefit

· Patient history· Family history· Medication history· Physical examination· Complete blood count· Quantitative immunoglobulins· Blood group (Rh)· Direct antiglobulin test· H pylori· HIV· HCV· BM (in selected patients)

· Antiphospholipid antibodies (patients with history of thrombosisor fetal loss)

· TSH or antithyroid antibodies· ANA in children· Pregnancy test in women of childbearing years· Viral PCR for parvovirus and CMV (selected refractory, febrile,or leukopenic patients)

· Platelet glycoprotein-specific antibodies

· Thrombopoietin assay· Reticulated platelets· Platelet-associated immunoglobulins· Serum complement· Bleeding time· Platelet survival studies

(Adapted with permission from Provan et al.5)HCV indicates hepatitis C virus; TSH, thyroid-stimulating hormone; and ANA, antinuclear antibody.

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qualitative defects in the regulatory T-cell population appear to becorrelated with persistence of chronic ITP. An association betweenan improvement in the peripheral blood regulatory T-cell numberand function and remission induction with ITP treatment has alsobeen reported.15

Suppression of platelet productionUsing indium-111–labeled autologous platelets, investigators havefound evidence not only of increased platelet clearance, but also ofimpaired platelet production.17,18 Recent studies have demonstratedinhibition of in vitro megakaryocyte growth and maturation byantibodies from some ITP patients.19 Evidence that patients withITP have autoreactive cytotoxic thymic (T) lymphocytes capable ofdirectly lysing platelets suggests that these lymphocytes may alsoinduce megakaryocyte injury and contribute to defective plateletproduction.16 Whereas megakaryocyte numbers and appearance inBM specimens appear normal in most patients with ITP whenviewed under light microscopy, electron microscopic studies of BMfrom ITP patients show extensive damage in the majority ofmegakaryocytes.20

TPO is the major physiologic regulator of megakaryocyte growthand differentiation.21,22 It is synthesized and secreted by the liver,and its production is constant, with no translational or posttransla-tional regulation.21 When TPO is released into the circulation, mostof the protein binds to TPO receptors on platelets and is cleared,with the platelets with the remaining TPO binding to receptors onBM precursors.21 TPO levels are inappropriately low for the degreeof thrombocytopenia in the majority of patients with ITP, and thisobservation provided the theoretical basis for treatment withTPO-receptor agonists.21,23

Management of primary ITP in adultsSeveral factors, including bleeding risk, toxicities of specifictherapies, patient age and comorbidities, and patient preference andlifestyle, must be considered before treatment is initiated in adultswith primary ITP.5 For children with ITP, when treatment is given,it is initially aimed at rapidly increasing the platelet count to a safelevel, then maintaining an adequate and safe count while awaiting aspontaneous remission. For adults, most of whom will have chronicITP, therapies are used to increase the platelet count to a safe leveland/or to prevent further bleeding with minimal toxicities. Mainte-nance of a platelet count � 30 � 109/L is an appropriate goal.Treatment should be considered when the platelet count is � 20-30 � 109/L, but occasionally it is appropriate to select a highertarget count.5 For secondary ITP, treating the underlying disease isusually the preferred approach.

Corticosteroid therapyCorticosteroids are the standard initial therapeutic agents5 and thoseused most frequently include prednisone, parenteral methylpred-nisolone, and dexamethasone. These are frequently used in combi-nation with IVIg and IV anti-RhD to rapidly increase platelet countsin patients with significant thrombocytopenia (� 5 � 109/L) andextensive bleeding manifestations.5

Prednisone is the steroid most frequently used in the treatment ofITP, and is given orally at a dose of 0.5-2 mg/kg daily. Inresponders, the platelet count will increase to � 50 � 109/L in a fewdays to several weeks, depending upon the baseline platelet countand whether IVIg or anti-RhD is used in conjunction with the drug.Bleeding may cease before an increase in the platelet count is seen.

When used alone, 65%-70% of patients respond.5,24,25 Responses inadults are rarely durable, with only 13%-17% of patients having anunmaintained normal platelet count at 1 year after treatment withprednisone alone.5,24,25

Early studies on the use of high-dose dexamethasone for thetreatment of refractory ITP were abandoned due to significanttoxicity and marginal efficacy.26 More recently, a study of a singlecourse of high-dose dexamethasone (40 mg/d � 4 days) in newlydiagnosed patients reported a high initial response (85%), with halfof the responding patients maintaining their response at 6 months.27

A multicenter trial of dexamethasone (40 mg/d � 4 days) repeatedevery 14 days for 4 courses produced an 86% response rate (plateletcount, � 50 � 109/L) and a 65% complete response rate (plateletcount � 100 � 109/L).28 At a 15-month median follow-up, 60% ofresponding adults had not relapsed, and for both adults and childrenwho obtained a complete response, 87% remained in remission.28

However, a recently reported randomized trial comparing 1 or2 cycles of the high-dose dexamethasone to 1 mg/kg prednisolonefailed to demonstrate superiority of the dexamethasone regimen.29

Additional studies will be needed to prove that this approachprovides superior long-term benefit.

