Monoclonal antibodies in the treatment of immune thrombocytopenic purpura (ITP)

Abstract

Immune thrombocytopenic purpura is characterized by antibody-mediated destruction of platelets and suboptimal platelet production. Initially the treatment of ITP includes corticosteroids, IgG-anti-D, and intravenous immunoglobulins. Splenectomy and monoclonal antibodies are usually considered for refractory and chronic ITP patients. There are new data suggesting that early administration of rituximab is important, and this antibody has been used as first-line therapy in adults. In this concise review the role of rituximab and other monoclonal antibodies is analyzed. These agents have the capability of sparing splenectomy and possibly curing the disease in some patients.

Keywords:

• Monoclonal antibodies
• ITP
• Rituximab
• Alemtuzumab
• Purpura

The incidence of adult-onset ITP ranges from 1·6 to 3·9 per 100 000 individuals/year, but the prevalence is higher due to the chronic nature of the disorder.1 The diagnosis of ITP requires the exclusion of other causes of thrombocytopenia and a platelet count of 100 000/mm³ or less. The disorder is characterized by autoimmune -mediated platelet destruction and also by suboptimal platelet production. The low platelet count results in bleeding symptoms such as petechiae and bruising, but serious and even fatal events also occur. The disease can be classified based on duration of thrombocytopenia, patient age and on the absence or presence of other causes.1,2

The international working group recommends classifying ITP according to duration using the terms ‘newly diagnosed’ for a disease less than 3 months from diagnosis, ‘persistent’ for an ITP lasting 3 to 12 months and ‘chronic’ if the duration is more than 12 months.2 The presentation of ITP is different in children and adults. Childhood ITP is usually acute in onset in the majority of patients. Thrombocytopenia generally is severe, but resolves spontaneously within a few weeks up to several months. Adult ITP is usually chronic, predominant in women and resolves after a therapeutic intervention.1,2 Initially the majority of patients are treated with prednisone or dexamethasone and (or) intravenous IgG. Splenectomy, monoclonal antibodies and thrombopoiesis-stimulating proteins are usually used as second- or third-line therapy. Recently, rituximab has been used in combination with dexamethasone as first-line therapy with promising results.3,4

Monoclonal Antibodies

Monoclonal antibodies (MoAbs) directed against antigens on the B and/or T cells have become a new approach in the treatment of patients with autoimmune cytopenias and their use is particularly promising for patients with ITP. However, most available evidence of effectiveness and safety of MoAbs is based on retrospective studies and there are few prospective trials. Rituximab, a chimeric antibody against CD20 B lymphocytes, is the most important monoclonal antibody and has been reported extensively in patients with chronic ITP.2^–5 The mechanisms of action more frequently studied include antibody-dependent cell-mediated cytotoxicity, complement dependent cytotoxicity, disturbed T-cell activation and direct apoptotic activity. Whereas more experimental approaches using other monoclonal antibodies include alemtuzumab and veltuzumab in small case series and case reports. A limitation for interpretation of these trials is the heterogeneity in criteria used for reporting responses and clinical outcomes.6^–8

In most reports, rituximab was administered at the dose developed for the treatment of lymphoproliferative disorders, (375 mg/m² once weekly for four consecutive weeks). In a systematic review by Arnold et al.,9 a response rate of 62·5% and a complete response of 46·3% was found; in this meta-analysis on 313 adult patients suffering from chronic ITP, the median duration of response was 10·5 months. On the other hand, a prospective study of 60 patients candidates for splenectomy by Godeau et al.10 reported an overall sustained response in 40 and 33·3% of cases at 1 and 2 years, respectively. In this study, the magnitude of the initial response was very important, 86% of patients whose platelet count rose up to normal level within the first 15 days after rituximab infusion had good responses at one year. In this setting, although in most patients a response occurs 3–8 weeks after the first infusion of rituximab, an interesting observation is the very rapid response following rituximab administration in a small proportion of patients, even if low doses of the antibody are given. Two patterns of response have been identified: early response with an increase in platelet count after the first or second infusion and late response with rise of the platelet count at weeks 6–8. It is possible that in patients with early administration of the antibody opsonized B cells saturate the reticulo-endothelial system. In late responders the decreased production of antiplatelet antibodies is responsible for an increase in the platelet count.5,9,10 Patients respond to rituximab regardless of the number of prior treatments including splenectomy, previous treatment with rituximab, and the interval between ITP diagnosis and rituximab treatment. However, patients with a disease duration of more than 10 years may have a reduced response rate, suggesting that using the antibody early in the course of ITP leads to better response.

