Is there a place for rituximab in the management of adult chronic primary immune thrombocytopaenia?

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1 3 Is there a place for rituximab in the management of adult chronic primary immune thrombocytopaenia? A. Janssens, D. Dierickx Splenectomy as treatment option is still the golden standard for patients with primary immune thrombocytopaenia (ITP) unresponsive to or relapsing after corticosteroid therapy, in case platelet counts are persistently low and/or bleeding risk is high. When patients are unable to undergo surgery or relapse after splenectomy thrombopoietin receptor (TPO-R) agonists are recommended, and are also reimbursed in Belgium. Rituximab has been used for treating relapsing or refractory ITP patients for almost ten years with an overall response rate of 60% and 20% long-term responders. However, randomised controlled trials are not available to establish optimal dose, schedule and timing of rituximab administration or to confirm efficacy and reveal long-term safety. For these reasons, rituximab has still no license for treating ITP. The Belgian Hematological Society, coordinator of the medical need program of rituximab in ITP, reserves, at this moment, rituximab for patients not responding to TPO-R agonists. (Belg J Hematol 2011;2:107-15) Introduction Immune thrombocytopaenia (ITP) is an acquired autoimmune disease characterised by an isolated low platelet count number (<100 x 10 9 /l). The disorder is classified as primary immune thrombocytopaenia in the absence of any obvious initiating and/or underlying cause, and as secondary ITP in association with autoimmune disorders (eg, systemic lupus erythaematosus, the antiphospholipid syndrome), some immunodeficiency syndromes (common variable immunodeficiency syndrome, adult lymphoproliferative syndrome), lymphoproliferative disorders (chronic lymphocytic leukaemia, Hodgkin s disease, large granular T-lymphocyte proliferation), persistent infections (eg, human immunodeficiency virus, hepatitis C virus or Helicobacter pylori) and vaccination. 1,2 Thrombocytopaenia caused by decreased platelet production, nonimmune increased platelet destruction or abnormal platelet distribution must of course be ruled out. Regardless of cause, very low platelet count correlates to some extent with increased bleeding risk. Additional factors including age, comorbidities, lifestyle, need for invasive procedures, need of treatment with anticoagulant or antiplatelet agents, tolerance of expected adverse events of treatment and patient s preferences should be assessed before making a decision about the appropriate management. The main treatment goal in all ITP patients must be to maintain a safe platelet count to prevent or stop bleeding and not to normalise the platelet count. 3 Newly diagnosed (<3 months after diagnosis) ITP Authors: A. Janssens MD, D. Dierickx MD, Department of Hematology Universitaire ziekenhuizen Leuven, Belgium. Please send all correspondence to: A. Janssens MD, Department of Hematology, Universitaire ziekenhuizen Leuven, Herestraat 49, 3000 Leuven, Belgium, tel: , ann.janssens@uz.kuleuven.be Conflict-of-interest: The authors have nothing to disclose and indicate no potential conflict of interest. Key words: primary immune thrombocytopenia, rituximab, splenectomy, thrombopoitin receptor agonists. 107

2 patients are managed with corticosteroids with or without intravenous immunoglobulins depending on the severity of thrombocytopaenia and/or of bleeding signs and symptoms. Although impressive responses are seen using these therapeutic agents, these responses are usually short lived. Thus, in adults, ITP is very frequently characterised by relapses upon tapering or discontinuation of treatment, requiring repeated courses of medical intervention. 1,2 It has been proposed to classify the disease as persistent ITP lasting 3 to 12 months when spontaneous remission is not reached (<10%) or complete response to therapy is not maintained and chronic ITP when thrombocytopaenia is lasting more than 12 months. 1 For decades splenectomy has been the standard management for ITP patients unresponsive or intolerant to corticosteroids. Although twothirds of patients attain a durable remission, morbidity and mortality of laparoscopic splenectomy are low in the hands of experienced surgeons and the incidence of overwhelming sepsis is reduced with recommended vaccination protocols and antibiotics initiated at first sign of a systemic febrile illness, physicians and patients frequently opt to postpone the removal of a healthy organ. 