itp and international guidelines: what do we know, what do we need?

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ITP and international guidelines: What do we know, what do we need? Francesco Rodeghiero, Marco Ruggeri San Bortolo Hospital, Department of Cell Therapy and Hematology, 36100 Vicenza, Italy Correspondence: Francesco Rodeghiero, San Bortolo Hospital, Department of Cell Therapy and Hematology, Viale Rodolfi, 37, 36100 Vicenza, Italy. [email protected] Available online: 20 March 2014 Presse Med. 2014; 43: e61e67 on line on ß 2014 Elsevier Masson SAS All rights reserved. www.em-consulte.com/revue/lpm AUTOIMMUNE CYTOPENIAS www.sciencedirect.com Quarterly Medical Review e61 Summary In the last decade, rituximab and thrombopoietin-receptor agonists (TPO-ra) have been introduced into the traditional armamentarium of Immune Thrombocytopenia (ITP), consisting in corticosteroids as initial treatment and splenectomy in those not responding or relapsing. A variety of immunosuppressive treatments were reserved for patients not responsive to splenectomy. These advancements have been incorporated in two international current guidelines: the first, produced by an international group of expert clinicians (International Consensus Report, ICR); the second, by a selected group of hematologists and methodologists with expertise in systematic reviews and guideline development, mainly from United States, without direct connection with pharmaceutical companies. This latter guideline was endorsed by the American Society of Hematology (ASH). A new standardized terminology has also been adopted, with a more clear definition of primary vs secondary ITP and a clear distinction between the different phases of the diseasenewly diagnosed, persistent, chronic (after 12 months from diagnosis). Both guidelines structure their suggestions on first, second and third- line treatments, with less attention to the different phases of the disease and its severity. There is a substantial agreement in proposing the initial treatment with oral corticosteroids and TPO-ra as third-line approach in patients unsuccessfully splenectomized in whom these agents appear to have the more favorable therapeutic profile. As to the second-line approach in patients failing corticosteroids, rituximab and TPO-ra could be valid alternatives to splenectomy but, unfortunately, the international guidelines fail to offer a consistent approach. Whereas ICR considers splenectomy at the same level of many other second-line treatments including rituximab and TPO-ra, ASH guideline definitely recommends reserving TPO-ra and rituximab to patients failing or with a contra-indication to splenectomy. As new data are being accumulated on long-term outcomes and toxicity of TPO-ra and the role of rituximab is being better defined for particular patients as second-line therapy, it will be possible to revisit the pros and cons of these options vs each other and splenectomy which, although less and less popular, maintains the highest curative potential, with an acceptable toxicity. The thrombotic risk in ITP should also be better defined and taken into account in guiding the treatment in the individual patients. Hopefully, new studies will be based more on clinical outcomes than on platelet count increase. The ultimate lesson of the insufficient evidence and disagreement among experts is that management of ITP should be tailored to the individual patients. In this issue Immune thrombocytopenic purpura: major progress in knowledge of the pathophysiology and the therapeutic strategy, but still a lot of issues Bertrand Godeau Pathogenesis of immune thrombocytopenia Douglas B Cines, Adam Cuker, John W Semple ITP and international guidelines, what do we know, what do we need? Francesco Rodeghiero, Marco Ruggeri Thrombopoietic agents: There is still much to learn James B. Bussel, Madhavi Lakkaraja Is B-cell depletion still a good strategy for treating immune thrombocytopenia? Bertrand Godeau, Roberto Stasi Novel treatments for immune thrombocytopenia Andrew Shih, Ishac Nazi, John G. Kelton, Donald M. Arnold Warm autoimmune hemolytic anemia: advances in pathophysiology and treatment Marc Michel Auto-immune neutropenia Aline Moignet, Thierry Lamy tome 43 > n84 > avril 2014 http://dx.doi.org/10.1016/j.lpm.2014.02.004

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Page 1: ITP and international guidelines: What do we know, what do we need?

