Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura is an autoimmune disease which involves opsonization of platelets by autoantibodies directed against different surface glycoproteins, leading to their premature destruction by the reticuloendothelial system. Management of patients with refractory ITP is difficult. Recent studies have shown that rituximab, a chimeric anti-CD20 monoclonal antibody, is useful in the treatment of these patients, with overall response rates of about 50%. Most published reports have included a small number patients including case reports. The present study reports the results of a retrospective Danish multicenter study of rituximab in the treatment of adult patients with refractory ITP. Thirty-five patients (median age 52 years, range 17-82 years, 17 males) were included. One patient had immune thrombocytopenia and neutropenia. All patients had received prednisolone (Pred). Next to Pred, 25 patients had been treated with high-dose IgG, and in 16 patients a splenectomy had been performed. Sixteen patients had been treated with azathioprine. Other treatments included, e.g., cyclosporine, danazol, cyclophosphamide, vincristine, interferon, and dexamethasone. The patients were treated with a dose regimen of 375 mg/m2 i.v. approximately once weekly for 4 consecutive weeks. Six patients received a fixed dose of 500 mg disregarding their weight supplemented by 100 mg of methylprednisone i.v. or 50-100 mg of Pred given as premedication together with an antihistamine just before infusion of rituximab. The large majority of patients also received Pred and, in some cases, other concomitant immunosuppressive treatment during part of their rituximab treatment. A complete response (CR) was defined as a rise in the platelet count > 100 x 10(9)/L, a partial response (PR) as a rise in the platelet count > 50 x 10(9)/L, and a minor response (MR) as a rise in the platelet count < 50 x 10(9)/L. No response (NR) was defined as no increase in the platelet count. Because 4 patients were treated twice, a total of 39 outcomes of rituximab treatment were evaluated. Rituximab proved to be effective in 17 of 39 treatments [overall response 44% with 7 CR (18%) (1 patient showed a CR twice), 6 PR (15%), and 4 MR (10%)]. In 9/13 cases of CR or PR, the response (platelet level > 50 x 10(9)/L) was prompt, 1-2 weeks after the first infusion. The remaining patients responded 3-8 weeks later. Patients with CR and PR have been in remission for a median of 47 weeks. In general the side effects were few. In 2 cases, the treatment was stopped because of side effects either during or after the first infusion. Two fatal outcomes were recorded. A 71-year-old female with severe lung disease died 6 days after the first infusion of respiratory failure. The other patient, a 73-year-old man also with severe chronic obstructive lung disease, died of pneumonia approximately 13 weeks following the last rituximab treatment. It is concluded that rituximab may be a useful alternative therapy in patients with severe and symptomatic ITP refractory to conventional treatment.     

利妥昔单抗治疗糖皮质激素无效的特发性血小板减少性紫癜疗效观察

目的 探讨利妥昔单抗治疗特发性血小板减少性紫癜(ITP)的疗效、安全性及治疗前后B细胞、血小板膜糖蛋白(GP)特异性自身抗体的变化.方法 利妥昔单抗(375 mg/m2,每周1次,连用4周)治疗12例糖皮质激素治疗无效的ITP患者,监测治疗前后的血常规、血清免疫球蛋白定量(IgG、IgM、IgA)、血小板GPⅡb/Ⅲa和(或)GP Ⅰ b/Ⅸ特异性自身抗体、CD+3、CD+4、CD+8、CD+19、CD+20细胞数.结果 4例完全有效,3例部分有效,2例微效,3例无效.随访中位时间5(0.5～12)个月,疗效均维持较好.有效患者治疗后血小板自身抗体均转阴.治疗前后血清IgG、IgM、IgA无明显变化,CD+3、CD+4、CD+8细胞数无明显变化.治疗后CD+19/CD+20细胞数(4.1±2.2)×106/L与治疗前(295.0±86.4)×106/L比较明显下降(P＜0.01).无严重不良反应.结论 利妥昔单抗治疗糖皮质激素无效的ITP患者安全、有效.     

Rituximab treatment for chronic refractory idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura (ITP) is characterized by mucocutaneous bleeding and a low platelet count caused by increased autoantibodies against self-antigens and T-cell mediated cytotoxicity. About 10-30% patients with ITP will become refractory ITP. Most of them will become refractory to corticosteroids and splenectomy, as well as other available agents such as intravenous immunoglobulins, danazol, or chemotherapy. B cells not only are the passive producers of immunoglobulins, but also play an important immunoregulatory role in pathophysiology of ITP. Rituximab, a chimeric anti-CD20 monoclonal antibody that specifically targets the CD20 molecule on the B-cell surface, is useful in the treatment of ITP through B cells depletion. Rituximab has multiple mechanisms of inducing cytotoxicity in vivo, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), direct apoptosis signaling, and possible vaccine effects. In most clinical reports, rituximab was given as an intravenous infusion at a dose of 375 mg/m(2) weekly for four doses. A total complete response (CR) of 33.2% and a total response of 52.9% were reported. Most results found that no clinical or laboratory parameters could predict treatment outcome. Though the infusion-related side effects of rituximab were common in ITP, it was well tolerated with rare severe side effects. In general, rituximab appears to be a promising immunotherapeutic agent for the treatment of refractory ITP. More controlled clinical trials are necessary to evaluate both the efficacy and long-term safety of the drug.     

