Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily Practice and Clinical Research?

Immune Thrombocytopenia Nomenclature, Consensus Reports, and Guidelines: What Are the Consequences for Daily Practice and Clinical Research? Marc Michel New insights into the pathophysiology and the natural history of immune thrombocytopenia (ITP) and new therapeutical approaches have emerged in the last 10 years that have made necessary the update of previous guidelines. An important step towards the harmonization on both the definition of the disease and the phases of the disease, the objectives of treatment, and the criteria of response to be used in clinical trials has been first made possible throughout the International Working group on ITP. This important step has been followed by an international consensus report and the updated American Society of Hematology (ASH) guidelines focused on the investigation and management of ITP taking into account the data from the most recent clinical trials in the field. In this article, the consequences and translation that these guidelines may have or not on daily practice and on future clinical trials are discussed and the few controversies are pointed out. Whereas these guidelines are helpul for the investigation of ITP and for the harmonization of clinical trials, some area of uncertainties do remain for the best management of ITP and especially the choice of the best second-line strategy in persistent ITP is still far from being consensual. Semin Hematol 50:S50–S54. C 2013 Published by Elsevier Inc.

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he American Society of Hematology (ASH) published a comprehensive guideline on immune thrombocytopenia (ITP) in 1996 mainly based on expert opinion, which has long been the standard reference for both the diagnosis and treatment of the disease.1 Following this, in 2003, the British Committee for Standards in Haematology published a guideline that provided a practical and rational approach to the investigation and management of patients with ITP in various clinical situations, also based on a systematic review of the literature.2 However, in the last 10 years, the emergence of new therapies—first rituximab3,4 and subsequently the thrombopoietin-receptor (Tpo-R)

Department of Internal Medicine, National Referral Center for Adult Immune Cytopenias, Henri-Mondor University Hospital, Cre´teil, France. Publication of this article was supported by the International Cooperative ITP Study Group (ICIS). Conflicts of interest: none. Address correspondence to Marc Michel, MD, Department of Internal Medicine, National Referral Center for Adult Immune Cytopenias, Henri-Mondor University Hospital, Assistance Publique Hopitaux de Paris, Universite´ Paris-Est Cre´teil, 51 Av. du Mal de Lattre de Tassigny, 94010 Cre´teil cedex, France. E-mail: [email protected] 0037-1963/$ - see front matter & 2013 Published by Elsevier Inc. http://dx.doi.org/10.1053/j.seminhematol.2013.03.008

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agonists4,5—supported by several prospective ⫾ randomized studies3–5 have significantly changed the ITP panorama. A significant effort has thus been made in the last few years not only to harmonize the terminology (definitions, phases of the disease, disease outcome) of ITP but also to update the recommendations and guidelines for both investigation and treatment of ITP taking these new insights into consideration. These efforts have translated into three distinct international publications reported in Blood,6–8 two of which came from international collaborative groups involved in ITP and were mainly based on expert opinion (most of the experts were involved in both manuscripts) and delphi-like panels,7,8 the third being an update of the 1996 ASH guidelines.9 A number of European countries such as France, Germany, Spain, Norway, and Sweden have also established national recommandations or guidelines adapted from these three publications (recently summarized by Ghanima et al).10 Since there might sometimes be a gap between guidelines and the daily clinical practice, the purpose of this article is to briefly analyze the impact that these publications may have already had on clinical practice and research, and to point out the questions and important issues that these guidelines did not address especially in term of management.