Available online: 20 March 2014

Presse Med. 2014; 43: e61–e67 on line on� 2014 Elsevier Masson SASAll rights reserved.

www.em-consulte.com/revue/lpmAUTOIMMUNE CYTOPENIASwww.sciencedirect.com

In this issue

Immune thrombocytopenicpurpura: major progress inknowledge of thepathophysiology and thetherapeutic strategy, butstill a lot of issuesBertrand Godeau

Pathogenesis of immunethrombocytopeniaDouglas B Cines, AdamCuker, John W Semple

ITP and internationalguidelines, what do weknow, what do we need?Francesco Rodeghiero,Marco Ruggeri

Thrombopoietic agents:There is still much to learnJames B. Bussel, MadhaviLakkaraja

Is B-cell depletion still agood strategy for treatingimmune thrombocytopenia?Bertrand Godeau, RobertoStasi

Novel treatments forimmune thrombocytopeniaAndrew Shih, Ishac Nazi,John G. Kelton, DonaldM. Arnold

Warm autoimmunehemolytic anemia: advancesin pathophysiology andtreatmentMarc Michel

Auto-immune neutropeniaAline Moignet, Thierry Lamy

tome 43 > n84 > avril 2014http://dx.doi.org/10.1016/j.lpm.2014.02.004

Quarterly Medical Review

ITP and international guidelines: What do weknow, what do we need?

Francesco Rodeghiero, Marco Ruggeri

San Bortolo Hospital, Department of Cell Therapy and Hematology, 36100 Vicenza, Italy

Correspondence:

Francesco Rodeghiero, San Bortolo Hospital, Department of Cell Therapy and Hematology,Viale Rodolfi, 37, 36100 Vicenza, [email protected]

Summary

In the last decade, rituximab and thrombopoietin-receptor agonists (TPO-ra) have beenintroduced into the traditional armamentarium of Immune Thrombocytopenia (ITP), consisting incorticosteroids as initial treatment and splenectomy in those not responding or relapsing. Avariety of immunosuppressive treatments were reserved for patients not responsive tosplenectomy. These advancements have been incorporated in two international currentguidelines: the first, produced by an international group of expert clinicians (InternationalConsensus Report, ICR); the second, by a selected group of hematologists and methodologistswith expertise in systematic reviews and guideline development, mainly from United States,without direct connection with pharmaceutical companies. This latter guideline was endorsed bythe American Society of Hematology (ASH). A new standardized terminology has also beenadopted, with a more clear definition of primary vs secondary ITP and a clear distinctionbetween the different phases of the diseasenewly diagnosed, persistent, chronic (after 12months from diagnosis). Both guidelines structure their suggestions on first, second and third-line treatments, with less attention to the different phases of the disease and its severity. Thereis a substantial agreement in proposing the initial treatment with oral corticosteroids and TPO-raas third-line approach in patients unsuccessfully splenectomized in whom these agents appearto have the more favorable therapeutic profile. As to the second-line approach in patients failingcorticosteroids, rituximab and TPO-ra could be valid alternatives to splenectomy but,unfortunately, the international guidelines fail to offer a consistent approach. Whereas ICRconsiders splenectomy at the same level of many other second-line treatments includingrituximab and TPO-ra, ASH guideline definitely recommends reserving TPO-ra and rituximab topatients failing or with a contra-indication to splenectomy. As new data are being accumulatedon long-term outcomes and toxicity of TPO-ra and the role of rituximab is being better defined forparticular patients as second-line therapy, it will be possible to revisit the pros and cons of theseoptions vs each other and splenectomy which, although less and less popular, maintains thehighest curative potential, with an acceptable toxicity. The thrombotic risk in ITP should also bebetter defined and taken into account in guiding the treatment in the individual patients.Hopefully, new studies will be b n on platelet count increase.

The ultimate lesson of the insufficient evidence and disagreement among experts is that

ased more on clinical outcomes tha

management of ITP should be tailored to the individual patients.