2 Increased understanding of the pathophysiology underlying ITP has led to the development of treatments targeting the suboptimal platelet production (thrombopoietin receptor (TPO-R) agonists) and depleting B cells (rituximab) in contrast to corticosteroids, immunoglobulins and splenectomy which increase platelets mainly by reducing their destruction rate. The TPO-R agonists, romiplostim and eltrombopag, are reimbursed in Belgium for chronic ITP patients refractory or intolerant to corticosteroids after splenectomy, or when surgery is contraindicated. Rituximab has been used extensively off-label for treating a range of autoimmune diseases, including ITP. We wondered if we can still propose a place for rituximab in the ITP treatment algorithm after reviewing the available literature. Efficacy of rituximab in ITP ITP was one of the first autoimmune disorders in which rituximab was tested, mainly because ITP was formerly thought to be essentially a B cell and autoantibody mediated autoimmune disease. Results of the use of rituximab in ITP have been reported extensively. However, most available evidence is based on retrospective case reports and case series, with only few prospective trials. Another major limitation of these trials is the impressive heterogeneity in criteria used for reporting responses and clinical outcomes. Despite these drawbacks rituximab appears to have efficacy in the treatment of ITP with overall (OR) and complete response (CR) rates exceeding 60% and 40% respectively. 4 Table 1 provides an overview of all publications regarding the use of rituximab in adult ITP. Papers in abstract form, not written in English language and publications describing less than 5 patients are not included in this table When information of response was given for splenectomised and non-splenectomised patients, no significant difference in CR and OR was seen between these two groups. 30 Patients with newly diagnosed or persistent/chronic ITP treated with rituximab in combination with dexamethasone as first line treatment, showed an OR of 63% and a CR of 43%. The response rates were similar for newly diagnosed and persistent/chronic ITP patients. 31 Long-term efficacy Response duration in patients with immune-mediated cytopaenias treated with rituximab has shown considerable variation ranging from one month to more than eight years. The achievement of complete response was associated with an average duration of response longer than one year in contrast to the partial responders who relapse between 6 months and 1 year. 4,30 Long-term follow up is limited in most case series. In this regard, Patel et al. reported in abstract form on their long-term follow up in ITP patients treated with rituximab. According to their findings, about 16% of the patients treated with rituximab will show a sustained response lasting longer than 2.5 years with little further relapse up to five years following rituximab administration. 32 In a prospective trial rituximab was given to adult splenectomy candidates. Good 1-year and 2-year responses were obtained in respectively 40% and 33% of patients with persistent or chronic ITP. When splenectomy was required later due to rituximab failure, rituximab does not seem to lower the response rate to splenectomy. 20 Optimal dosing schedule The optimal rituximab schedule in immune-mediated haematological disorders has not been established. In most reports dosage was 375 mg/m² once weekly for 4 consecutive weeks, just as in early non- 108

3 3 Table 1. Responses with rituximab in immune thrombocytopaenia (ITP). Author ref Number of patients (n) Age (year) Previous splenectomy (%) OR/CR (%) Response duration (months) Saleh / Stasi / Giagounidis / Narang / Shanafelt / Zaja / Cooper /32 <3-39+ Narat / Braendstrup (39R) / Zaja NR 14 73/ Penalver / Scheinberg NR 87/87 3+ Schweizer / Garcia-Chavez /28 Median 54(CR) and 18 (PR) Provan / Godeau /NR 24+ Pasa /14 6+ Zaja /43 RFS: at 2 yr: 45% Fairweather 23 7 NR 86 86/ Medeot / Alasfoor / Kelly Mean: 50 NR 54/NR NR Dierickx (43R) /63 PFS at 1 yr: 70% Hasan NR 23 68/46 NR Aleem (29R) / Ref=reference, OR=overall response rate, CR=complete response rate, R=rituximab courses, NR=not reported, PR=partial response, PFS=progression free survival, NS=not significant, RFS=relapse free survival, yr=year. Hodgkin s lymphoma studies. However, as the B cell mass in immune-mediated disorders is expected to be less high, recently lower doses (100 mg weekly for 4 consecutive weeks) have been used successfully in the treatment of ITP. Levels of B cell depletion, duration of B cell depletion and response rates appeared similar to those of patients treated with conventional dosages, although some concern exists with regard to duration of response. One possible hypothesis may be the fact that low dose rituximab may cause insufficient extravascular B cell depletion, especially in the spleen. 