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ITP nomenclature, consensus reports and guidelines

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TERMINOLOGY According to the new definitions for terminology,7 the acronym ITP remains but should not stand anymore for ‘‘idiopathic thrombocytopenic purpura’’ but rather for ‘‘immune thrombocytopenia’’ since a significant proportion of patients with ITP do not have purpura. Moreover, to avoid any misdiagnosis and to take into account the variability of the normal range of the platelet count in different populations, a platelet cut-off of less than 100  109/L is now required for considering the diagnosis of ITP. Looking at the last 200 publications reported on PubMed (http://www.ncbi.nlm.nih.gov/pubmed) on September 10, 2012, using only the acronym ‘‘itp’’ as a keyword (and after the exclusion of basic science and animal models reports); it appears that 80% of them are in keeping with the new standards of terminology and that the terms immune, idiopathic, or seldom autoimmune thrombocytopenic purpura are still used in only approximately 20% of the reports. Furthermore, 90% of these publications use a platelet number of 100  109/L as the threshold for considering ITP diagnosis and quote at least one of the three references6–8 mentioned in the introduction. The degree of compliance with this terminology seemed much less obvious in ongoing or planned clinical trials focused on ITP as they appear on the www.clinicaltrials.gov website but this point was more difficult to determine as several trials appearing on the website could have been designed prior to the publication of guidelines and consensus reports.

PHASES OF THE DISEASE One of the major new concepts provided by the International Working Group (IWG) focused on ITP was to split the disease into three different phases based on what is known of the natural history of ITP especially in adults.7 While ITP has formerly been defined as ‘‘chronic’’ if it lasted for more than 6 months and ‘‘acute’’ if it was a self-limited and transient disease, the IWG members agreed on three distinct phases of the disease, namely (1) the initial

phase, ‘‘newly diagnosed ITP,’’ from the time of diagnosis up to 3 months; (2) ‘‘persistent,’’ between 3 and 12 months from diagnosis; and (3) ‘‘chronic phase,’’ now defined as a disease duration of more than 12 months, a period of time beyond which the occurrence of a spontaneous remission becomes less likely although still possible.11 This distinction of three different phases is actually very important in term of potential consequences in that it suggests that different therapeutic options should be considered for every phase and at least theoretically implied that both the time of splenectomy, the recognized ‘‘gold standard’’ of treatment for adult chronic severe ITP as well as the use of Tpo-R agonists licensed in Europe only for chronic ITP should be postponed (Figure 1). Has this terminology now entered into clinical pratice? Again, looking at the recently designed trials listed on the www.clinicaltrials.gov website, it appears that a number of studies do not include specifically the phase in the eligibility criteria taking into account these new definitions while few others do (eg, Prednisone or Dexamethasone in Treating Patients With Newly Diagnosed, Previously Untreated Primary Immune Thrombocytopenic Purpura, ClinicalTrials.gov Identifier: NCT00657410; The Efficacy of Dexamethasone Versus Dexamethasone Combined With Rituximab in Patients With Newly Diagnosed Idiopathic Thrombocytopenic Purpura (ITP) NCT00909077).12 The terms ‘‘refractory,’’ ‘‘untreated ITP,’’ or yet ‘‘steroid-resistant ITP’’ are still predominantly used in most of the studies. However, it is likely that this new terminology will be increasingly used in future in clinical trials in order to facilitate the comparison of data from different studies and to improve our knowledge about the natural history of the disease.

DEFINITION OF RESPONSE TO TREATMENT: WHERE DO WE STAND IN RECENTLY DESIGNED CLINICAL TRIALS? The report from the IWG proposed standardization of the criteria for response to therapy that should be

« acute ITP »