IVIg and IV anti-RhDSeveral treatment trials have clearly demonstrated that in 65%-80%of patients treated with IVIg, the platelet counts increase within24-48 hours.3,5,30 Duration of response is rarely greater than10-14 days. Initial treatment regimens, in which 0.4 g/kg wasinfused daily for 5 days, have been supplanted by a higher-doseregimen of 1 g/kg daily for 1 or 2 days. This latter regimen isassociated with longer daily infusion time and greater toxicity,including infusion reactions, headaches, occasional aseptic meningi-tis, hemolytic anemia due to alloantibodies, acute renal failure, andrare thrombotic events, primarily in the elderly. The concomitantuse of corticosteroids may enhance the platelet response, reduceinfusion reactions, and result in fewer headaches.

Patients who are Rh positive, not significantly anemic, and still havetheir spleens are candidates for treatment with anti-RhD. Beforeinitiating treatment with anti-RhD, patients should be Rh typed andhave a direct antiglobulin test performed. Treatment with the USFood and Drug Administration (FDA)–approved dose of 50 �g/kgcan result in an increase in the platelet count to � 50 � 109/L innearly 80% of patients, but requires 48-72 hours for a clinicallysignificant response.3,5,31 Infusions of 75 �g/kg have been associ-ated with a more rapid increase in the platelet count equivalent tothat reported with IVIg treatment.32 The duration of response toanti-RhD therapy is usually longer than that observed with IVIgtreatment, averaging 21 days.33 Treatment with anti-Rh immuno-globulin typically results in a mild hemolytic anemia with anaverage decrease in hemoglobin of 1-1.5 g. Occasional episodes ofintravascular hemolysis resulting in renal failure and rare cases ofdisseminated intravascular coagulation and death have also beenreported.5

SplenectomySplenectomy is the historical “gold standard” for the treatment ofchronic ITP. A systematic review of the medical literature hasshown that 65% of patients will have unmaintained remissionslasting 10 years or longer. In the majority of these patients, theprocedure appears to be curative.34 The response rate in the firstweek is nearly 85%, with 20% of patients relapsing within weeks toyears.34 However, even after relapse, patients appear to be less

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refractory to medical treatment.34 Patients older than 45 yearsappear to have a lower response to splenectomy.34 At present, thereare no readily available clinical or laboratory markers that arepredictive of response to splenectomy, although there it has beensuggested that hepatic sequestration of autologous indium-111–labeled platelets may be predictive of a poor response.35

Laparoscopic splenectomy is associated with lower complicationrates and faster recovery, no greater need for accessory splenec-tomy, and no loss in efficacy.36 Splenectomized patients shouldhave yearly influenza vaccinations and, if a fever occurs, the patientshould immediately receive parenteral broad-spectrum antibioticsthat are effective against pneumococcus. This is true no matter howmany years have elapsed since the splenectomy and despiteimmunization. Other long-term outcomes after splenectomy areunknown, particularly in regard to uncommon events such aspulmonary hypertension or vascular dementia.37,38

Anti-CD20 therapy (rituximab)B-lymphocyte depletion using rituximab, a humanized anti-CD20mAb, has shown limited but reproducible efficacy in patients withchronic ITP.39,40 Up to 60% of patients will have an initial increasein their platelet count, with an estimated 1/3 of patients obtaining aninitial (1-year) unmaintained complete response (plateletcount, � 100 � 109/L) with the use of the standard lymphomaregimen of 375 mg/m2 rituximab weekly for 4 weeks.39,40 Nearly allpartial responders will relapse within 1 year, whereas nearly allcomplete responders will maintain their response for at least 1 year.Approximately one-half of complete responders will relapse within4 more years. Although repeat treatment of the relapsed completeresponder can result in a high rate of response,41 the safety of thisapproach has not been fully evaluated. Concerns about the use ofanti-CD20 therapy include the development of progressive multifo-cal leukoencephalopathy and reactivation of hepatitis B. These risksmay be lower in ITP patients than in patients with lymphoma andother systemic autoimmune disorders, because patients with ITP aregenerally not intrinsically immunosuppressed by their disease orreceiving additional immunosuppressive therapies. Common, butless serious, toxicities include first-infusion reactions such as feverand chills and serum sickness, the latter being especially common inchildren.42 Although total Ig levels rarely decrease, patients cannotmount a normal humoral antibody responses to some vaccines formonths after treatment. Therefore, it may be preferable to immunizepatients before the initiation of rituximab therapy because splenec-tomy may need to be performed within the 6- to 9-month periodafter rituximab therapy. The optimal dose and frequency of ritux-imab administration for the treatment of ITP remains unknown.43