19,22 Hemato-Oncologie voor Volwassenen Nederland (HOVON) randomised 156 corticosteroid refractory ITP patients between conventional dosage, 750 mg/m 2 once weekly for two weeks and 375 mg/m 2 once weekly for 2 or 4 weeks depending response. Overall response at day 71 showed no difference between the 3 dosing regimens. 33 So far, the best and most cost-effective strategy to be used in ITP is therefore not totally established. Repeated treatment with rituximab Retreatment with rituximab has been described as an attractive way to prolong duration of response. In ITP response rates after a second course of rituximab were comparable to those after the first treatment cycle. 34 In the large series of Cooper et al. retreatment was successful in approximately 75% of patients initially responding to rituximab. 11 Hasan et al. reported on retreatment with rituximab in 20 ITP patients who had achieved a response to prior rituximab. Response rates were 75% with 50% of the patients showing a CR, and similar response du- 109

4 ration when comparing first and second rituximab course. Giving a higher dose of rituximab in a nonresponder seemed not to be effective even if rituximab was combined with a lymphoma-like chemotherapy regimen. 28 Maintenance therapy with rituximab may improve duration of response but has not been investigated yet. Pretreatment factors predictive for response Pre-treatment factors associated with better OR rates in ITP include younger age, female gender, shorter duration of the disease, achievement of CR and fewer previous treatments. 6,11,15,18,22,24 However these factors were not confirmed in all studies. So currently no identifiable patient characteristics have been consistently shown to be predictive for response to treatment with anti-cd20 therapy. Mechanism of action of anti-cd20 in ITP Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody against CD20, which is expressed on the surface of premature and mature B lymphocytes, but not on pro-b cells or plasma cells. The mechanisms of action of rituximab in lymphoproliferative disorders include antibody-dependent cell mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct apoptotic activity, disturbed T cell activation and possible vaccinal effects. Although the existence of autoimmune human diseases has been recognised for several decades, the pathogenic mechanism of autoimmune pathology leading to failure of self tolerance remains poorly understood. B cells play a role by producing and secreting autoantibodies, producing inflammatory cytokines and acting as antigen presenting cells, supporting activation of T cells. 35 As a consequence depletion of B cells by rituximab was introduced as a new treatment option in immune-mediated disorders. However, as this depletion occurs in all patients treated with rituximab irrespectively of their response, other mechanisms of action may play an important role as well. The production of autoantibodies by autoreactive B cells is regulated by cellular mechanisms, involving mainly responses to signalling from CD4 positive T lymphocytes (Th). Autoimmune disorders are characterised by imbalances between Th1 and Th2 subsets, in favour of Th1 cells. Recently published data from ITP patients have shown that this pattern is skewed towards an increase in Th2 cells during remission of the disorder, suggesting that active disease may be predominantly caused by Th1 activation. 36,37 Stasi et al. showed that reversal of this Th1/Th2 imbalance was also seen in patients responding to rituximab, whereas the Th1/Th2 ratio remained unchanged in non-responders. 38 In addition to the important role of Th cells, CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) have recently emerged as natural immune master regulators, playing a major role in maintenance of peripheral tolerance. Deficiency in generation and/ or defective functions of Tregs may contribute to loss of immunologic self tolerance in autoimmune disorders by failure to suppress autoreactive T and B cells, which results in continued autoantibody production. Stasi et al. reported their findings in rituximab-treated ITP patients, particularly responders, who showed restored numbers of Tregs as well as restored regulatory functions, compared with pre-treatment findings. 39 Finally, rituximab also induces down regulation of CD40 and CD80 on B cells, leading to further disturbed T cell activation. 