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GloANAAPAASHBCSEMAFDAGL

ICR

ITP

IVIgIWGLA

TPO

F Rodeghiero, M Ruggeri

Up to 1996, when George et al., on behalf of the AmericanSociety of Hematology published a practice guideline (GL) (inshort, ASH-1996 GL) [1] for diagnosis and treatment of ImmuneTrombocytopenia (ITP), at that time called idiopathic thrombo-cytopenic purpura, no international guidelines were availablefor this disorder. ASH-1996 GL gained worldwide reputation andwide application. Splenectomy emerged as the most effectivetreatment with an acceptable safety profile, as further confir-med by a systematic review by Kojouri et al., restricted to adults[2]. Subsequently, Vesely et al. (again from George’s group) intheir detailed review showed that none of the many treat-ments available for patients refractory to surgery had sufficientevidence to support their effectiveness and safety [3]. Aconsensus-based guideline produced and published underthe umbrella of the British Society of Haematology in 2003(in short, BCSH-GL) [4] also deserves consideration for itsdiffuse appreciation and updated review of literature. Twonew major treatment options became available and gaineddiffuse use in more recent time: anti-CD20 chimeric humanantibody (rituximab), primarily registered for the treatment ofCD20 positive large cell lymphomas by Food and Drug Adminis-tration (FDA) in 1997 and subsequently proposed also forautoimmune disorders like ITP (reviewed in Arnold et al.) [5]and, in the last decade, a novel class of agents that increaseplatelet production by stimulating the thrombopoietin (TPO)receptor, currently known as TPO-receptor agonists (TPO-ra)[6]. These new treatments were considered in the internationalconsensus report guidelines (ICR GL in short) [7] and in anupdate of previous ASH guidelines (in short, ASH-2011 GL) [8].These more recent GL, particularly ASH-2011 GL, substantiallyadopted the standardized terminology, definition and outcomecriteria proposed by an International Working Group (IWG) onITP [9]. To facilitate the reader, a summary of this new termi-nology and related definitions is reported in box 1.

ssary Antinuclear antibodies

Antiphospholipid antibodies American Society of HematologyH British Society of Haematology

European Medicine Agency Food and Drug Administration

GuidelineInternational Consensus ReportImmune Thrombocytopenia

Intravenous Immunoglobulins International Working Group

Lupus anticoagulant-ra Thrombopoietin-receptor agonists

The discussion will be limited to diagnosis and management ofITP in adults focusing on those aspects with insufficient evi-dence and that remain unsettled or controversial. Table Isummarizes the main characteristics of current GL.A striking difference between ICR and ASH-GL is that in the ICRGL the different therapeutic options are strictly listed in alphaorder so as to show no preference for a particular treatment.ASH document is more similar to traditional GL in that it offers amore detailed level of evidence and the strength of evidence isextensively used to recommend or suggest managementoptions. Both documents emphasize the limited number ofrandomized clinical trials comparing the outcome of differenttreatments in terms of response rate and duration upon whichto base clinical recommendations. Moreover, the treatmentshould be tailored to the individual patient taking into accountthe presence and severity of bleeding, the rapidity of responseand the expected side effects and costs. A more in-depth andcritical comparison of ICR and ASH 2011 GL has been recentlypublished [10].

DiagnosisPrimary immune thrombocytopenia identifies an autoimmunedisorder characterized by an isolated platelet count < 100 �109/L with or without bleeding manifestations, in absence ofother causes or disorders that may be associated with throm-bocytopenia. Recommendations for the diagnosis of ITP do notpresent major differences between the different GL. The recom-mendations of the ICR, in which children and adults are consi-dered together, may represent a good synthesis of the currentaccepted practice for diagnosis of ITP and the reader is referredto this report. Some points deserve further attention.At variance with previous GL, which suggested bone marrowexamination in selected patients, that is older than 60, beforesplenectomy in adults, before corticosteroid administration inchildren, in unresponsive to intravenous immunoglobulins(IVIg) [1,4], a different position is taken in the more recentASH-2011 GL. It recommends that for children and adolescentsbone marrow examination ‘‘is not necessary’’ in cases with thetypical features of ITP, even in those not responding to IVIg(grade 1B) and suggests that bone marrow is not necessary alsobefore starting treatment with corticosteroids or before sple-nectomy (grade 2 C). For adults, it suggests that bone marrowexamination is not necessary in cases with typical ITP irrespec-tive of age (grade 2 C). In our policy, a bone marrow aspirationis usually carried out under local anesthesia to immediatelyexclude blood malignancies for patient or patient’s familyreassurance. The investigation of platelet survival and site ofplatelet sequestration using indium-labeled autologous plate-let scanning is currently considered of uncertain benefit. Thisview has been supported by a recent literature review [11].Search for antiplatelet antibodies remains controversial and

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Box 1

Immune Thrombocytopenia (ITP): definitions and terminology.

