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Keywords:

  • bleeding;
  • thrombopoietin;
  • thrombopoiesis;
  • chronic immune thrombocytopenic purpura;
  • platelet

Summary

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

There is currently no consensus on how best to manage refractory immune thrombocytopenic purpura (ITP). In part, this reflects the need for individualized treatment due to the wide spectrum of patients' requirements and responsiveness to therapies. The objective of this review is to provide a clinically useful guide to current management strategies. This article suggests investigations to identify factors that may exacerbate thrombocytopenia and underlie poor therapeutic responses, and highlights emerging therapies, including the thrombopoietic agents, which are anticipated to dramatically alter the natural history of “refractory” ITP. Morbidity, mortality and heath-related quality of life are also discussed.


Incidence and definition of ‘refractory’ ITP

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

Immune thrombocytopenic purpura (ITP) is a relatively common disorder, affecting around 5–10 adults per 100 000 in the western world. A systematic review of 49 articles reported that the common definition of ‘refractory ITP’ was a low platelet count persisting after splenectomy and the need for active treatment to maintain a ‘safe’ platelet count (platelet cut-off values ranged from ≤20 × 109/l to ≤50 × 109/l) (Ruggeri et al, 2008). Fewer than 10% of patients who are initially diagnosed with ITP would eventually fit these criteria (Portielje et al, 2001; George, 2006).

The term ‘refractory’ may be used in a number of different ways in the context of ITP. Whether a specific platelet count, lack or brevity of response to treatment, disease duration, and/or presence or severity of bleeding symptoms should be incorporated in the definition of refractory disease remains controversial. The consensus definition of refractory ITP is further complicated as an increasing proportion of patients and clinicians now pursue alternative treatment strategies prior to considering splenectomy as therapeutic strategies for ITP expand. Novel therapies currently under clinical investigation effectively increase platelet counts and reduce bleeding in a high percentage of “refractory” pre- and postsplenectomy patients who require further treatment, including those who do not respond to other therapies.

An international committee has been established to work towards consensus in terminology in ITP (http://www.tcpeha.org). Their preferred definition of ITP comprises:

  • 1
    Persistent and severe thrombocytopenia (platelet count ≤20 × 109/l);
  • 2
    Continuing requirement for therapies to increase and sustain the platelet count; although patients may or may not respond well to treatment;
  • 3
    Failure to respond to splenectomy, if attempted.

The development and use of standardized terminology and definitions in ITP would greatly facilitate comparisons of clinical trials for emerging and existing therapies and thereby encourage the development of evidence-based management guidelines.

Pathophysiology: accelerated platelet destruction and disturbed platelet production

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

The relative importance of a number of immunopathological pathways may explain differences between patients in the severity and/or duration of their thrombocytopenia, and its response to treatment. The primary event in the initiation of ITP is presumed to be the development of antiplatelet antibodies, which induce accelerated platelet clearance by FcγR-bearing mononuclear cells of the reticuloendothelial system, primarily those in the spleen. Classically, platelet destruction has been thought to overwhelm the thrombopoietic capacity of the bone marrow. Additional immune disturbances also play a role. In particular, T cell dysfunction may contribute to the thrombocytopenia, not only by regulating the biogenesis of autoantibody-producing B-cell clones, but also via direct cytotoxicity to platelets and megakaryocytes (Olsson et al, 2003; Panitsas et al, 2004; Sayeh et al, 2004). Complement activation may promote platelet phagocytosis and possibly mediate direct complement-mediated platelet lysis in some patients (Kurata et al, 1985).

For many years, it had been assumed that platelet production was enhanced in compensation for the accelerated immune platelet destruction. This was based on radioactive allogeneic platelet survival studies, and strongly supported by the typical bone marrow histology of patients with ITP showing normal or increased numbers of megakaryocytes. However, there is now substantial evidence indicating that impaired thrombopoiesis contributes to the thrombocytopenia of ITP. In the late 1980s, studies of platelet kinetics using radiolabelled autologous (instead of allogeneic) platelet transfusions indicated that platelet survival in ITP was longer than previously thought (up to 3 d), and that turnover or production of new platelets was not increased (Stoll et al, 1985; Ballem et al, 1987; Gernsheimer et al, 1989). In support of this, ultrastructural studies of the bone marrow revealed that megakaryocytes are often damaged and apoptotic in ITP, and patient plasma containing antiplatelet antibodies inhibits megakaryocyte differentiation in vitro (Chang et al, 2003; Houwerzijl et al, 2004).

