Rituximab for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP): report of three cases

Three patients (one with idiopathic thrombocytopenic purpura [ITP] and two with thrombotic thrombocytopenic purpura [TTP]) were treated with rituximab (anti-CD20 chimeric antibody) at a dose of 325 mg/m2 administered weekly after they failed standard therapies. The patient with ITP who did not respond to steroids and anti-D antibody administration achieved augmentation of her platelet counts up to 180 x 10(3)/microL after four doses of rituximab. Six months later, when her counts started to decrease, she received maintenance therapy with an additional course of 4 standard doses of antibody that resulted in consolidation of her platelet counts around 100 x 10(3)/microL. One patient with TTP and concurrent idiopathic nephropathy who was previously treated with plasmapheresis, steroids, and vincristine improved only after 4 weekly administrations of the antibody. Moreover, his nephrotic-range proteinuria resolved after he received rituximab. The other patient with chronic TTP who still relapsed after splenectomy received 5 doses of rituximab with concomitant plasmapheresis. His thrombocytopenia improved slowly, and his platelet count stabilized at 300 x 10(3)/microL. All three patients showed evidence of response to anti-CD20 antibody with improvement in clinical outcome as well as augmentation of platelet counts to normal levels. We conclude that rituximab is a useful immunomodulating adjunct in the treatment of refractory ITP and TTP.     

Refractory autoimmune thrombocytopenic purpura: responses to treatment with a recombinant antibody to lymphocyte membrane antigen CD20 (rituximab)

"Refractory" autoimmune thrombocytopenia represents a life-threatening condition, having failed to respond to a variety of therapeutic measures. We report a series of cases, all failing splenectomy and multiple therapeutic programs, including, in two patients, marrow transplant. Five of the six cases reported responded to a recombinant antibody to the lymphocyte membrane antigen CD20 (rituximab), an agent commonly employed in the treatment of non-Hodgkin's lymphoma. Our experiences over a period of 4 years are documented. The results support the use of this product, rituximab, in the treatment of patients with autoimmune thrombocytopenia who have not attained a hemostatically effective platelet count following splenectomy and require a continuing therapeutic management program.     

Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura

The role of rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, in the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP) has not been determined. The effectiveness and side effects of this therapeutic modality were investigated in a cohort of 25 individuals with chronic ITP. All patients had ITP that had been resistant to between 2 and 5 different therapeutic regimens, including 8 patients who had already failed splenectomy. Patients were scheduled to receive intravenous rituximab at the dose of 375 mg/m(2) once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but were of modest intensity and did not require discontinuation of treatment. A complete response (platelet count greater than 100 x 10(9)/L) was observed in 5 cases, a partial response (platelet count between 50 and 100 x 10(9)/L) in 5 cases, and a minor response (platelet count below 50 x 10(9)/L, with no need for continued treatment) in 3 cases, with an overall response rate of 52%. In 7 cases, responses were sustained (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In patients with a complete or partial response, a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome, although there was a suggestion that women and younger patients have a better chance of response. In conclusion, rituximab therapy has a limited but valuable effect in patients with chronic ITP. In view of its mild toxicity and the lack of effective alternative treatments, its use in the setting of chronic refractory ITP is warranted. (Blood. 2001;98:952-957)     

Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.     

Dapsone for refractory chronic idiopathic thrombocytopenic purpura

Summary. Fifteen patients with refractory chronic idiopathic thrombocytopenic purpura (ITP) were treated with dapsone (lOOmg/d) for 1-31 months. The overall response rate to dapsone was 40%. Five patients responded in 1 month and one patient in 2 months. No pretreatment characteristics -sex, age, platelet count or duration of ITP - were correlated with response to dapsone. Treatment was well tolerated. The most frequent adverse effect was dose-related haemolytic anaemia. In our experience, dapsone provides an inexpensive and well-tolerated alternative for patients with ITP who had inadequate reponses to conventional therapy.     

Successful treatment of autoimmune hepatitis and idiopathic thrombocytopenic purpura with the monoclonal antibody, rituximab: case report and review of literature.

Rituximab, a chimeric monoclonal anti-CD20 antibody, has shown activity in several autoimmune disorders. We describe a case of a 52 years old female who was diagnosed with idiopathic thrombocytopenic purpura and concomitant autoimmune hepatitis (AIH), both non-responsive to steroids. She was subsequently treated with rituximab, which resulted in a rapid increase in her platelet count and an unexpected normalization of her hepatic biochemical tests. Both her platelet count and her hepatic biochemical tests remained normal for over 5 months. In this case, rituximab showed an impressive clinical response for the treatment of AIH, and it may be considered as an alternative treatment in patients who do not respond to corticosteroid therapy. Prospective randomized studies in AIH are needed to validate this observation.     