TPO receptor agonists: romiplostim and eltrombopagRomiplostim was the first TPO receptor agonist to enter clinicaltrials.44 Subsequently, 2 randomized, placebo-controlled studieswere published, one in splenectomized patients and the other innonsplenectomized patients.45 In both studies, the same dosingregimen was used with progressive weekly increases in dosedepending on the platelet count, beginning at 1 �g/kg and increas-ing to 15 �g/kg. Rescue medications were allowed for overtbleeding or very low counts associated with a high risk of bleeding.Concomitant medications such as prednisone could be decreased orstopped as the platelet count increased.

In both trials, unequivocal efficacy was demonstrated. Durableresponse (platelet count, � 50 � 109/L for 6 of the last 8 weeks and

no rescue therapy) was seen in 38% of splenectomized patients andin 61% of nonsplenectomized patients. The overall response rate(platelet count, � 50 � 109/L on 4 of 24 weeks) was 79% insplenectomized patients and 88% in nonsplenectomized patients.45

There were no responses in the splenectomized patients and only a14% response rate in nonsplenectomized patients taking placebo.There were significant reductions in the use of concomitantmedications such as prednisone and reduced use of rescue medica-tions (eg, IVIg, anti-RhD, or prednisone).45 No tachyphylaxis wasseen over the 6 months of study, nor did any important toxicitiesemerge, such as an increased incidence of thromboembolic eventsor myeloid malignancies. Due to rare instances of increased BMreticulin that were observed in patients at higher doses, the highestrecommended dose for treatment is now 10 �g/kg. “Rebound”thrombocytopenia with platelet counts decreasing to less thanpretreatment baseline levels occurred in up to 5%-10% of patientswho stopped treatment abruptly. Romiplostim was licensed inAugust 2008 based on these 2 studies.

Patients who entered 1 of the 2 previous studies were eligible toenter a long-term maintenance study validating the efficacy andsafety of romiplostim use for up to 3 years of follow-up.46 Overall,this study showed that the long-term use of romiplostim as amaintenance therapy was feasible. Platelet counts could be main-tained for years without the need to significantly increase the dose.Many patients learned to give weekly injections at home. Noimportant new toxicities were identified with extended use. Ninecases of BM reticulin fibrosis were identified, but no cases ofmyelofibrosis/myeloid metaplasia. Whether this incidence is signifi-cantly higher than that which occurs in patients with ITP success-fully treated with other agents requires additional study.

An open-label, 52-week randomized trial of romiplostim versusstandard of care reported a higher rate of platelet response (plateletcount, � 50 � 109/L at any scheduled visit), lower incidence oftreatment failure and splenectomy, and less bleeding in the romiplos-tim-treated patients The starting romiplostim dose in this study was3 �g/kg and the rate of platelet response was 2.3 times that observedin the standard-of-care group.47 However, utility beyond 52 weekscompared with patients who were treated with splenectomy isunknown. Another study has reported safety and efficacy ofromiplostim in 22 children.48 In this small, 12-week randomizedtrial of patients 12 months to 18 years of age, platelet countsof � 50 � 109/L for 2 consecutive weeks was achieved in 88% ofpatients in the romiplostim group compared with none in theplacebo group. Romiplostim treatment was well tolerated, with noserious adverse events.48

Eltrombopag is the first oral TPO receptor agonist to completeclinical trials and to be licensed for use in the United States. In theinitial published study, eltrombopag was given for 6 weeks in dailydoses of 30 mg, 50 mg, and 75 mg, and results were compared withpatients given placebo.49 Responses were seen in 70%-80% ofpatients at the 2 highest eltrombopag doses compared with 11% inthose receiving placebo.48 No important toxicity was seen andbleeding decreased as the platelet counts increased. A second studyreported similar results for thrombocytopenic patients with hepatitisC infection, allowing continued antiviral chemotherapy withoutdose reduction or interruption.50