Thrombopoietin (TPO) is the primary growth factor that regulates megakaryocyte development and platelet production. A prospective study of over 200 patients with ITP found no correlation between TPO levels and platelet counts, and neutralizing anti-TPO antibodies were detected in only one patient who, despite this, had TPO levels within the normal range (Aledort et al, 2004). When compared to other disorders, such as aplastic anaemia, amegakaryocytic thrombocytopenia, and following myeloablative therapy, TPO levels in ITP are lower despite equally severe thrombocytopenia (Porcelijn et al, 1998; Gu et al, 2002). Moreover, the efficacy of TPO receptor agonists in ITP suggests that platelet production is suboptimal and may be enhanced to overcome the immune-mediated platelet destruction in a large proportion of patients (Rice et al, 2001; Nomura et al, 2002; Bussel et al, 2006, 2007a; Newland et al, 2006; Kuter et al, 2008).

This dual explanation for the thrombocytopenia has important implications for therapy. The acute (first 24 h) platelet response to intravenous immunoglobulin (IVIG) and intravenous (IV) anti-D correlates with the number of large platelets (newly-produced platelets) prior to treatment, suggesting that patients with a higher rate of platelet production may respond better to therapies that reduce platelet destruction (Karpatkin & Charmatz, 1969; Michel et al, 2005). Accordingly, a patient with a particularly low rate of platelet production may be more refractory to these therapies.

Investigations to identify factors that may contribute to ‘refractoriness’

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

An important cause of refractoriness to immunomodulatory treatment for ITP is an alternative diagnosis of a non-immune thrombocytopenia. The thrombocytopenia of patients with ‘true’ ITP (i.e. due to autoimmunity) may, in addition, be initiated or exacerbated by certain factors. Probably the most common, especially in older patients, is myelodysplastic syndrome (MDS) presenting with isolated thrombocytopenia. Inherited thrombocytopenias, such as the May Hegglin (MYH9)-related disorders are also often missed (Bader-Meunier et al, 2003). Additional/alternative causes of thrombocytopenia, and suggested investigations to identify them, are listed in Table I and detailed in the following section. Although uncommon, these are more frequent in the group of patients who do not respond well to standard treatments for ITP.

Table I.   Suggested differential diagnosis and investigations for patients with refractory ITP.
Factors that may exacerbate the thrombocytopenia in true ‘primary’ ITPSuggested laboratory evaluation or management to consider
 Drugs e.g. valproic acid, quinine-quinidine, oestrogensConsider alternative drugs or dose reductions (e.g. reduce valproate levels to <100 mg/l); drug dependent antiplatelet antibody testing
 InfectionPolymerase chain reaction for human immunodeficiency virus, hepatitis C, Epstein-Barr virus, cytomegalovirus, parvovirus, human herpesvirus-6 and -8; screen for Helicobacter pylori
Secondary ITP
 Systemic lupus erythematosus and other collagen diseasesAntinuclear antibody (ANCA), anti-double-stranded DNA, C3, C4, p-ANCA, c-ANCA
 Common variable immune deficiencyQuantitative immunoglobulin levels; postvaccination specific antibody titers
 Evans syndromeDirect antiglobulin test, reticulocyte count, evidence of haemolysis
 Autoimmune lymphoproliferative syndromeFlow cytometry for CD3+ CD4/CD8 TCRαβ+ T cells
 Malignant lymphoproliferative B cell disorders e.g. chronic lymphocytic leukaemia, lymphomaFull blood count, smear, and flow cytometric analysis
 Non-haematological malignanciesInvestigate as clinically appropriate
 Paroxysmal Nocturnal HaemoglobinuriaFlow cytometric analysis of CD55 and CD59 expression on peripheral blood cells
 Thrombotic thrombocytopenic purpuraLevels of ADAMTS13 and its inhibitor
Non-immune disorders mimicking ITP
 InfectionSee above
 Other malignant/dysplastic marrow disorder e.g. myelodysplastic syndromeBlood and bone marrow studies including fluorescent in situ hybridization as part of cytogenetic analysis
 Inherited thrombocytopeniasBlood smear, duration of thrombocytopenia, family history, associated findings, molecular testing

Drug-induced thrombocytopenia

Medications are important to consider as a cause of “secondary” ITP. Drug-induced or exacerbated thrombocytopenia usually resolves rapidly following discontinuation of the medication. Well-recognized causes of thrombocytopenia include heparin, quinidine, and valproic acid but many drugs and other agents including foodstuffs, i.e. tahini, have been implicated in causing ITP in individual cases. A web site, created by the team of Dr. James George, lists these agents and their reported frequencies (http://w3.ouhsc.edu/platelets/ditp.html).

Although the initiation of ITP may have been idiopathic, its perpetuation or resistance to treatment may be attributable to subsequent initiation of a medication. For example, a “routine” thrombocytopenia becoming refractory to treatment associated with oestrogen use has been reported in four patients (Onel & Bussel, 2004). While women with ITP may use oestrogen therapy to ameliorate heavy menstrual bleeding and as preventative therapy for steroid-induced osteoporosis, cessation of oestrogen should be considered in patients with refractory thrombocytopenia.