chronic ITP

BEFORE

6 months Newly-diagnosed ITP (initial phase) 3 months

Persistent phase

Chronic phase

12 months NOW

Disease onset

Figure 1. New definitions for the phases of the disease.6

M. Michel

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used in clinical trials. Hence, a complete response (CR) has been defined as an increase in platelet count to 4 100  109/L, and a clinically relevant response as a platelet increase to 4 30  109/L with at least a twofold increase of the baseline (ie, pretreatment) count and the absence of bleeding. Obviously, the expected time of response as well as the duration of the response could be highly variable depending on the mechanism of the drug or procedure. The ASH 2011 guidelines also recommend use of the same criteria.9 These definitions, which were not addressed in past guidelines, are also an important step towards standardization for future clinical trials and have already been used in recently designed and/or ongoing trials (see, eg, the study design of the NCT01356511 and NCT01525836 trials on www.clinicaltrials.gov). Conversely, in ongoing trials designed to assess the efficacy of Tpo-R agonists in childhood ITP, a durable response has been defined as an increase of the platelet count Z 50  109/L over at least 6 of the 8 last weeks of the treatment period (studies NCT01444417 and NCT01520909). This criterion is the same as the one previously used in the romiplostim pivotal studies in adult ITP,13 but some researchers would consider this to be an unnecessarily high cut-off since a count of 30109/L is usually regarded as ‘‘safe.’’

INITIAL WORKUP TO RULE OUT SECONDARY ITP The criteria for diagnosis of ITP in both children and adults in both the international consensus report and the new ASH guidelines8,9 are similar and both agreed on the unproven or uncertain benefit of various tests, including measurement of antiplatelet antibodies or the bleeding time. The only important difference beetween these two guidelines was the place of the bone marrow examination, which was considered as required in selected patients (especially in patients aged 60 years and above) in the consensus report whereas in the ASH guideline, it was considered as ‘‘not necessary irrespective of age in patients presenting with typical ITP’’ (grade 2C recommendation). There are insufficient data in the literature to estimate compliance in daily practice with these recommendations. The relevance of performing or not at time of ITP onset some tests such as the direct antiglobulin test, the antinuclear antibodies or antiphospholipid antibodies remain a matter of debate.

GUIDELINES AND RECOMMENDATIONS FOR TREATMENT Newly Diagnosed ITP There is general agreement that adults with a count ofo30  109/L with bleeding at diagnosis

require treatment. The platelet count alone is not the only consideration.8 The efforts made by the IWG on ITP for proposing and validating a consensual bleeding assessment tool14 tailored for ITP are an important step toward the standardization of the management. The first line of treatment for newly diagnosed ITP is generally agreed and based on the use of corticosteroids ⫾ intravenous immunoglobulin (IVIg) since anti-D is not licensed and available for ITP in most if not all European countries. The treatment strategy in adults with newly diagnosed ITP has not changed significantly in the last 10 years and overall, by using corticosteroids ⫾ IVIg, approximately 85%–90% of the patients have at least a transient initial response. The ‘‘only’’ controversial question in adult ITP not answered by the recent guidelines is whether dexamethasone may be better than a course of prednisone/prednisolone in terms of the magnitude and the duration of response.15,16 To address this question, the statement reported in the 2011 ASH guidelines, ‘‘longer courses of corticosteroids are preferred over shorter courses of corticosteroids or IVIg as first-line treatment,’’ is ambiguous and not very helpful. As suggested in the international consensus report,8 only a prospective randomized controlled trial comparing the efficacy of a single course of dexamethasone at 40 mg/d for 4 days with a ‘‘standard’’ corticosteroids regimen (prednisone at 1 mg/kg per day over 2–4 weeks) could answer this question. However, indirect evidence suggests that dexamethasone is unlikely to modify the natural course of ITP,4 and some of the data suggesting the opposite were biased by the use of repeated (every 4 weeks) courses of dexamethasone.15 In newly diagnosed childhood ITP, the debate has long been focused on whether or not the ‘‘wait and watch’’ strategy (ie, observation) should be preferred to the ‘‘intervention’’ one. The 2011 ASH guidelines, based on review of the data from the literature,9,12 now clearly recommend that children with no bleeding or mild bleeding should

Table 1. First-Line Treatment Options

Clinical Situation Newly diagnosed ITP

Therapy Option  Dexamethasone  or    

Prednisone (?) Methylprednisolone IVIg Intravenous anti-D (Rho) immunoglobulin

Abbreviations: ITP, immune thrombocytopenia; IVIg, intravenous immunoglobulin.