40 A small proportion of patients, even if low doses of rituximab are given, experience a response in the first week following rituximab administration. It has been suggested that such prompt responses could result from macrophage Fc-receptor blockade by rituximab-opsonised B cells, referred to as immune complex decoy hypothesis. 41 Taken together it is clear that rituximab interferes with both B and T cell participation in antibody production. Mechanism of resistance of anti-cd20 in ITP Despite the high number of responses to rituximab in immune-mediated disorders, a substantial proportion of patients fail to respond. The mechanisms of this failure are largely unknown and may be heterogeneous. Possible explanations include insufficient B cell depletion, especially in lymphoid organs outside the peripheral blood, the presence of FcγR polymorphisms and evolution to B cell independent T cell expansion. Safety of rituximab in ITP Although rituximab generally is considered well tolerated and safe, severe and life threatening events have been described. A systematic review of pub- 110

5 3 lished reports describing the use of rituximab in adult ITP patients reported on safety. Among the 29 reports (306 patients), nine deaths (2.9%) occurred. However, in most cases an association with rituximab could not be confirmed. 4 Infusion related complications The incidence of infusion related side effects in immune-mediated disorders seems comparable with the incidence reported in lymphoproliferative diseases. In a systematic review 21.6% of patients showed mild to moderate adverse events, of which 83.3% were infusion related. Rare, life-threatening symptoms such as bronchospasm, angioedema, hypoxia and shock have been described. 4 Infectious complications An important concern with the use of rituximab has been the risk of developing infection. Pooled data from 356 patients who received rituximab monotherapy (for lymphoma and immune-mediated disorders) showed the incidence of infectious events to be 30%, of which 19% were bacterial infections, 10% viral infections, 1% fungal infections and 6% infections of unknown aetiology. Severe infections including sepsis occurred in only 1% during the treatment period and in 2% during the follow-up period. Indeed, in clinical trials use of rituximab has been associated with respiratory tract infections, sepsis, urinary infections, gastroenteritis, cellulitis, septic arthritis, viral infections (influenza, hepatitis B, herpes zoster, herpes simplex, adenovirus), systemic candidiasis and aspergillosis. No published reports of reactivation of Mycobacterium tuberculosis were found. In case reports, case series and retrospective studies, infections with non-tuberculous mycobacteria, cytomegalovirus, West Nile virus, JC virus, BK virus, parvovirus and enterovirus, Pneumocystis jirovecii and parasitic infection like babesiosis were reported. 42 Since the introduction of rituximab, hepatitis B reactivation has been seen in HBsAg-positive and in HBsAg-negative/anti-HBc-positive patients. Reactivation is also a well-known complication of cytotoxic therapy so the real impact of rituximab is not entirely clear in a setting of treatment with immunochemotherapy. However, hepatitis B screening should always be performed prior to starting rituximab treatment. In the setting of ITP, other treatment options must be offered in case of hepatitis reactivation risk. Another emerging infectious problem in patients treated with rituximab and other monoclonal antibodies is progressive multifocal leukoencephalopathy (PML). PML is a usual fatal infection caused by reactivation of the JC virus. Heavily pretreated lymphoma patients seemed the most vulnerable although two patients with ITP were also affected, one having received only corticosteroids and rituximab without any other immunosuppressive therapy. 43 In the past five years a registry has been set up by rheumatologists in France, looking at the safety of rituximab in rheumatoid arthritis outside clinical trials. The registry has included more than 1,000 patients, some of whom have received up to eight courses of rituximab over years. The overall incidence of infection was slightly higher than the one reported in clinical trials, but not a single case of PML has been reported. 5% of patients over time acquired a secondary hypogammaglobulinaemia. Effect on vaccine response Suboptimal responses to vaccination have been documented within the first six months after treatment. Routine vaccinations against S. pneumoniae, N. meningitides and H. influenza type B should be given 4 weeks prior to the first dose of rituximab each time splenectomy could be another treatment option during the 6 months following rituximab therapy. 