Infection-related thrombocytopenia

Infections have been implicated as an instigating factor in acute ITP, especially in children, and also may underlie acute exacerbations of thrombocytopenia. Antigenic mimicry has been proposed as a mechanism by which viruses could trigger the development of ant-platelet autoantibodies (Musaji et al, 2004); in addition, the phagocytic activity of macrophages may be enhanced following infection (Musaji et al, 2004, 2005), and murine studies indicated that picogram quantities of lipopolysaccharide (LPS) synergized with antiplatelet antibody therapy to exacerbate thrombocytopenia (Tremblay et al, 2007).

Chronic infections, particularly human immunodeficiency virus (HIV) and hepatitis C virus infection (HCV), are well known causes of secondary ITP. A clear relationship is demonstrable between HIV viral load and the degree of thrombocytopenia (Kaslow et al, 1987). Management of refractory thrombocytopenia in HIV-associated ITP may therefore require antiretroviral therapy. In HCV the situation is more complex. Suppression or eradication of HCV has not been universally linked to platelet improvement, and treatment of HCV with interferon may exacerbate thrombocytopenia and precipitate serious hemorrhage (McHutchison et al, 2007).

Other chronic infections that may be less clinically apparent can contribute to the pathology of refractory ITP, in particular Helicobacter pylori (H. pylori), and cytomegalovirus (CMV). Therefore it may be prudent to investigate for H. pylori and CMV in patients with persistent or treatment-resistant ITP. Higher response rates of ITP associated with H. pylori eradication have been reported in Japan and Italy as compared to the United States and other European countries (Kuwana & Ikeda, 2006), possibly due to different strains of H. Pylori or to the immunogenetics of the populations. CMV may directly infect platelets and megakaryocytes, promoting immune destruction (Xiao et al, 2006). Recent studies in China have suggested that acute ITP in childhood is frequently associated with CMV infection although this does not seem to be very common in the United States (Levy & Bussel, 2004). Experience in four patients with refractory ITP suggested that eradication of CMV dramatically improved response to ITP therapies (DiMaggio & Bussel, 2007). These CMV cases were largely asymptomatic; accurate and timely identification of the infection requires polymerase chain reaction (PCR).

Associated immune disorders

The detection of associated immunodeficiency is particularly important to direct therapy, as some treatments for ITP may be less effective in these patients and also have more serious adverse effects. The association of ITP with autoimmune haemolytic anaemia (AIHA), and sometimes neutropenia, occurs in Evans syndrome, which may often be associated with underlying immunodeficiency, especially common variable immune deficiency (CVID). These patients typically endure unremitting disease characterized by frequent exacerbations that may be severe. Rituximab and/or mycophenalate mofetil are often useful, although response to treatment is variable, and tachyphylaxis can develop (Norton & Roberts, 2006). Flow cytometric analysis of peripheral blood T-cell subsets has been recommended for patients with suspected Evans syndrome to exclude underlying autoimmune lymphoproliferative syndrome (ALPS) (Teachey et al, 2005; Norton & Roberts, 2006). If CVID is identified, the use of IVIG is probably warranted as a mainstay of treatment even if other treatments, such as rituximab or splenectomy are also required for persisting thrombocytopenia or anemia.

Other diagnoses to consider

More than 21 syndromes of inherited thrombocytopenia are recognized, although there is overlap in these syndromes. Even in very experienced clinics, only around 60% of these patients can be assigned a specific syndrome. Reports of unsuccessful splenectomies and administration of immunosuppressive chemotherapy to these patients are not infrequent, indicating the potential for confusion with refractory ITP (Bader-Meunier et al, 2003). In our clinical experience, paroxysmal nocturnal haemoglobinuria (PNH) and thrombotic thrombocytopenic purpura (TTP) may rarely mimic ITP, with an isolated thrombocytopenia showing no overt evidence of haemolysis.

Myelodysplastic syndrome is a relatively common condition in elderly patients in which, like ITP, the marrow is typically hypercellular in conjunction with marked peripheral cytopenia. Patients with longstanding diagnoses of ITP may eventually have repeat bone marrow examinations that reveal clinical or cytogenetic MDS. Enhancing the confusion is the fact that the thrombocytopenia of MDS is at least partly autoimmune in certain cases (Cines et al, 1985). Hodgkin disease and chronic lymphocytic leukaemia (CLL) are usually evident at the time of the diagnosis of secondary ITP. Very occasionally, CLL may be in a very early state and must be suspected in the presence of a mild lymphocytosis and may be further characterized by immunophenotyping with flow cytometry.