ITP nomenclature, consensus reports and guidelines

Table 2. Strength of Recommendations for

Second- and Third-Line Treatments in Adults With Chronic ITP Treatments

Strength of Recommendation Consensus ASH Report Guidelines

Second-line treatments TPO receptor agonists Rituximab Splenectomy Third-line treatments TPO receptor agonists

A B C

2C 2C 1B

A

1B

be managed by observation alone regardless of platelet count (grade 2B), which is a major change from the 1996 guideline (Table 1).

Persistent and Chronic ITP The best second-line treatment in both adults and children is still a matter of debate and this point has not been addressed either by the international consensus report or by the ASH guidelines, mainly because there is no clear answer from review of the literature, and there is no drug specifically licensed in Europe for persistent ITP. Most experts and national guidelines9,17 now agree that splenectomy, the long-recognized gold standard second-line therapy18 should be delayed as much as possible and considered only in patients with chronic and severe (ie, serious bleeding) ITP, and they also agree that the long-term use of corticosteroids should be avoided.8 However, there were significant discrepancies in the strength of recommendation between the international consensus report and the ASH

-Steroids* -IVIg* -(Anti-D)

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guidelines (see Table 2). Indeed, whereas Tpo-R agonists were stongly recommended by the IWG, the strength for recommending splenectomy was higher in the ASH guidelines as summarized by the following statement ‘‘we recommend splenectomy.for patients who have failed corticosteroid therapy’’ (grade 1B) (ie, either unresponsive or who have a relapse after a transient initial response). These differences reflect the fact that the best corticosteroidsparing strategy for the management of a patient with severe persistent ITP, in adults as in children, is far from being established. In keeping with these uncertainties, some studies have clearly shown the high degree of heterogeneity in the choice of second-line treatment among various European countries,19 this choice being mainly based on personal experience, on the availability of the drugs, and on the patient profile,9 as well as pharmacoeconomic criteria, noting that for expensive drugs, the rate and mode of reimbursement may be highly variable. In the future, a particular effort should be made in order to find and test the efficacy and safety of new second-line therapeutic options for persistent ITP. Figure 2 summarizes the different treatment options that may be used in different phases of disease in adults with ITP who require treatment. The use of Tpo-R agonists for few months could be an attractive way for managing persistent ITP in adults as a bridge toward splenectomy, but currently their high cost limits promotion of their wider use.

CONCLUSION Great efforts have been made in the last 5 years to harmonize the terminology and definitions for ITP and to provide some recommendations about who should be treated and how, taking into account the place of new therapies that have emerged in the past 10 years. The translation of these new definitions into recent clinical studies and beyond is increasing

- corticosteroids (less is better)

- dapsone, danazol, vinka-alkaloids (?) - Rituximab (?) Consider - TPO-R agonists (?)

Splenectomy

O N S E T

T0

3 months

* Hp eradication 12 months if applicable

-TPO-R agonists* -Rituximab -Immunosuppressors (azathioprine)

Note : * labelled for ITP

Figure 2. Therapeutic options for first-, second-, and third-line treatment in adult ITP (Europe).

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reflecting a rather good compliance with the guidelines. However, despite these efforts, there are still some unmet clinical needs that none of the recent reports have addressed due to a lack of data. It is thus still difficult to provide strong recommendations to the clinicians for the management of persistent ITP. In the future, based on better knowledge of the pathophysiology of the disease, it will be necessary to promote collaborative prospective clinical trials to assess the efficacy and safety of new secondline treatments currently being developed in other autoimmune disease (such as drugs targeting B cells, costimulatory molecules, or interleukin-17). Moreover, some recommendations could be provided for the management of secondary ITPs, which may require a more specific approach. Lastly, the panels of experts should integrate colleagues from other parts of the world, in addition to those from Europe and North America, who may have different perspectives on the disease.

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