Treatment of relapsed idiopathic thrombocytopenic purpura with the anti-CD20 monoclonal antibody rituximab: a pilot study

We performed a prospective pilot study on 12 patients to evaluate the efficacy of the anti-CD20 monoclonal antibody rituximab in relapsed idiopathic thrombocytopenic purpura (ITP). Inclusion criteria were relapse of ITP with a thrombocyte count <20 000 micro L-1 and unsuccessful corticosteroid treatment. Eleven patients had a previous splenectomy, five patients had unsuccessful cytotoxic treatment, and six patients were refractory to intravenous immunoglobulins before rituximab therapy. Response criteria were as follows. Complete remission (CR): normalization of thrombocyte count for at least 30 d. Partial remission (PR): an increase of thrombocytes to above 30 000 microL(-1) for at least 30 d. Minor response (MR): any increase above 30 000 microL(-1) for less than 30 d but more than 10 d. No response (NR): failure to achieve any of the above responses. Treatment plan: We administered 375 mg m(-2) of rituximab once weekly on up to four consecutive weeks, unless there was early CR. Five patients (41%) achieved CR, two patients (17%) PR, and two patients MR (overall response rate 75%, median follow-up of responders 320 d). Four CR patients are ongoing; one CR patient relapsed after 6 months. Adverse events included excessive thrombocytosis in one patient as well as minor infusion-related (grade I) toxicities in four patients. We conclude that rituximab is a promising agent in the treatment of relapsed ITP.     

Chronic refractory idiopathic thrombocytopenic purpura (ITP) and anti-CD20 monoclonal antibody: a case report.

Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disorder characterized by accelerated and premature destruction of platelets by reticuloendothelial system. CD20, a trans-membrane B-cell-specific antigen, is a potential target for treatment of certain malignant and nonmalignant plasma cell disorders including refractory ITP. Rituximab is a genetically engineered human anti-CD20 monoclonal antibody, which is approved for the treatment of low-grade non-Hodgkin's lymphoma. Recent clinical reports suggest that rituximab may be useful in treating certain patients with chronic refractory ITP. A 59-year-old woman with refractory ITP was placed on rituximab (four weekly doses of 375 mg/m(2)) and her condition and platelet count were observed for 18 months. There was a gradual increase in platelet count and she was symptom free in this period and no side effects of the drug were reported. Anti-CD20 antibodies are likely to be used in the treatment of refractory ITP cases, but further studies about treatment schedule and criteria for patient selection should be done.     

Rituximab in the treatment of relapsing idiopathic thrombocytopenic purpura

About 25 to 30% of patients with idiopathic thrombocytopenic purpura (ITP) are resistant to standard treatment with steroids and splenectomy. In these patients with chronic refractory ITP, there is no proven algorithm for standard care. Recently, the chimeric anti-CD20 monoclonal antibody rituximab was considered as an alternative treatment option in this patient group. We present a patient with frequently relapsing ITP after treatment with prednisone, splenectomy and high-dose dexamethasone. Since he experienced increasing side effects due to the steroids, he was treated with rituximab 375 mg/m2, once weekly for four weeks, resulting in a complete long-lasting response (follow-up seven months).     

Rituximab before splenectomy in adults with primary idiopathic thrombocytopenic purpura: a meta-analysis

Primary immune thrombocytopenia (ITP) is an acquired immune-mediated disorder with absence of any underlying cause. Corticosteroids are the standard initial treatment. Splenectomy is the main second-line treatment. A trend to delay or avoid splenectomy has developed thanks to new agents like rituximab. Few studies have assessed the response rate to rituximab in chronic ITP. We performed the first meta-analysis of randomized clinical trials and observational studies on rituximab as an effective splenectomy-avoiding option in adult chronic ITP. Overall methods were adapted from published guidelines for meta-analysis (meta-analysis of observational studies in epidemiology and preferred reporting items for systematic reviews and meta-analyses). Two haematologist investigators carried out study selection and data extraction independently, recording overall response rate (ORR) and complete response (CR) as primary assessment criteria. Of 364 records were identified through electronic databases. Of 19 retrospective or prospective observational studies were retained after removing duplicate studies and full-text analyses. The ORR was 57% (95% confidence interval [CI]: 48-65), for 368 non-splenectomized patients after rituximab; CR was 41% (95% CI: 0·33-0·51) for 346 patients. Results were stable for ORR and CR in all sub-analyses. In univariate or multivariate mixed-effect meta-regression, age was the most relevant effect. According to our results, rituximab should be used in earlier in non-splenectomized patients.     