Treatment options for refractory ITP

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

At present, there is no consensus for the treatment of refractory ITP. This is primarily because of the need for individualized treatment due to the wide variation between patients in terms of their unique needs and preferences, underlying pathophysiology, bleeding propensity, platelet responses to specific therapies, toxicities of treatments, and local availability especially for investigational agents. Nonetheless, treatment algorithms designed by a consortium of ITP specialists would be useful, especially in challenging cases. A management algorithm that outlines the suggested investigations for underlying/exacerbating factors of the thrombocytopenia and lists the conventional and investigational therapeutic agents discussed in the following section is presented in Fig 1.

image

Figure 1.  An investigation and treatment algorithm for patients with a diagnosis of ITP who are poorly responsive to first-line therapies. The available therapies are not listed in any suggested order of preference, as there is no consensus on this at present and the choice of agents should be chosen according to the individual patients clinical needs and preferences. TPO-R agonists are highlighted in red as they still available only in clinical trials. *Multi-agent therapy - IVIG and methylprednisolone plus IV anti-D and/or vincristine for induction and danazol plus azathioprine for oral maintenance therapy (Boruchov et al, 2007). ITP, immune thrombocytopenic purpura; IVIG, intravenous immunoglobulin; HIV, human immunodeficiency virus; H pylori, Helicobacter pylori; CMV, cytomegalovirus; SLE, systemic lupus erythematosis; ALPS, autoimmune lymphoproliferative syndrome; CVID, common variable immune deficiency; MYH9-RD, May Hegglin anomaly related disorders; MDS, myelodysplastic syndrome; CLL, chronic lymphocytic leukaemia; PNH, paroxysmal nocturnal haemoglobinuria; TTP, thrombotic thrombocytopenic purpura; TPO, thrombopoietin.

Download figure to PowerPoint

The goal is to maintain a platelet count at which minor bleeding symptoms (petechiae, bruises, oral bleeding) and treatment-related toxicities are acceptable, and the risk of major, life-threatening haemorrhage (gastrointestinal, intracranial) is minimal, while incorporating patient choice and quality of life. This typically involves long-term maintenance therapy with occasional additional treatments to achieve a rapid increase in the platelet count as required. Other approaches directed at reducing bleeding without necessarily altering the platelet count may be especially useful for patients with refractory ITP (Table II).

Table II.   Approaches to reduce bleeding in ITP (not directed at increasing the platelet count).
Oral contraceptive pill or hormonal intra-uterine device (e.g. Mirena®) to reduce menorrhagia
Avoidance of non-steroidal anti-inflammatory drugs and other therapies that may interfere with platelet function
Antifibrinolytic agents (especially for mouth and nose bleeding)
Proton-pump inhibitors for gastritis

First line therapies: low-dose corticosteroids, IVIG therapies

A proportion of ‘refractory’ patients respond to but continue to require first-line treatments for ITP, corticosteroids and IVIG. Very low or intermittent doses of glucocorticoids (5 or 10 mg daily or alternate days) or repeated IVIG or IV anti-D infusions may be useful to achieve acute platelet count increases or as maintenance therapy in certain patients with low counts and bleeding who cannot be managed in another way. This may reduce requirements for corticosteroids, although the highest ‘safe’ dose is not well defined. Toxicities of prolonged corticosteroid therapy often become debilitating over time; even low doses may accelerate the development of osteoporosis or diabetes mellitus. Frequent immunoglobulin infusions may become frustrating for some patients, and side effects such as headache, fever-chill reactions, or chronic anemia may be significant. IV anti-D is less effective in patients who have undergone splenectomy (Scaradavou et al, 1997). As patients become increasingly refractory to therapy with these agents, alternative treatment options are required (Bussel et al, 1988).

Splenectomy

The spleen is the primary site of antibody production and clearance of antibody-coated platelets, and splenectomy will have been performed or carefully considered in the majority of patients who have chronic refractory ITP. Splenectomy may be performed laparoscopically, and offers a 60–70% chance of cure for patients with chronic ITP, (Kojouri et al, 2004; Vianelli et al, 2005). The site of platelet destruction, as indicated by 111In-labelled autologous platelet studies, has been reported as a strong predictor of likely response to splenectomy (Najean et al, 1997), although these studies are not widely available and the findings have not been confirmed. In this study, over 90% of patients with primarily splenic platelet destruction achieved remission while suboptimal responses were seen in the 90% of patients with hepatic or diffuse platelet destruction (Najean et al, 1997). Most relapses to splenectomy occur in the first 2 years although a small number continue to relapse after that time (Kojouri et al, 2004).