Primary ITP

� Autoimmune disorder characterized by isolatedthrombocytopenia (platelet count in peripheralblood < 100 � 109/L) with no other causes or disorders thatcan be associated with thrombocytopenia

� Primary ITP is a diagnosis of exclusion; at present there are noreliable clinical or laboratory parameters that allow accuratediagnosis

� The main clinical problem of primary ITP lies in the increased riskof bleeding, although bleeding symptoms may not always bepresent

Secondary ITP

� All forms of immune thrombocytopenia, except for primary ITP*

Stages of the disease

� Newly diagnosed ITP: within the first three months followingdiagnosis

� Persistent ITP: between 3 and 12 months following diagnosis.This includes patients who have spontaneous remissions orwhose complete response at the end of the first therapy is notmaintained over time.

� Chronic ITP: lasting more than 12 months

Severe ITP

� This term indicates cases with bleeding symptoms at onsetwhich require therapeutic intervention, or with development ofnew bleeding symptoms that require additional therapy withdifferent treatment or a higher dose

Refractory ITP

� Two criteria have to be fulfilled at the same time: the lack ofresponse or relapse after splenectomy with severe ITP or ableeding risk that needs treatment according to the GP

� Temporary response to corticosteroids or to intravenousimmunoglobulins does not exclude a refractory form

*The acronym ITP is followed by the name of the associateddisease in brackets, for example: secondary ITP (associated toLupus); secondary ITP (associated to HIV); secondary ITP (drug-induced). In titles of manuscripts, abstract, shortened forms can beused such as lupus-associated ITP or HIV-associated ITP, etc.

ITP and international guidelines what do we know, what do we need?AUTOIMMUNE CYTOPENIAS

testing is not suggested by the ASH-2011 GL, while the BCSH-GLadmits its utility in some refractory cases. H. Pylori testing isconsidered worthwhile in refractory patients by the BCSH-GL,whereas in ICR GL the detection of H. Pylori infection, preferablyby urea breath test or stool antigen test, should be consideredat baseline. ASH-2011 GL only states that this test is notnecessary in children. The presence of antinuclear antibodies

tome 43 > n84 > avril 2014

(ANA) may indicate a propension to develop autoimmunedisorders. The occurrence at diagnosis of antiphospholipid anti-bodies (APA) or lupus anticoagulant (LA) in patients without ahistory of thrombosis in the last months and with no evidenceof additional autoimmune manifestations may be evident in upto 30% of cases. It remains to be investigated by prospectivestudies if these patients, still to be considered having primaryITP [9], will deserve a different prognosis and/or treatment.

ManagementWe shall mainly consider the most recent international guide-lines (ASH-2011 and ICR) since they are updated to consider thenewest treatment approaches and to adhere as much aspossible to the accepted international nomenclature of thisdisease, making narrative reference to particular relevantpublications for specific issues. Inferences regarding the effi-cacy of treatment will continue to be based mainly on plateletcount as the more reliable surrogate outcome measure.

Who should be treated?

There is substantial agreement, despite different formulations,that treatment, at least in newly diagnosed patients, is indi-cated in presence of bleeding manifestations or anyway ifplatelet count is below 30 � 109/L. In absence of bleeding,a platelet count of 20 � 109/L is a compelling case for treat-ment [12]. Standardized description of bleeding symptoms andgradation of their severity, as proposed by the IWG on ITP [13],could facilitate a more consistent approach in deciding whichpatients need treatment and better dictate the type of treat-ment. A symptom-based approach has already proved useful indeciding the most appropriate management in critical situa-tions that could demand immediate treatment with high-doseIVIg, platelet transfusion or hospital admission [14]. Betterpredictors of bleeding risk and individualization of indicationsaccording to age, gender, concomitant medications, life-styleand patient’s expectations should be addressed by futurestudies. An emerging issue is represented by patients present-ing with ITP while taking or requiring some form of antithrom-botic medication, a situation increasingly encountered in clinicalpractice.

Newly diagnosed ITP

Treatment is aimed at rapidly obtaining a safe platelet count toprevent or stop hemorrhages and to ensure an acceptablequality of life, avoiding as much as possible treatment-relatedadverse effects. Corticosteroids, IVIg or anti-D Ig are consideredfirst-line treatments by ICR [7] and ASH-2011 [8]. Corticoste-roids remain the mainstay of treatment and prednisone 1 mg/day for 3–4 weeks followed by tapering in another 2–3 weeks isa general standard approach. Some treatments have beenproposed with the aim of increasing the response rateand duration of response. A definite advantage of high-dose

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Table I

Main characteristics of principal guidelines on ITP

GL (year) Panel Method foranalysis consensus

Pros Cons Utility in difficultcases

ASH-GL (1996) 15 professional membersfrom USA and Canada only

COI not disclosed

Explicit, by votingRank of

agreement provided

Detailed and complete.Endorsed by ASH

Not of immediatereadability.

