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The role of rituximab in ITP
patients into normal controls caused thrombocytopenia, thus imputing the cause of the disease to a plasma-derived factor.4 This “factor” was subsequently identified as an IgG anti-platelet antibody, directed against platelet glyco- protein (GP) IIb/IIIa and/or the GPIb-IX-V complex.5 Very rarely, antibodies against GPIa-IIa or GPIV can be found (5%).18
Antibody-opsonized platelets are then recognized through the Fcγ-receptors by macrophages in the spleen, liver and bone marrow, phagocytized and prematurely destroyed.19 Other mechanisms through which antibodies can mediate platelet destruction are complement deposi- tion with intravascular lysis and induction of platelet apoptosis.20–23 Plasma from patients with ITP also inhibits megakaryocyte growth and function in the bone mar- row.6,24
The Ashwell-Morell receptors in hepatocytes have been invoked as a further pathogenic mechanism, because they physiologically remove desialylated, “old” platelets from the circulation. Anti-GPIb/IX autoantibodies are thought to enhance the desialylation of GPIb, increasing hepatic clearance of platelets.25,26
Many abnormalities have been shown in T cells of patients with ITP: an altered Th1/Th2 balance, with an increased number of Th1 T-helper cells27,28 and a decrease in the number and function of regulatory T cells.29,30 The abnormal activation of cytotoxic CD8+ T cells may also have a role in the pathogenesis of ITP, contributing to both platelet destruction and impaired platelet production.31
Circulating thrombopoietin levels in ITP are not increased proportionally to the level of thrombocytope- nia, and are usually normal or only slightly increased.32
Early history of rituximab
In the late 1980s, the idea of using monoclonal antibod- ies that recognize tumor-associated antigens for the treat- ment of hematologic malignancies became reality, and rit- uximab became a well-tolerated and highly effective option initially used for patients with multi-refractory lym- phoproliferative diseases.7 CD20, a transmembrane glyco- protein expressed on the surface of normal and malignant B cells, appeared ideal for targeted therapy, because it does not shed from the cell surface and is not internalized upon antibody binding.33 CD20 is expressed from early pre-B to mature B lymphocytes, but is not expressed on hematopoi- etic stem cells, plasma cells or other cells of the body.34 Rituximab is a type 1 IgG1-κ human-mouse chimeric monoclonal antibody directed against CD20, which acts through three mechanisms: complement-dependent cyto- toxicity, antibody-dependent cellular cytotoxicity and induction of direct apoptosis of the target cell.35
The first report of a case in which rituximab was used for the treatment of an autoimmune disease was pub- lished in 1998, when a patient with a cold agglutinin dis- ease and a small IgM paraprotein was successfully treated with four weekly infusions of rituximab.36 A few years later, in 2001, the first report of the successful use of ritux- imab for the treatment of ITP associated with a low-grade non-Hodgkin lymphoma was published.37 Since then, rit- uximab has been widely used for the treatment of autoim- mune manifestations associated with lymphoproliferative disorders, and, because it is a therapy borrowed from lym- phomas, the dose schedule of 375 mg/m2 weekly for 4
weeks also became the “standard dose” of rituximab in autoimmune diseases.
Since CD20 is also expressed in normal B cells, there was a strong rationale for using rituximab to deplete pathological antibodies in autoimmune diseases. One of the first cases, published in 2000, was that of a young man with refractory myasthenia gravis who, after four stan- dard doses of rituximab, experienced a complete clinical response with disappearance of anti-acetylcholine recep- tor antibodies, and he did not relapse.13 This case was an impressive proof of principle that transient B-cell deple- tion secondary to rituximab treatment may positively modulate the immune system, inhibit the production of autoantibodies, and cause long-term clinical improve- ment.
Rituximab in immune thrombocytopenia
In 2001, Stasi et al. reported the results of the first prospective study in which 25 patients with chronic ITP were treated with four weekly infusions of rituximab at a dose of 375 mg/m2. The overall response rate (ORR) was 52%, with 28% sustained responses. No clinical or labo- ratory parameters were found to predict treatment response, but they noticed that women and younger patients had a better chance of response, and that, in some patients who relapsed, retreatment was effective.38
Subsequent studies showed that the overall initial response to rituximab used as second- or further-line of therapy ranges between 52% and 73%, with the complete response (CR) rate ranging between 20% and 54%39-48, 56, 58, 68 (Table 1). In a systematic review including 313 adult patients with chronic ITP, a response rate of 62.5% and a CR rate of 46.3% were found, with a median duration of response of 10.5 months.42
Three different patterns of response can be distin- guished: a first group of patients respond rapidly, within the first month; in the second group, the platelet count starts increasing after 3-4 weeks, and a CR is achieved within 8 weeks after treatment; in the third group of patients, the platelet count increases very slowly, only reaching normal values 3 months after therapy.46
Only two randomized, placebo-controlled studies have been performed. One very small pilot randomized trial compared rituximab with placebo as second-line therapy. No difference in terms of treatment failure (65.6% vs. 80.8%)47 was found between the two groups. Overall platelet count response (i.e. platelet count ≥30x109/L) was achieved by 62.5% of the patients in the rituximab group and 73.1% in the placebo group at 6 months.
In the much larger RITP trial,48 the rate of treatment fail- ure was not significantly different between patients given rituximab or placebo (58% vs. 69%), and the ORR was 81% in the rituximab group compared to 73% in the placebo group. Improvements in platelet counts were seen up to week 72 in the rituximab arm.
Rituximab doses
“Standard dose” rituximab results in a marked reduction of malignant and non-malignant B cells in peripheral blood and bone marrow.49 Since the total mass of B cells is much smaller in patients with ITP than in patients with lym- phoma, it was not clear whether a lower dose of ritux- imab or a different schedule could be equally effective.
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