Rituximab treatment of ITP is well tolerated, the most common adverse events being temporary grade 1–2 infusion-related reactions. Severe toxicity, including anaphylactoid reaction, serum sickness and thrombocytosis, resulting in treatment discontinuation are rare.5,9,10

First-Line Therapy

MoAbs have also been used as first-line therapy in adults. A multicenter phase III trial investigated the efficacy of combined treatment with rituximab and dexamethasone in previously untreated adult ITP patients. In this randomized study, 103 patients received 40 mg/day of dexamethasone for four consecutive days with or without rituximab (375 mg/m² weekly for 4 weeks, starting on day 7). At six months a sustained response was higher in patients treated with dexamethasone plus rituximab than in those treated with dexamethasone alone, 63 vs 36% respectively. It is important to note that of the 52 patients initially treated with dexamethasone alone, 27 received rituximab plus dexamethasone as rescue therapy, and 15 patients (55·5%) achieved a sustained response. It seems that the early administration of rituximab confers important benefit.3

Low-Dose Rituximab

The efficacy of lower doses of rituximab (100 mg/weekly for 4 weeks) has also been reported. In a prospective study of 28 adult patients low-dose rituximab induced an overall response in 75% and complete response in 43%; and after a median follow-up of 11 months 33% patients relapsed. No infusion-related toxicity was observed and all patients achieved B-cell depletion.11 Another randomized trial compared dexamethasone, 40 mg/d on days 1–4 with or without rituximab, 100 mg on days 7, 14, 21 and 28. Overall response at day 28 and sustained response was 80·6 and 77·4% vs 74·2 and 38·7% in the experimental group vs glucocorticoid group. It is important to note that 41 patients in this study were free of any previous treatment.4 Potential advantages of using antibodies at lower doses include avoidance of severe side effects, steroid-sparing effects, splenectomy-sparing capacity, the possibility to administer in repeated courses, and decreased cost.

Other Options

Newer anti-CD20 MoAbs have been and are being developed. Veltuzumab, a humanized MoAb, has similar effects to rituximab, but with a significantly slower off-rate probably explaining its superior efficacy. Low doses of veltuzumab are required, given either intravenously or subcutaneously, with decreased toxicity and immunogenicity. This antibody has an interesting activity and is effective in chronic ITP patients.7

There are a few reports on the use of alemtuzumab in the treatment of ITP. This antibody, a humanized IgG specific for the CD52 antigen expressed in lymphocytes, induces profound lymphopenia; B cells and NK cells recover after 4 to 6 weeks, but T cells reach normal levels at slower rate. It has been effective in the treatment of patients with autoimmune cytopenias.12 Lim et al.6 in 1993, first reported the results of treatment with alemtuzumab in six patients with refractory ITP, four patients responded. In three patients the remission lasted 4–9 months.

We recently reported the treatment of eleven ITP patients refractory to first-line therapy with the combination of low doses of alemtuzumab (10 mg subcutaneously for 3 days) plus rituximab (100 mg i.v. weekly for 4 weeks); overall response rate (ORR) was 100%, complete response was observed in five patients. The median duration of CR was 46 weeks. Therapy was well tolerated in all patients.8 The rationale for combining the two monoclonal antibodies was their reported single-agent activity, and the possibly synergistic effect, based on the fact that T lymphocytes are involved in the control of expansion of immunoglobulin-producing, autoreactive B-lymphocyte clones. In fact, it has been noted that all patients, even those treated with low doses of rituximab, achieve B-cell depletion, but only some of them respond to the action of the antibody, therefore is clear that B-depletion has the capability, at least in some patients, to revert abnormalities of T- cells, including alterations of the Treg subset.4,11

Rituximab provides an option for second-line therapy, especially in those patients not responding to glucocorticoids, and could serve as an alternative to splenectomy. No trial has directly compared rituximab to splenectomy in patients with ITP unresponsive to glucocorticoids, nor has any trial compared different regimens of rituximab. Lower doses seem to be associated with similar efficacy, improved safety profile and lower cost.

Nowadays, it is clear that ITP is a disease of increased platelet destruction and low platelet production, therefore in addition to splenectomy and rituximab directed to reduce the platelet destruction, thrombopoietin mimetics, like eltrombopag and romiplostin, can now be used in order to ameliorate thrombocytopenia. However, these drugs do not suppress the immune pathogenic mechanism and require continuous administration. In contrast, rituximab and other MoABS have the potential for sparing splenectomy and even possibly cure the disease in some patients.