Offers clear directionsto cliniciansNational GL

Major in mostcircumstances

BCSH-GL (2003) 9 professionals from UK onlyCOI not disclosed

Not explicit Detailed and completeUpdating from ASH-GL

Endorsed by BCSH

Not of immediatereadabilityNational GL

Major in mostcircumstances

ICR (2010) 20 professionalsInternational

representation.COI disclosed

Not explicit Detailed and completeif appendix considered.Offers the most updated

summary ofavailable evidence

Not of immediatereadability

Less directivein providing advice

International GL

Major in mostcircumstances

Requires considerationof the electronic appendix

ASH-GL (2011) 7 professionals (3 experts inITP management) without COI

12 professionals with COIas reviewers only

Not explicit New terminology adoptedRecommendations only

if evidence-basedEndorsed by ASH

Impartiality

Gray areas notaddressed

Most emphasison evidence less on

clinical expertiseInternationalGL, mainly US

Minor utility incomplex cases

ASH: American Society of Hematology; BCSH: British Society of Haematology; COI: conflict of interest; GL: Guideline; ICR: International Consensus Report; ITP: immuneThrombocytopenia.

F Rodeghiero, M Ruggeri

dexamethasone is not demonstrated in terms of responseduration over 6–12 months [15–17] and should be prospecti-vely further investigated. Rituximab, with or without steroids,has failed to demonstrate a significant improvement overconventional treatments in newly diagnosed patients or any-way a clear net benefit overcoming its adverse events [18].

Persistent ITP: a neglected area in current GL

Patients still remaining thrombocytopenic after 3 months fromdiagnosis or initial treatment are classified in two distinctphases: persistent (between 3 to 12 months) or chronic afterat least 12 months since they may still obtain a long-termremission or be apparently cured mainly during the first 12months or even later [19]. Thus splenectomy, once moreliberally proposed [1] is currently reserved for patients stillrequiring treatment after one year or more from initial treat-ment. Unfortunately, none of the available GL specificallyaddresses patients with persistent ITP (as no data are availablein literature apart from anecdotal evidence in sparse cases). Inboth ICR and ASH-2011 GL, patients not responding to first-linetreatments (corticosteroids, IVIg, anti-D) are lumped togetherin a single heterogeneous category irrespective of the differentphases of disease (newly diagnosed, persistent or chronic ITP).

This precludes separate considerations for patients failing initialcorticosteroids but still with a short disorder duration – and thusat a more favorable prognosis – from those with a moreadvanced disease and thus probably already exposed tomore lines of medical treatments. Both GL just suggest that,if splenectomy is deemed necessary, surgery should be defer-red for at least 6 months (ICR) or 12 months (ASH-2011) fromdiagnosis.Considering that 50 to 80% of initially treated patients willrelapse and require further treatment after failing initial corti-costeroids, the most appropriate treatment of patients withpersistent ITP represents an area of major clinical interest bur-dened by unacceptable uncertainty. A general rule is to sparethese patients treatments with long-term adverse effects such asprolonged use of corticosteroids, immunosuppressive drugs orchemotherapy. Sometimes, on demand therapy is the onlytreatment used at the time of or in anticipation of high riskbleeding situations. In other cases, the lowest effective dose ofcorticosteroids is maintained for weeks or months [12]. Dapsone,an inexpensive drug with a well-established safety profile, couldalso prove useful in this setting [20]. Danazol administrationcould also be a useful alternative [21] to spare corticosteroidsuntil a decision on splenectomy has, eventually, been taken.

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ITP and international guidelines what do we know, what do we need?AUTOIMMUNE CYTOPENIAS

However, with the advent of TPO-ra which have a response ratein 60–70% of cases and are apparently devoid of major short-or medium-term toxicity [22–24], one could consider totreat with these agents patients at risk of bleeding while inpersistent phase as a bridge to splenectomy, thus sparing themmore toxic agents or more demanding treatments like in-hospital administration of IVIg. This approach will allow tosafely manage patients while waiting for a possible remission,either spontaneous or facilitated by these agents as recentlysuggested [25,26], or to take a definite orientation towards atreatment with curative potential like splenectomy or rituxi-mab. This is clearly an area that deserves further studies.