Treatment of refractory thrombocytopenic purpura with cyclophosphamide

Cyclophosphamide, an immunosuppressive agent, was administered as an additional mode of therapy to 30 patients with idiopathic thrombocytopenic purpura (ITP) refractory to conventional management. Of 22 previously tested by splenectomy an excellent response was achieved in 12, who remained in complete hematologic remission for 14–96 months after therapy was discontinued; a fair response in 3, with definite increase in platelets, but not to normal levels; and a poor response in 7 who failed to improve. Of 8 nonsplenectomized patients who failed to respond to steroids or maintain a response after steroids were discontinued, 4 were considered excellent, 1 required continued therapy to remain in remission (good response), 2 were fair, and 1 was poor. Remission was observed in 2–10 weeks in both groups and appeared to be related to duration of disease; presence of disease for less than 1 year was associated with a much better response to treatment (11 of 15) when compared with disorders lasting over 2 years (6 of 15). Cyclophosphamide therapy offers additional means of treating patients with ITP who fail to respond to conventional therapy and may serve as an alternative to splenectomy when surgery is contraindicated.     

Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results

Objective:  To evaluate the long-term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP).
Patients and methods:  Twenty-six patients with active and symptomatic ITP relapsed or refractory received weekly infusions of rituximab 375 mg/m² for 4 wk. Median time from diagnosis to rituximab was 34.5 months . The following parameters of efficacy and toxicity were considered: complete response (CR) and partial response (PR), relapse rate, relapse-free survival (RFS), therapy-free survival (TFS), short- and long-term toxicity.
Results:  CR and PR were 14/26 (54%) and 4/26 (15%), respectively. Median time of observation was 56.5 months (range 39–77). Nine of the 18 responding patients relapsed after a median of 21 months (range 8–66); 9/26 patients (35%) maintained the response, with a median follow-up of 57 months (range 39–69), and 11/26 (42%) did not necessitate further therapy; estimated 5 yr RFS and TFS were 61% and 72%, respectively. Younger age and shorter interval from diagnosis to rituximab appeared indicators of better outcome. Rituximab administration was associated with two episodes of short-term toxicity, with one case of serum sickness syndrome; no infectious or other significant long-term complications were documented.
Conclusion:  Rituximab therapy may achieve long-lasting remission in nearly one-third of patients with relapsed or refractory ITP, with a good safety profile.     

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.     

Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab

The only established treatment for patients with thrombotic thrombocytopenic purpura (TTP) is plasma exchange against fresh frozen plasma. For cases refractory to plasma exchange, no generally treatment schedule exists. One option is immunosuppressive therapy with corticosteroids and vincristine. Rituximab is a chimeric monoclonal antibody directed against the CD20 antigen, and it has been successfully used in B-cell malignancies and is being investigated in autoimmune diseases. Its efficacy in TTP has not yet been determined. We report two female patients with severe TTP refractory to multiple courses of plasmapheresis, high-dose steroid treatment, and vincristine who responded after adding rituximab while continuing plasmapheresis.     

High-dose intravenous methylprednisolone for acute childhood idiopathic thrombocytopenic purpura

49 children with acute idiopathic thrombocytopenic purpura (ITP) were divided into non-treatment, oral prednisone (2 mg/kg), and high-dose intravenous methylprednisolone (HIVMP) treatment groups which consisted of 17, 16 and 16 children respectively. Platelet counts rose above 150,000/microliters over a 2-week period in 5 (29.4%) children in the first group, 5 (31.2%) in the second group and 15 (93.7%) children in the third group. Platelet counts reached the normal level in only 3 days in 11 (68.7%) children treated with HIVMP. Initially, antiplatelet antibodies (APA) were shown by the Handin and Stossel method in every patient. With normalization of platelet counts, the antibodies decreased but could still be detected in every case; antibody decrease was greater in the HIVMP group. With the exception of mild cushingoid appearance, none of the major corticosteroid side effects was observed in the treated children.     

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, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia

The introduction of first alpha-interferon and later the purine analogues has revolutionized the treatment of hairy cell leukaemia (HCL). However, there are still some patients that initially or eventually fail to respond and, thus, there is a need for alternative treatment modalities. We have treated 11 HCL patients (eight relapsing and three newly diagnosed) with a chimaeric monoclonal antibody, rituximab, in a dose of 375 mg/m2 once a week for 4 weeks. The response rate was seven out of eleven (64%) with six complete remissions and one partial remission, all which have lasted between 0 and 34 months (median 14 months). Rituximab appears promising in the treatment of HCL and warrants further studies.     