High-dose intravenous IgG for chronic idiopathic thrombocytopenic purpura in adults

Summary Sixteen adult patients of mean age 48 years with chronic ITP were studied for platelet response to high-dose (0.4 g/kg body weight per day for five consecutive days) intravenous polyvalent intact IgG in the absence of any concurrent treatment. The platelet count returned to normal values in nine patients, a partial response (rise in the platelet count between 50 and 150 ×10⁹/l) was observed in three cases. One patient refractory to any other treatment went into a sustained remission. In the other responsive patients the response was only transient. Among seven splenectomised patients only three responded to IgG infusions versus nine in the non-splenectomised group. The length of ITP history appeared as a more critical factor for the response to IgG than previous splenectomy.     

Rituximab in the treatment of idiopathic thrombocytopenic purpura (ITP)

The objective of this study was to evaluate the efficacy and safety of rituximab in the treatment of patients with idiopathic thrombocytopenic purpura (ITP). A prospective study was performed at Mubarak Al-Kabeer University Hospital involving the use of rituximab in 14 patients who had previously been treated with steroids, steroid sparing drugs, and splenectomy. Several variables have been collected and analyzed including age, gender, treatment received prior to rituximab, co-morbid condition, platelet count before treatment, response to treatment, duration of response, relapses, response to re-treatment, and adverse effects. Of the 14 treated patients, complete remission was achieved in 11 patients, partial remission in two patients, and no response in one patient. Median duration of responses were 12.5 months, ranging from 2 to 19 months. Four patients had at least one relapse. Responses were seen in splenectomized and non-splenectomized patients. This study is the first attempt to evaluate the efficacy and safety of rituximab in the treatment of ITP in the Middle East area. Our findings support the result of other case reports, case series, and pilot studies; however, a randomized control trial is needed to confirm the results of our study.     

Pulsed intravenous high-dose dexamethasone in adults with chronic idiopathic thrombocytopenic purpura

The role of pulsed high-dose dexamethasone (DXM) in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) is still uncertain. Following an early report in which it was described as an effective and well-tolerated treatment with a sustained platelet response in 100% of cases, a number of subsequent studies have failed to confirm such favorable results. As all these studies were conducted on small numbers of patients, we investigated further the effectiveness and side effects of this therapeutic modality in a larger cohort. Thirty-two patients with chronic ITP were scheduled to receive six monthly courses of intravenous DXM at the dose of 40 mg/day for 4 consecutive days. All patients had ITP that had been resistant to between two and five different therapeutic regimens, including 9 patients who had already failed splenectomy. All patients had to be seen 2 weeks after each cycle to asses their response as well as secondary effects. Three patients failed to respond and clinically required other therapy. Thirteen patients (41%) had a partial (platelet count between 50 and 100 x 10(9)/liter) or complete (platelet count >100 x 10(9)/liter) response to treatment, responses being mostly transient. Responses were observed early during the course of treatment, usually right after the first cycle of DXM. There were no late responses. Side effects were mild and did not require discontinuation of treatment. No clinical or laboratory parameter was found to predict treatment outcome. We conclude that high-dose DXM has a limited effect in patients with chronic ITP. Novel approaches and controlled multicenter trials may help identify new therapeutic strategies for this disease.     

Severe Evans's syndrome secondary to interleukin-2 therapy: treatment with chimeric monoclonal anti-CD20 antibody

Interleukin-2 (IL-2) acts by increasing the efficiency of the immune system to exert a tumoricidal effect. Although it is well known that immune stimulation with IL-2 plays a role in unmasking autoimmune phenomena such as autoimmune thyroiditis, hematological effects such as anemia and thrombocytopenia are more frequently due to toxic non-immune mechanisms. We describe a patient who developed severe Evans's syndrome [autoimmune hemolytic anemia (AHA) and immune thrombocytopenic purpura (ITP)] secondary to IL-2 therapy. ITP was refractory to multiple treatment modalities including steroids and splenectomy. ITP and AHA were initially managed with intravenous gamma globulin therapy and frequent blood transfusions, respectively. Ultimately, immunosuppressive therapy with cyclophosphamide and chimeric monoclonal anti-CD20 antibody (rituximab) were successful in inducing complete remission of Evans's syndrome.     

Anti-CD20 monoclonal antibody therapy in refractory immune thrombocytopenic purpura

Multiple agents have been tried in patients with refractory immune thrombocytopenic purpura (ITP); however, none of these stands as a clear first choice. We administered rituximab, 375 mg/m2 weekly x 4, to four patients with refractory ITP. With a median follow-up of 7 months, one patient has achieved a complete response, proving the possible efficacy of such a therapeutic modality in this context.