40 Haematological complications Although rare, cytopaenias and especially late onset neutropaenia (LON) are a well-known complication of rituximab therapy. The time period between the administration of rituximab and the occurrence of LON can vary widely, although most cases have been reported between 2 and 12 months following therapy. Several hypotheses for this phenomenon have been suggested. 44 Whether late onset cytopaenia is a contra-indication for future rituximab administration has not been clarified. Other complications Rituximab has been associated with intestinal perforation and obstruction, although the exact contribution of the monoclonal antibody remains unknown. A severe and feared complication seems to be delayed interstitial pneumonitis, which was in most cases however reversible after prompt initiation of treatment with corticosteroids

6 Tabel 2. Splenectomy compared to rituximab and thrombopoietin receptor (TPO-R) agonists. Splenectomy Rituximab TPO-R agonists Intervention surgical pharmacological pharmacological ITP specific no no yes Response prediction no no no Short term response 85% 60% 80% Long term response 66% <20% 80% Curative yes <20% not expected Short term toxicity perioperative infusion related, headache complications mucocutaneous reactions Long term toxicity life long risk of sepsis infections (HBV, PML,...), hypogammaglobulinaemia, late onset cytopaenia thrombosis, bone marrow reticulin Cost 3,500 for the hospitalisation (600 for the intervention) 1,113 (4x100mg) 7,798 (4x700mg) Eltrombopag 25mg; 1090,43 /28d 50mg; 2173,76 /28d Romiplostim 250μ; 602,5 /weekly 500μ; 1205 /weekly ITP=immune thrombocytopaenia, HBV=hepatitis B virus, PML=progressive multifocal leukoencephalopathy. Conclusion ITP is thought to have a relatively benign course. However there is a definite risk of severe and potentially fatal bleeding in patients with persistently low platelet counts (<30 x 10 9 /l). This means that a 30-year-old woman remaining thrombocytopaenic due to ITP loses 20 years of her potential life expectancy. At the age of seventy, the predicted loss is still nine years. 45 The initial treatment options for patients with persistent or chronic ITP relapsing after or refractory to corticosteroids can be divided into an irreversible surgical approach (splenectomy) and a pharmacological approach. This pharmacological approach can be a short-term therapy with induction of remission being the treatment goal (rituximab) or a chronic maintenance therapy (TPO-R agonists). Other immune modulating agents (cyclosporine A, azathioprine, cyclophosphamide, danazol) are characterised by low response rates and significant long-term side effects making patients and physicians today reluctant to start these modalities as second-line treatment. In Belgium, treatment with TPO-R agonists is reimbursed for the one third of patients not responding to or relapsing after splenectomy and being refractory or intolerant to corticosteroids. The short- and long-term responses of these agents are unparalleled ( 80%) as long as treatment is continued because no curative potential can be expected. Many patients might choose this treatment option because there is good tolerability and low long-term toxicity. Longer follow-up is needed to be sure that the increased bone marrow reticulin seen in approximately 5% of patients poses no clinical problem It was in this patient group, failing splenectomy, that we used rituximab off-label frequently before the TPO-R agonists became available. In a systematic review the overall response rate to rituximab was estimated to be 60% although a sustained response was seen only in 20% of patients. 4,32 However, we can expect that these long-term responders will have been cured. Treatment is given once weekly for four consecutive weeks what is a short treatment course and can be an advantage. The optimal dose is still not established. Some case studies used 100 mg instead of 375 mg/m 2 weekly for 4 consecutive weeks with comparable response rates. When the response duration would also be equivalent, this low dose could become standard and be more cost-effective. Rituximab is generally considered a well-tolerated and safe treatment although severe and life-threatening events have been described. Infusion-related symptoms were the most frequent reported adverse events. It is not clear whether rituximab makes ITP patients more susceptible to infections as most of these patients received prior immunosuppressive or cytotoxic treatments. However, it may be appropriate to avoid rituximab in ITP patients with a positive hepatitis B screen and during or immediately following any viral infection. Another important concern is the possible induction of PML, which is 112