The treatment of adult idiopathic thrombocytopenic purpura. Infusion of vinblastine in ITP

16 adult idiopathic thrombocytopenic purpura (ITP) patients, with mean age 51 years, were treated by 5 weekly slow intravenous infusions of vinblastine (0.1 mg/kg). When a complete or partial response (CR or PR) was obtained, slow infusions were repeated at 2-weekly then monthly intervals, as maintenance therapy. In 4 cases with ITP of recent onset, but presenting contraindication or failure to prednisone and high dose intravenous immunoglobulins, CR was obtained in all patients after 4 to 15 days (mean 9.5). Only one of these patients relapsed. In 12 cases of refractory chronic ITP (of whom 10 had been splenectomized), there were 2 CR, 6 PR and 4 failures. The 8 responding patients had a mean interval to response of 20 days. The 6 PR were short and did not exceed 15 days. Our results do not support a superiority of this treatment compared to other modes of administration of vinca alkaloids in ITP (intravenous bolus, vinca loaded platelets).     

Acute idiopathic thrombocytopenic purpura in children

Acute idiopathic thrombocytopenic purpura (ITP) characteristically follows a viral illness in preschool children. The exact role of viruses in the pathogenesis of this disorder remains uncertain, but the finding of markedly elevated levels of platelet-associated IgG serves to distinguish it from the chronic form of the disease and permits speculation on the mechanisms of platelet destruction. Although the spleen is important in both antibody production and platelet destruction, bone marrow synthesis of IgG has also been shown to be increased. The clinical course may be alarming, but mortality is low and prognosis excellent. Controversy has surrounded the role of steroids in the management of acute childhood ITP in retrospective studies. Controlled studies, however, indicate that thrombocytopenia is reversed sooner in treated patients. New assays for platelet-associated IgG offer new insights into this disorder and will allow delineation of acute and chronic disease at the time of diagnosis.     

Cyclic thrombocytopenia in a patient treated with cyclosporine for refractory idiopathic thrombocytopenic purpura

Cyclic thrombocytopenia (CT) is a rare disorder with cyclic changes of the platelet counts. Though the pathogenesis of this disorder has not been clarified, recent reports suggest that periodic destruction and/or ineffective production of platelets may be important causes of the disease. We report a case of a patient with refractory idiopathic thrombocytopenic purpura (ITP) in whom CT developed after cyclosporine A (CyA) therapy. There was an inverse relation between platelet counts and the serum levels of platelet-associated immunoglobulin G (PAIgG). The ploidy of bone marrow megakaryocytes also had an inverse relation with platelet counts. When the platelet count was low, the ploidy of megakaryocytes increased (P < 0.01). The number and area of bone marrow megakaryocytes were unrelated to platelet counts. These results indicate the possibility of platelet destruction caused by immunological mechanisms in CT. Cyclosporine A could have certain but fluctuating regulatory effects against antibody production for circulating platelets, which could lead to cyclic changes of the platelet counts. This case also suggests that CyA can be effective in severe refractory ITP. Regulatory mechanisms of platelet production and destruction and appropriate doses of CyA should be further studied in autoimmune-mediated thrombocytopenias. Am. J. Hematol. 56:272–276, 1997. © 1997 Wiley-Liss, Inc.     

Absence of platelet response after eradication of Helicobacter pylori infection in patients with chronic idiopathic thrombocytopenic purpura

Eradication of Helicobacter pylori infection has been associated with the correction of thrombocytopenia in patients with idiopathic thrombocytopenic purpura (ITP). We have analysed the response to eradication of H. pylori in a series of 56 adult patients with chronic ITP. Forty patients had H. pylori infection (71%) that was eradicated in 23 of 32 evaluable patients (72%). Platelet counts did not significantly vary according to H. pylori treatment outcome. Three of 56 patients (5%) achieved a partial response attributable to H. pylori eradication. Therefore, detection of H. pylori infection should not be routinely included in the initial work-up of ITP.     

抗CD20抗体治疗慢性特发性血小板减少性紫癜机制的研究

目的:通过抗CD20抗体(Rituximab,商品名:美罗华)与慢性特发性血小板减少性紫癜(cITP)骨髓体外培养,了解cITP患者B细胞的活化与凋亡的状况。方法:选择cITP患者30 例,对照组缺铁性贫血患者10例,进行骨髓体外培养,于培养前、培养3 d、培养6 d、培养9 d,检测B细胞相关分子(CD19、CD20、CD23)和透射电镜观测淋巴细胞凋亡状态。结果:cITP患者骨髓CD20、CD23分子表达显著高于对照组CD20、CD23分子表达(P<0.01)。加抗CD20抗体和加半量抗CD20抗体培养前后B细胞相关分子(CD19、CD20、CD23)检测结果差异有统计学意义(P<0.01)。加抗CD20抗体组透射电镜观测有淋巴细胞凋亡。结论:抗CD20 抗体能靶向性地与表达CD20抗原的B细胞结合,通过抗体抗原反应,诱导B细胞加速凋亡。