Patients not responding or relapsing aftercorticosteroids or other first-line therapies

A striking difference between ICR and ASH-2011 GL consists inthe different position assigned to splenectomy in the treatmentstrategy.ICR GL reports in alpha order a list of several second-linetreatments which includes splenectomy together with manymedical therapies such as azathioprine, cyclosporine A, dana-zol, dapsone, mycophenolate mofetil, rituximab and TPO-ra,vinca alkaloid. All these options, including TPO-ra, are purposelylisted in alphabetical order so as to show no preference for aparticular therapy. Noteworthy, the ICR experts did not findconsensus (or evidence) for preferring splenectomy over any ofthe considered second-line medical treatments despite ack-nowledging that surgery could produce up to 66% of sustainedresponses after 5 years.Consequently, TPO-ra, a treatment that requires continuous,possibly lifelong administration and is currently approved onlyfor chronic ITP, and whose long-term effects are not yet fullyevaluated [22–24] is placed in ICR proposal at the same level ofevidence as splenectomy. However, when it comes to patientsfailing first and second-line therapies, without any mention ifthey were splenectomized or not, ICR GL makes a recommen-dation of category A in favor of TPO-ra. This position has beenovertly criticized [27]. A further element of perplexity consistsin failing to consider the different aims of ‘‘single-shot’’ treat-ments aimed at obtaining long-term or indefinite remission,like splenectomy and rituximab, with the ‘‘maintenance’’approach of TPO-ra.At variance with ICR GL, ASH-2011 GL, acknowledging thatsplenectomy remains the only treatment that provides sus-tained remission without a concomitant therapy in a highproportion of patients, places splenectomy as a turningpoint in deciding further treatments in patients with chronicITP. ASH-2011 GL recommends splenectomy for patients whohave failed corticosteroid therapy and TPO-ra only if they are atrisk of bleeding and relapsed after splenectomy (thus follow-ing the definition of refractory ITP by the international workinggroup for ITP) [9] or have a contra-indication to splenectomy

tome 43 > n84 > avril 2014

and have failed at least one other therapy. Both recommen-dations receive grade 1B. Noteworthy, these recommenda-tions are in keeping with the European Medicine Agency (EMA)approved indication for TPO-ra but not with the FDA, which is inagreement with the recommendations of the ICR GL. In ASH-2011 GL, rituximab and TPO-ra are suggested for considerationwith grade 2 C in patients at risk of bleeding who have eitherfailed one line of therapy such as corticosteroids, IVIg, sple-nectomy or rituximab or did not undergo splenectomy(TPO-ra).In general, the published guidelines do not provide a practicalalgorithm of preferred treatment sequence in chronic ITP. Toaddress this limitation, Ghanima et al. [28] recently presentedan instructive clinical case-study followed by an in-depth dis-cussion of the pros and cons of the three major treatmentmodalities in chronic ITP including splenectomy, TPO-ra andrituximab. The authors’ main conclusion is that treatmentshould be individualized, with an active participation of thepatients to the decision-making process, considering severalindividual factors like bleeding history, comorbidities, conco-mitant therapies, life-style, expectations and compliance.

Refractory

Refractory patients are defined on the basis of two criteria [9].First, they should have failed splenectomy or have relapsedthereafter. Second, they should either exhibit severe ITP (cli-nically relevant bleeding) or have a risk of bleeding that in theopinion of the attending physician requires therapy. The aim oftreatment in these patients should be to maintain a plateletcount sufficient to prevent clinically significant bleeding. Bothrecent GL agree to recommend TPO-ra acknowledging theefficacy of these agents, in term of platelet increase andreduction of bleeding symptoms, also in patients who havefailed splenectomy and second-line medical treatments.It can be estimated that a few percentage of patients (around3–5%) of those initially responding to same first or second-linetreatments including splenectomy, TPO-ra and rituximab ulti-mately fail to respond to almost all available therapies andremain with a platelet count below 10–20 � 109/L. Thesepatients are at very high risk of severe or even fatal bleeding[29,30], current GL do not provide any indication and ICR GL justmentions some treatments (campath-1H, combination chemo-therapy and hematopoietic stem cell transplantation) empha-sizing their associated considerable toxicity and the very limitedevidence supporting their use. Novel agents are eagerly awai-ted [15].