7 3 Key messages for clinical practice 1. Immune thrombocytopaenia (ITP) is not just a matter of autoreactive B cells and antiplatelet antibodies but also a matter of an altered balance between Th1 and Th2 cells and deficient or defective regulatory T cells. 2. Platelet responses to rituximab seem comparable in splenectomised and nonsplenectomised ITP. 3. B cell targeted therapy can cure about 20% of ITP patients by reversing the autoimmune process. 4. The optimal dose, schedule and timing of rituximab administration in patients with ITP is unknown because randomised controlled trials are lacking. 5. No anti-cd20 monoclonal is or will be licensed soon in ITP. fatal in almost 100% of cases. Although the role of rituximab in the reactivation of the JC virus is also not established because most patients with PML received also chemotherapy, corticosteroids or other immunosuppressive agents next to rituximab, one of the two ITP patients with PML received only a short course of corticosteroids next to rituximab. Treatment with TPO-R agonists is also recommended and reimbursed in Belgium for patients at risk for bleeding and having a contraindication to splenectomy. In a randomised controlled trial (RCT) it has been shown that non-splenectomised ITP patients treated with romiplostim had a higher rate of platelet response, lower incidence of treatment failure and splenectomy, less bleeding and fewer blood transfusions and a higher quality of life than patients treated with standard of care. 49 Rituximab monotherapy was also given to splenectomy candidates with persistent or chronic ITP. In a prospective trial good 1-year responses were obtained in 40% and good 2-year responses in 33% of patients. In these responding patients rituximab could thus be an effective splenectomy-avoiding treatment option. Response to splenectomy after failure to rituximab was 60% with a median follow-up of 18 months, which is comparable to historical data. This means that response to splenectomy was not compromised by previous treatment with rituximab. 20 The only available RCT compared dexamethasone monotherapy with dexamethasone and rituximab as first line treatment in newly diagnosed or persistent/chronic ITP. The combination arm achieved an OR of 63% against 36% for the dexamethasone alone. 56% of patients refractory to dexamethasone could be salvaged effectively by dexamethasone plus rituximab. These findings suggest that a short course of dexamethasone therapy does not negate the effects of subsequent rituximab therapy. It was hypothesised that reversing B and T cell abnormalities in the beginning of the disease could prevent the generation of clonal T cells and the evolution to chronic ITP. Although platelet responses were comparable with the already reported case series and prospective trials response duration seemed to be better, corroborating the hypothesis that better long-term effect can be achieved when rituximab is administered early in the course of the disease. In conclusion, splenectomy must - in our opinion - still be recommended for patients who are unresponsive to or relapse after initial corticosteroid therapy in case platelet counts are persistently low and/or bleeding risk is high. With a century of experience efficacy and toxicity of splenectomy is well known. Successful splenectomy is a once only cost, which is very well affordable in Belgium. When patients are unable to undergo surgery or relapse after splenectomy TPO-R agonists are recommended, and are also reimbursed in Belgium. Multiple trials, randomised or not, have confirmed high platelet response rates and good tolerability. Although 5-year safety data for romiplostim raises no alarming concerns, further follow-up is needed. The need for 113

8 continuous treatment and the high costs are disadvantages. Rituximab has been used for treating relapsing or refractory ITP patients for almost ten years. RCT s are not available to establish optimal dose, schedule and timing of rituximab administration, to confirm efficacy and reveal long-term safety. Although late adverse events of rituximab, reported especially in patients with lymphoma, are rare the risk/benefit can be acceptable in a malignancy but unacceptable in an immune-mediated disorder. For these reasons, rituximab has still no license for treating ITP (Table 2). The Belgian Hematological Society coordinates the medical need program of rituximab in ITP. At this moment, rituximab can be obtained for ITP patients not responding to TPO-R agonists. After review of the available literature, we agree with this position. 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