Patients who relapse following splenectomy may have accessory spleens. Platelet responses following excision of accessory spleens are less common than for the initial procedure (Velanovich & Shurafa, 2000) although patients who relapse late following initial splenectomy have a higher rate of response (Schwartz et al, 2003).

Currently, there is a trend towards a decreased rate of splenectomy in ITP (George, 2006). Although a safe procedure in the vast majority of patients, complications include surgical mortality, thromboembolic events, and overwhelming sepsis, and the long-term effects remain poorly understood (Dolan et al, 2007). With the emergence of alternative therapies, clinicians increasingly consider delaying splenectomy until later in the course of the disease to allow more time for spontaneous resolution (Cooper et al, 2002; George et al, 2003; Cines & Bussel, 2005; Kuter et al, 2008).

Second-line therapies: danazol, immunosuppressive agents (azathioprin, mycophenalate mofetil, vinca alkaloids, cyclosporin A, dapsone) and cytotoxic chemotherapy (cyclophosphamide)

A proportion of patients will be truly refractory to first line therapies and to splenectomy, and require further treatment with primarily immunosuppressive second-line therapies. Data on the current second-line treatment options available for these patients have been reviewed extensively elsewhere (Vesely et al, 2004; George, 2006; Arnold & Kelton, 2007; Godeau et al, 2007) and an algorithm potentially suggesting how and where they might be used exists (Cines & Bussel, 2005). The discussion below is therefore focused on emerging treatment strategies, namely anti-B cell therapy with rituximab, multi-agent therapy and the thrombopoietic growth factors (Fig 1).

Rituximab

Rituximab, a monoclonal anti-CD20 antibody that induces transient depletion of B cells, was originally introduced for the treatment of non-Hodgkin lymphoma and is now emerging as an effective and relatively safe therapeutic option for patients with refractory ITP. In a large, systematic review of the efficacy and safety of rituximab treatment in 313 patients with ITP, 62·5% of patients had a platelet response (platelet count ≥50 × 109/l). A ‘complete response’ (platelet count >150 × 109/l) occurred in 46·3% of patients, and a ‘partial response’ (platelet count 50–150 × 109/l) in 24% (Arnold et al, 2007). Preliminary data available in abstract form indicates that approximately 1/3 of the complete responders following initial therapy remained in remission for more than 1 year, and around half of these patients continued their response for at least a further 5 years (Cooper et al, 2004; Patel et al, 2006).

Rituximab is associated with manageable infusion-related side effects. Serious adverse events including fatalities have been identified (Arnold et al, 2007; Cooper et al, 2007), although many of these were apparently unrelated to the rituximab and occurred in high-risk patients with multiple co-morbidities. Vulnerable patients include hepatitis B carriers and patients with systemic lupus erythematosus (SLE) receiving multiple chemotherapeutic agents in conjunction with rituximab. In a review comparing the efficacy and safety data for splenectomy and rituximab, both the rate and the duration of response were found to be substantially lower following rituximab (Cooper et al, 2007). No significant difference was found in response rates to rituximab between splenectomized and nonsplenectomized patients but patients with a longer duration of ITP (over 10–15 years) had lower response rates than other patients (Cooper et al, 2007).

New insights into the mechanism underlying response to rituximab in ITP indicate that, in parallel with B-cell depletion, significant changes occur in the T-cell compartment in patients who respond to rituximab with an increase in platelet count but not in the nonresponders (Stasi et al, 2007). The authors speculated that in the nonresponders to rituximab, the abnormal oligoclonal T-cell accumulation was no longer reliant on B-cell co-stimulation.

One important caveat is that the optimal dosing regimen for the use of rituximab in ITP has never been formally established. Doses lower than the standard 375 mg/m2 × 4 (100 mg/week for 4 weeks) are effective in ITP, and may have a more favourable side-effect profile in addition to substantially lower cost (El-Najjar et al, 2006; Provan et al, 2007). Further study of dosing regimen and when lower doses would be effective is required.

Re-treatment is successful in approximately 75% of patients who respond to rituximab but subsequently relapse (Cooper et al, 2007). The immunological toxicities of repeated therapy have not been fully explored.

Multi-agent therapy for acute platelet increases and maintenance therapy

It was recently reported that multi-agent therapy is effective in a majority of patients who are refractory to IVIG or corticosteroids when administered as single therapies. (Boruchov et al, 2007). For acute induction therapy, patients received IVIG and methylprednisolone plus IV anti-D and/or vincristine and 71% responded, 66% to a platelet count over 50 × 109/l. Of the 17 evaluable patients who subsequently started on danazol plus azathioprine as oral maintenance therapy, 76% achieved platelet counts over 50 × 109/l (Boruchov et al, 2007). The multiagent regimen was well tolerated.