A third confirmatory study was a 6-week randomized, placebo-controlled trial that compared 50 mg of eltrombopag againstplacebo.51 That study demonstrated a 59% response rate in the

Hematology 2011 387

eltrombopag arm, based on an increase in platelet countto � 50 � 109/L compared with a 16% increase in platelet count inthose taking placebo. Bleeding manifestations were decreased inresponders, but returned to baseline levels after the medication wasdiscontinued and platelet counts declined. In that study, reboundthrombocytopenia upon drug withdrawal was rare and no statisti-cally significant organ toxicity was seen. However, some patientsdeveloped significant liver enzyme increases requiring cessation ofmedication. Accordingly, the FDA has required a black boxwarning concerning the need to monitor liver function in patientstaking eltrombopag.51

A 6-month randomized study trial comparing eltrombopag withplacebo showed results comparable to the 6-month pivotal trial ofromiplostim.52 A long-term extension study reported in abstractform has confirmed the durability of platelet responses.53 Inaddition, long-term follow-up of all patients enrolled in eltrom-bopag trials found a lower frequency of thromboembolic eventsthan was reported in earlier studies.54

Monitoring and management of side effects of TPOmimeticsGiven the mechanism of action of TPO mimetics, the side effects ofconcern are the development of BM fibrosis, venous thromboembo-lism, myeloid malignancies, and rebound thrombocytopenia. Reticu-lin fibrosis (grade 2 or above) is rare with the use of TPO mimeticsand can be monitored by paying close attention to blood counts andmorphologic abnormalities on peripheral blood smear. The exactincidence of this complication is unclear, but reticulin fibrosisappears to be a rare, dose-dependent phenomenon that resolves aftercessation of the TPO mimetic.55 No significant increase in incidenceof venous thromboembolism has been reported in patients whoreceived romiplostim or eltrombopag compared with the incidencein ITP patients, and thromboembolic events have not been shown tobe correlated with platelet counts.54 However, these agents shouldbe used with caution in patients with known predispositions toarterial or venous thrombosis. No increase in myeloid malignancieshas been reported so far in patients treated with either agent. Theincidence of rebound thrombocytopenia is � 10% with either agentand can be managed by close monitoring of platelets count in the 4weeks after discontinuation of treatment. Patients who develophepatotoxicity with eltrombopag should not be rechallenged withthe drug except under exceptional circumstances. Hepatotoxicityhas not been observed with romiplostim.

Single-agent treatment of refractory ITPAzathioprine, danazol, cyclophosphamide, cyclosporine A, andmycophenolate mofetil have shown limited efficacy in the treatmentof ITP. No single agent induces unmaintained remission in � 30%of refractory cases, and this is particularly true in patients refractoryto splenectomy.56 In one report, pulse cyclophosphamide induced acomplete response in 13 of 20 patients, 8 of whom remained inremission with a median follow-up of 2.5 years.57 Even autologousstem cell transplantations have only been found to have a 25%-33%response rate and are without multi-year follow-up data.58

Controversies in ITP therapyThe high response rates reported in randomized trials of refractorypostsplenectomy patients treated with TPO receptor agonists haveestablished these agents as the drugs of choice for this group ofpatients. However, the choice of second-line therapy in newlydiagnosed patients who fail corticosteroids is much more controver-

sial. Options include: (1) laparoscopic splenectomy, with its lowmorbidity and the highest documented rate of durable remission;(2) rituximab treatment before splenectomy, with 1 of 5 patients inunmaintained remission at 5 years; or (3) chronic and potentiallyindefinite therapy with a TPO receptor agonist to maintain a safeplatelet count without the use of additional immunosuppression orsplenectomy. A long-term randomized trial of sequenced postcorti-costeroid therapy could provide clinical data for a more logicaltreatment algorithm.

DisclosuresConflict-of-interest disclosure: H.A.L. has received research fund-ing from Shionogi and Amgen, has consulted for GSK and Amgen,and has been affiliated with the speakers’ bureau for GSK. V.P. hasbeen affiliated with the speakers’ bureau for and received honorariafrom Amgen and GlaxoSmithKline. Off-label drug use: Thismanuscript discusses the use of eltrombopag and romiplostim inliver disease and ritmiximab in ITP.

CorrespondenceHoward A. Liebman, Professor of Pathology and Medicine, Divi-sion of Hematology, Keck School of Medicine, 1441 Eastlake Ave,NOR 3466, 9172, Los Angeles, CA 90033; Phone: (323) 865-3950;Fax: (323) 865-0060; e-mail: liebman@hsc.usc.edu.

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