Special considerations and conclusionsPrimary ITP still remains a diagnosis of exclusion and no clinicalor laboratory marker is able to predict the future natural historyin the individual patients. In particular, the clinical relevance oftesting for H. Pylori, APA/LA or ANA remains unsettled. It is

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apparent from our discussion that current GL fail to provide anunanimous consensus on the best management approach,particularly in patients failing first-line treatments, and thatseveral issues demand further investigation. Moreover, anopen criticism has been expressed on the methodologicalissues that should inform the production of GL, with a specificreference to ITP [10]. The place of splenectomy remains dis-puted, despite it is the only ‘‘curative’’ approach with two thirdsof patients remaining in remission for more than 10 years fromsurgery [31], with minimal/moderate toxicity [24]. The pos-sible increased risk of thrombosis in ITP is currently debated. Ina retrospective evaluation of one thousand patients with ITPrequiring at least one line of treatment in 7 referral centers inItaly [32] the arterial and thrombotic risk was only slightlyincreased, while it was higher in splenectomized patients withan hazard ratio of 3.5, in keeping with a large retrospectivestudy conducted in USA on the basis of administrative data [33].The risk of thrombosis in ITP, particularly in splenectomizedpatients, should thus be considered before undertaking othertreatments associated with increased thrombotic risk. It is stillnot fully clarified if this is the case with TPO-ra. In fact, asurprisingly higher annualized risk of thrombosis was appa-rently reported in patients treated with TPO-ra [22–24]. Ofcourse, the finding that some patients treated with TPO-ra mayachieve a response or complete response of variable durationafter their suspension, although still limited to a thin percen-tage of patients, is encouraging and may favor their use beforesplenectomy. However, ‘‘spontaneous’’ improvements of ITP

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Aledort LM, Ballem PJ et al. Idiopathicthrombocytopenic purpura: a practice gui-deline developed by explicit methods forthe American Society of Hematology. Blood1996;88:3-40.

[2] Kojouri K, Vesely SK, Terrell DR, George JN.Splenectomy for adult patients with idiopa-thic thrombocytopenic purpura: a systema-tic review to assess long-term plateletcount responses, prediction of response,and surg ica l compl icat ions . Blood2004;104:2623-34.

[3] Vesely SK, Perdue JJ, Rizvi MA, Terrell DR,George JN. Management of adult patientswith persistent idiopathic thrombocytopenicpurpura following splenectomy: a systema-tic review. Ann Intern Med 2004;140:112-20.

[4] Guidelines for the investigation and mana-gement of idiopathic thrombocytopenic

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are described even after 2 o 3 years from diagnosis in nonsplenectomized patients as shown by a large retrospectiveobservational study, aimed at calculating the incidence ofcomplete or partial remissions in a cohort of 114 adult patientswith severe ITP during a long follow-up [19]. In this study, aresponse rate higher than 80% was reported in non splenec-tomized patients, so that the authors suggest that splenectomymay be delayed for up to 3 years, when the chances ofremission become very low.Future trials on ITP treatment should possibly focus more onbleeding manifestations and related morbidity than on justcorrecting platelet count. We should be aware that plateletcount is a surrogate endpoint with several limitations that doesnot immediately translate into a substantial clinical benefit,particularly if the treatment-related toxicity is relevant. ACochrane review criticized the results of clinical trials withTPO-ra due to the lack of clear evidence of their ability toreduce major bleeding and to improve survival. While thiscriticism should not be over emphasized, [34] a better balancecould be achieved among the various stakeholders involved inthe process of approval and assessment of new treatments forITP [35–38]. In this regard, EMA is preparing new guidelines forfuture trials.

childol 20F, Croin C

safethic

MedGeor

GT

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ewla, Busepornt oloodCrower Mlogyline f011

Disclosure of interest: Francesco Rodeghiero is in the speakers’ bureau forAmgen, GlaxoSmithKline and member of Data Safety Monitoring Board forSuppremol, Marco Ruggeri: None.

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ITP and international guidelines what do we know, what do we need?AUTOIMMUNE CYTOPENIAS

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