Thrombopoietin receptor (TPO-R) agonists

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

The recognition that platelet production in ITP is suboptimal led to treatments that enhance thrombopoiesis. Following the identification and cloning of TPO in 1994 (Bartley et al, 1994; Lok et al, 1994; de Sauvage et al, 1994; Wendling et al, 1994), unmodified recombinant human TPO (rHuTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) were developed. Although these agents were primarily tested in chemotherapy-induced thrombocytopenia, PEG-rHu-MGDF was shown to increase platelet counts in three out of four patients with refractory ITP (Nomura et al, 2002). Clinical development of these agents was abruptly halted when both patients and healthy platelet donors receiving PEG-rHu-MGDF developed antibodies that cross-reacted with endogenous TPO, resulting in severe, prolonged thrombocytopenia (Li et al, 2001). Nonetheless, these studies demonstrated ‘proof of principal’ that stimulation of TPO-receptors with TPO growth factors could successfully and substantially increase platelet counts in healthy individuals, patients with ITP and in other thrombocytopenias (Andemariam et al, 2007).

The ‘second generation’ thrombopoietic growth factors are anticipated to dramatically change the management of ITP. These agents include TPO peptide thrombopoietic agonists [romiplostim or Nplate (formerly known as AMG 531)] and non-peptide, small molecule, TPO-R agonists [Eltrombopag (also known as promacta) and AKR-501]. Romiplostim and eltrombopag have completed phase I-III trials and both appear likely to be approved by the US Food and Drugs Administration before the end of 2008. A phase I trial of AKR-501 in healthy volunteers has been completed, and phase II study in patients with chronic ITP is well underway. Reviews of thrombopoietic growth factor therapy in ITP are available (Andemariam et al, 2007; Bussel, 2007; Kuter, 2007; Newland, 2007; Panzer, 2008). Therefore, discussion here is focused on the most recent data for the two agents most advanced in clinical development.

Short-term treatment with thrombopoietic agents increases platelet counts and decreases bleeding symptoms in patients with chronic ITP

Short-term (6-week) treatment with romiplostim and eltrombopag has been shown to produce dramatic platelet increases in the majority of patients with chronic ITP. Many of the patients successfully treated in these trials were refractory to splenectomy, and often the clinicians’ most difficult-to-treat patients (Bussel et al, 2006).

Romiplostim, a TPO-R peptide agonist, produced dose-dependent platelet increases in platelet count in healthy volunteers (Wang et al, 2004) and patients with chronic ITP when administered a single subcutaneous injection in two phase I-II trials (a total of 40 patients) (Bussel et al, 2006; Newland et al, 2006). In a study of weekly injections of romiplostim for 6 weeks (1 or 3 μg/kg) versus placebo, 12 of 16 (75%) of patients given romiplostim had their platelet counts at least doubled and increased to more than 50 × 109/l from a baseline of less than 30 × 109/l. Mean peak platelet counts were 135 × 109/l for 1 μg/kg and 241 × 109/l for 3 μg/kg doses respectively (Bussel et al, 2006).

Eltrombopag is a small molecule, TPO-R agonist administered as a daily oral tablet. In an international, multi-centre placebo-controlled trial of 118 adults with chronic ITP who were refractory to at least one standard treatment for ITP, platelet counts of over 50 × 109/l were achieved in 70% and 81% of patients receiving 50 mg and 75 mg doses for up to 6-weeks (Bussel et al, 2007a). Just under half of these patients had previously undergone splenectomy. These patients were found to respond equally well as patients who had not had a splenectomy. Bleeding symptoms assessed using the World Health Organization bleeding scale decreased as platelet counts increased and recurred as platelet counts fell to pretreatment levels following cessation of therapy. A second 6-week phase 3 study, available in abstract form, confirmed the results of the first study (Bussel et al, 2007b).

Efficacy and safety of long-term therapy with thrombopoietic agents

Results from two parallel 6-month multicentre trials with romiplostim were recently published, involving 63 splenectomized and 62 non-splenectomized patients (Kuter et al, 2008). In the 6-month study of romiplostim, a ‘durable platelet response’, defined as a platelet count ≥50 × 109/l during 6 or more of the last 8 weeks of treatment, was achieved in 38% of splenectomized patients and 61% of nonsplenectomized patients (Kuter et al, 2008). Either durable platelet responses or ‘transient responses’ (defined as at least four platelet counts of ≥50 × 109/l from weeks 2 to 25) occurred in 79% of splenectomized and 88% of nonspenectomized patients and very few of the placebo patients. More patients treated with romiplostim were able to discontinue all of their concomitant ITP medications (52% in romiplostim group versus 19% of placebo group), and more patients in the placebo group received rescue therapies during the study period (P < 0·0001) (Kuter et al, 2008).

