Rituximab appears to be a useful immunotherapeutic
agent for the treatment of refractory ITP
Fundacion Hospital de
Puerta de Hierro
Immune thrombocytopenic purpura (ITP) is a common autoimmune disorder characterised by isolated thrombocytopenia, the exclusion of other causes of thrombocytopenia and mucocutaneus bleeding that range in severity from mild to life-threatening.[1–3] In ITP patients with persistent low platelet counts (<30 x 109/ l), the rate of fatal bleeding (usually due to intracranial haemorrhage) was estimated in 0.02 to 0.04 cases per patient-year, but it was increased (~0.13 cases per patient-year) among patients over 60 years of age.
ITP is caused by increased platelet destruction mediated by platelet-reactive autoantibodies’ clearance by FcyR-bearing mononuclear cells of the reticuloendothelial system, primarily those in the spleen. Recently, a much more complex situation has been envisaged, in which impaired platelets production and T-cell mediated platelet destruction play a significant role, while dysfunction occurs in more than one step of the immune regulation.
Corticosteroids, intravenous immunoglobulins and anti-D therapy can increase platelet count by 60–80%, but these effects are often transient. Splenectomy as second-line therapy has been shown to be successful in two-thirds of patients. Immunosuppressive drugs have also been effective, but are toxic and do not always alleviate symptoms.[1,9] Approximately 30-35% of ITP patients do not respond to therapy, even to splenectomy, making it necessary to explore other therapeutic options.
Rituximab is a murine/human chimeric monoclonal antibody anti-CD20 that induces specific and transient depletion of B-cells. It was originally introduced for the treatment of non-Hodgkin’s lymphoma. The rationale for its use in ITP relies on its potential to eliminate autoreactive B-cell clones. Rituximab causes depletion of CD20+ B-cells by Fc-mediated toxicity, antibodydependent cell-mediated cytotoxicity and apoptosis.
B-cell depletion induced by rituximab lasts for up to 6 months and then the B-cell pool is repopulated by inmature (CD38++, CD10+, CD24++) B-cells, followed by naive (CD27-) B-cells. Memory B-cells (CD27+) may remain reduced for up to 2 years. CD20 is not expressed on stem cells or mature plasma cells, thus leukopenia and hypogammaglobulinemia are uncommon.
The durable response also raises an intriguing question about the mechanism of action of rituximab. This mechanism might not be due simply to a general reduction in antibody production. Recently, patients with ITP have been found to be deficient in a subset of relatively rare T lymphocytes called T regulatory lymphocytes (T-regs; CD4+, CD25+, Foxp3+), that appear to play a critical role in maintaining peripheral tolerance. Interestingly, in patients with chronic ITP who respond to rituximab, T-reg populations return to normal.
In addition, by removing the pathogenic B-cell pool, rituximab may indirectly cause the removal of autoreactive T-cells, or the normalisation of other cellular immune defects in patients with ITP.
Rituximab was found to be effective and safe in a large systematic review. Of 313 ITP patients treated with rituximab, half of them with splenectomy, achieved complete response (platelet counts >150 x 109/l) 46.3% of patients (95% CI, 29.5-57.7%), partial response (platelet counts 50 to 150 x 109/l) 24.0% (CI, 15.2-32.7%) and overall response (platelet counts > 50 x 109/l) 62.5% (CI, 52.6-72.5%). Median time to response was 5.5 weeks (range 2-18) and median duration of response was 10.5 months (range 3-20) with a 15-20% rate of long-term complete response.
A multi-institutional retrospective Spanish study evaluated the effectiveness of rituximab in the treatment of 89 patients with chronic ITP. The study showed that 31 patients (35%) maintained response (platelets >50 x 109/l), with a median follow-up of 9 months (2-42), and in 12 patients more than 1 year. The unique predictor of a maintained response was to reach complete response. Heavily-treated patients and those with longer ITP duration (>10 years from diagnosis) had a worse response.
Cooper et al. reported that 16 out of 57 patients (28.1%) of the complete responders sustained the response more than 1 year following rituximab, and patients who had a longer duration of ITP (>15 years) were less likely to respond. Around half of the patients with good response, continued their response for at least another 5 years. Such initial response of at least 1 year was predictive of lengthy (>5 years) durable remissions in a majority of patients.
Recently, rituximab has been investigated in the early stages of ITP as a means of obviating or delaying splenectomy. In a single-arm study, 60 non-splenectomised patients with ITP for more than 6 months, who failed one or more previous treatment, 40% of the patients achieved a platelet count of 50 x 109/l or greater 1 year after rituximab was given.
Also, rituximab has been used in patients with previously untreated ITP. In a recent randomised trial comparing dexamethasone and dexamethasone with rituximab in ITP patients not previously treated (n=101), a platelet count response (>50×109/l) at 6 months was achieved by 36% vs 63% of patients respectively (p 0.004) yet a considerable number of patients crossed over to rituximab. Responses were maintained for a median of 18 months.
This suggests that using rituximab early in ITP may be more beneficial than waiting until late response occurs. Corroborative evidence derived from a study in 2007 that correlated rituximab-induced platelet count response with normalisation of T-cell abnormalities in ITP, suggested that response to rituximab may be more likely at an early stage of the illness, when T-cell expansion is still dependent on B-cell co-stimulation.
A critical factor is that the optimal dosing regimen for the use of rituximab in ITP has never been formally established. Patients who received as little as one dose of rituximab were able to achieve a complete response, an observation noted by various groups.[15,20] Doses lower than the standard 375mg/m2 x 4 (100mg/ week for 4 weeks) are effective in ITP, and may have a more favourable side-effect profile.21 In a prospective study to evaluate the activity of lower dose rituximab with 28 adult patients with ITP, 75% (21/28) achieved a response (platelet count >50 x 109/l) while 43% achieved a complete response (platelet count >100 x 109/l). After a median follow-up of 11 months (range 3-18), 33% of the patients (7/21) relapsed and needed further treatments.
In those patients who did relapse, there was a 75% chance of responding to a second therapy, usually with the same type of response (ie, complete or partial response), but subsequent relapse.
Rituximab, in general, is well tolerated with manageable infusion-related side-effects. Most of these events were recorded during the first infusion. These can be ameliorated by premedication with steroids, paracetamol and chlorpheniramine. Serious adverse events including fatalities have been identified [14,23] although many of these were apparently unrelated to the rituximab therapy and occurred in high-risk patients with multiple comorbidities. No long-term toxicities among ITP patients treated with rituximab have been described.
In patients with lymphoma, rituximab results in a modest increase in the frequency of bacterial infections, but the risk may be lower for patients with autoimmune diseases. However, rituximab treatment has been associated with reactivation of viral infections which include hepatitis B (in vulnerable patients such as hepatitis B carriers), CMV, varicella-zoster virus, JC virus and others. Recently, there have been reports of 57 patients with progressive multifocal leukoencephalopathy, a rare demyelinating disease caused by reactivation of latent JC virus in the brain after rituximab treatment. Up to 92% of the adult population is JC virus-seropositive. Fifty-two patients out of 57 had lymphoproliferative disorders and only 5 had autoimmune diseases. One of these was an ITP patient who had also received other immunosuppresive drugs.
In summary, rituximab appears to be a useful immunotherapeutic agent for the treatment of refractory ITP.
It produces a sustained increase in platelet count in about one-third of patients resistant to previous treatments. The optimal dose, frequency of administration and duration of treatment remain unclear. Rituximab has acceptable toxicity but the long-term adverse effects for ITP patients are presently unknown.
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