Long-term treatment studies with romiplostim and eltrombopag are ongoing, and preliminary data for both are available in abstract form (Bussel et al, 2007c,d). Prolonged use of TPO-R agonists in ITP appears to be a safe therapeutic option and may be effective even in patients considered to have refractory disease. The long-term trial with romiplostim includes patients treated for over 3 years and demonstrates apparent safety and efficacy of this approach. The great majority of the patients responded, to achieve platelet counts >50 × 109/l and, for the responders, two thirds of their counts were >50 × 109/l. The median platelet count was stably maintained for at least the first 2 years of the study and there was a low rate of exposure-adjusted, side effects.

The long-term trial with eltrombopag is also ongoing; preliminary safety and efficacy data for 89 subjects who had received treatment for a median duration of 151 d (2–333 d) have been presented in abstract form indicating that eltrombopag is well tolerated and sustained increased platelet counts during long-term treatment in the majority of patients (Bussel et al, 2007d). In this trial, patients were also able to taper or discontinue concomitant ITP medications.

Tolerability of TPO-R agonists: common mild-moderate side effects with romiplostim and eltrombopag

The TPO-R agonists appear to be very well tolerated, and few significant adverse events were reported for either romiplostim or eltrombopag. A 2-year update from the long-term extension study of romiplostim (published in abstract form) reported no trend for increasing adverse events with prolonged drug exposure (Bussel et al, 2007c). For optimal effect, no food must be taken 2 h before and 2 h after eltrombopag ingestion.

Outstanding concerns: potential, serious adverse events with TPO agents

The tolerability of these agents appeared impressive in the published short-term studies and as safety data accumulates from long-term studies. However, the use of thrombopoietic growth factors raises a number of concerns regarding potentially serious toxicities, the true likelihood of which is not yet known. Potential, adverse consequences of TPO-R stimulation have been identified although the majority of these have not been observed in clinical practice. These include autoantibody formation, thrombosis due to thrombocytosis or platelet activation, rebound worsening of thrombocytopenia upon cessation of treatment, increased bone marrow reticulin or collagen, stem cell depletion or stimulation of malignant haematological cells, and stimulation of solid tumour growth (Kuter, 2007). Preclinical trials of eltrombopag identified an association with cataract formation in young rodents but this was not observed in trials conducted in primates. The clinical trials with this agent have incorporated extensive eye screening programs and no evidence of this effect has been detected in humans. Potential toxicities of particular concern are discussed individually below.

Unlike for the first generation thrombopoietic agents, no neutralizing antibodies that cross-react with endogenous TPO have been identified in any of the patients receiving either agent. One patient who received romiplostim in the long-term extension study developed a neutralizing antibody to the study drug, but there was no cross-reaction with endogenous TPO and no effect on platelet response to therapy.

No stimulation of solid tumour growth has been observed. However, malignant haematopoietic cells are known to express the TPO-R, and preliminary reports from early trials of thrombopoietic therapy in MDS patients presented in abstract form indicated that in a small number of patients, romiplostim therapy lead to had increased blast counts (Kantarjian et al, 2007).

The endogenous rate of thrombosis is higher in the ITP population than in healthy controls (Aledort et al, 2004; McMillan & Durette, 2004), and an increase in the incidence of thrombosis is a potential risk associated with the use of thrombopoietic growth factors. However, the rate of thromboembolic events observed in patients on the clinical trials of romiplostim and eltrombopag is not increased over that seen in the placebo controls.

A rebound worsening of thrombocytopenia on cessation of therapy was observed in a minority of patients (four of 41 treated with romiplostim on the 6 week trial) (Bussel et al, 2006), attributed to increased clearance of endogenous TPO by the expanded megakaryocyte mass. Therefore, cessation of treatment with TPO mimetic agents without tapering should be avoided.

The primary concern with the TPO-R agonists is the treatment-induced increase in bone marrow reticulin, thought to be due to increased transforming growth factor-β that is released by megakaryocytes and platelets in the bone marrow (Chagraoui et al, 2002). Although this finding has only been reported in eight patients treated with romiplostim thus far (Bussel et al, 2007c), bone marrow examination has not been done routinely in any of the clinical trials with the second-generation TPO agents and trials of the small molecules have not yet been for more than 6 months. The pathological implications of increased bone marrow reticulin are not well understood. Development of collagen fibrosis, myelofibrosis, or clonal myeloproliferative disorders has not been observed in any case with any agent thus far.

Role of TPO-R agonists in chronic refractory ITP

The kinetics of the platelet increase in patients who respond to the thrombopoietic agents is different to that seen with IVIG and IV anti-D, which typically occur within 12–48 h at high dose. On average, platelet responses to an effective dose of thrombopoietic growth factors commences at day 5 to 10, peaks around 14 d after initiating therapy, and returns to baseline at day 21.

The response rate of around 80% seen with both romiplostim and eltrombopag is as high as that reported for corticosteroids, IVIGs, and splenectomy and higher than that for any other treatment of ITP including rituximab; in addition, the TPO-R agonists are well tolerated and very few side effects are seen. These findings were observed in patients who were typically difficult to treat with conventional management, and many were able to discontinue other therapies after initiating these agents. Therefore, it is anticipated that TPO-R agonists will play a major role in the management of refractory ITP. Whether there is a difference in response to TPO-R agonists between splenectomized and non-splenectomized patients requires further study. After being treated with TPO-R agonists for long periods of time, certain patients have improved and been able to maintain platelet counts following discontinuation of thrombopoiesis stimulation if, as long-term exposure accumulates, this extends to more patients, then this would imply that these agents may possibly have a curative effect in addition to being a long-term maintenance treatment.

Morbidity, mortality and prognosis of refractory ITP

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

As there have been few large, well-controlled studies of outcomes in ITP published recently, data discussed here is based on the larger studies of refractory ITP published in 2004 and earlier. In a prospective, long-term follow-up study of 105 patients with ITP who were refractory to splenectomy and required additional therapy (McMillan & Durette, 2004), the majority of patients eventually attained stable remission, either spontaneous or after treatment, on average within 4 years. One third required continuing treatment to maintain their remission. Just fewer than 30% of patients remained unresponsive to treatment (platelet counts ≤30 × 109/l), and these patients endured a difficult disease course with significant morbidity and mortality. Sixteen percent died of ITP (10% from bleeding and 6% from complications of therapy). A further 15% died of unrelated causes (primarily malignancy and cardiovascular disease).

In an earlier study of 114 patients, 8% of patients had chronic ITP refractory to therapy 2-years after initial diagnosis. These patients had a 4-fold increased mortality compared with the general population, and a 4-fold increased morbidity compared with other patients (Portielje et al, 2001). Of note, bleeding and infection (attributed to treatment-related immunosuppression) contributed equally to the deaths in the refractory patients, and deaths due to infection were higher when responding patients were also considered.

These studies draw attention to both the difficult course for many patients and the treatment-associated burden of mortality and morbidity, highlighting the need for effective, less toxic therapeutic options for this patient group.

Health-related quality of life (HRQOL)

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

The impact of chronic ITP on daily functions and quality of life (HRQOL) was studied in 73 adult patients using the Short-Form 36, which includes social functioning, vitality, mental health and emotional scores (McMillan et al, 2008). Patients with ITP had remarkably poor HRQOL scores, significantly worse not only than those of the general population but also than patients with many other chronic diseases, including hypertension and arthritis, and as low as diabetes. Several ITP therapies, chronic corticosteroid therapy in particular, are associated with significant morbidity (Portielje et al, 2001), and multiple HRQOL domain scores were worse among patients who required ITP treatment than those with no medication. Whether this was due to detrimental effects of treatment on HRQOL, or alternatively a reflection of lower HRQOL among those with more severe disease was not clarified. HRQOL assessment has been incorporated into several of the recent trials of emerging therapies.

Concluding remarks

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References

Although ITP is generally considered a benign disease, the mortality, morbidity and impact on quality of life for the refractory subgroup of patients is significant, both due to the disease itself and as a consequence of its treatment. The term ‘refractory’ was traditionally reserved for patients who did not respond (at all) to therapy, particularly to splenectomy. As the number of available treatments increases, a more sophisticated approach to combinations of agents is developed, and as patient reluctance to undergo splenectomy increases, the general application of the term refractory is shifting. Although a consensus definition of refractory ITP has not been achieved, the concept of failing to respond to treatment(s) not limited to splenectomy, and the requirement for ongoing treatment remain important components of the definition. Therapies currently in clinical development offer new options for managing these difficult-to-treat patients. In particular, if the safety and tolerability are confirmed in long-term ongoing trials, the thrombopoietic agents are likely to evoke a dramatic shift in the natural history and management of chronic ITP, and hopefully change the prevalence of ‘refractory’ ITP, converting it into a relatively rare condition.

References

  1. Top of page
  2. Summary
  3. Incidence and definition of ‘refractory’ ITP
  4. Pathophysiology: accelerated platelet destruction and disturbed platelet production
  5. Investigations to identify factors that may contribute to ‘refractoriness’
  6. Treatment options for refractory ITP
  7. Thrombopoietin receptor (TPO-R) agonists
  8. Morbidity, mortality and prognosis of refractory ITP
  9. Health-related quality of life (HRQOL)
  10. Concluding remarks
  11. Acknowledgements
  12. References
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