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.     

Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP)

Plasma exchange is the standard treatment for thrombotic thrombocytopenic purpura (TTP). For patients refractory to plasma exchange, treatment options are limited and often unsuccessful. The platelet thrombi that form in acquired TTP are believed to result from the presence of procoagulant ultralarge multimers of von Willebrand factor (VWF) in the circulation due to autoantibody inhibition of VWF cleaving protease (ADAMTS-13), the enzyme that normally cleaves the ultralarge multimers. Rituximab, a chimeric monoclonal antibody against CD20, has been recognized as a useful therapy for antibody-mediated autoimmune disease. We therefore treated four patients with recurrent TTP with 2 or 4 weekly doses of rituximab in addition to corticosteroids, vincristine, plasma, or continuing plasma exchange. Three patients responded with prompt improvement in microangiopathic hemolytic anemia and thrombocytopenia, which allowed plasma exchange to be discontinued or avoided and prednisone to be rapidly discontinued. Two of the 3 responders have remained in unmaintained complete remission for 13+ months. The third patient relapsed at 13 months; a second course of rituximab and prednisone resulted in an unmaintained remission for 6+ months. All four patients were tested for ADAMTS-13 activity and its inhibitor at a point in their course when samples were available. Low ADAMTS-13 activity was noted in 3 patients tested at relapse, and the inhibitor activity was detectable in 2 patients. ADAMTS-13 activity increased during remission in one of these 2 patients although the patient had a persistence of the inhibitor. One patient tested only during remission had a normal ADAMTS-13 level. We conclude that rituximab may have a role and deserves further study in the treatment of patients with relapsing TTP.     

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 for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature

Deficiency of von Willebrand factor (VWF) cleaving protease ADAMTS13 has been demonstrated to be the proximate cause of a subset of thrombotic microangiopathic haemolytic anaemias (MAHA) typical for thrombotic thrombocytopenic purpura (TTP). ADAMTS13 gene mutations cause the hereditary form; acquired deficiency has been attributed to presence of an autoantibody, which may represent a specific subset of MAHA best termed 'autoimmune thrombotic thrombocytopenic purpura'. We describe a patient with relapsing TTP because of ADAMTS13 inhibitors, who failed to achieve sustained remission despite therapies with plasma exchange, steroids, vincristine, staphylococcal protein A and splenectomy. The ADAMTS13 inhibitor titre remained elevated and clinical stability was only maintained by plasma exchange every 2-3 d over a period of 268 d. The patient then received rituximab therapy (eight doses of 375 mg/m2 weekly), during which she required five plasma exchanges in the first 10 d, two exchanges in the next 3 weeks, and none thereafter for 450 d and ongoing. The ADAMTS13 inhibitor titre decreased and enzyme activity increased. We compared this case with that of seven previously reported TTP cases also treated with rituximab; experience suggests that rituximab therapy deserves further investigation for patients with either refractory or relapsing TTP caused by ADAMTS13 inhibitors.     

Reevaluation of the prognostic factors for splenectomy in chronic idiopathic thrombocytopenic purpura (ITP): a report on 181 cases

From 1973 to 1986 we splenectomized 181 patients with chronic ITP after platelet kinetic studies with 51Cr or 111In. Mean age at diagnosis was 34 (range 4-79 yr). Follow-up of at least 1 yr after splenectomy was available in every patient. 141 patients (78%) achieved remission (platelets greater than 100 x 10(9)/l by 3 months after splenectomy), of whom 9 subsequently relapsed. Among the 40 non-responders at 3 months, 3 achieved a later remission spontaneously. Factors associated with response to splenectomy included a high post-operative platelet count (p = 0.0001), younger age at the time of surgery (p = 0.0077) and predominantly splenic sequestration of platelets (p = 0.0002), the two latter factors being partially correlated. In a multivariate analysis, however, only post-operative platelet count and age retained an independent prognostic significance, whereas the sequestration site of platelets had only borderline value. These results are discussed in the context of indications of platelet kinetic studies in chronic ITP, before splenectomy is considered.     

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.     

Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT)

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.     

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.     

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.     

Pulsed high-dose dexamethasone in refractory chronic idiopathic thrombocytopenic purpura: a report on 10 cases

Summary. We treated 10 patients who had chronic refractory idiopathic thrombocytopenic purpura (ITP) with high-dose dexamethasone (DXM, 40mg/d for 4 sequential days every month). The interval from diagnosis ranged from 49 to 300 months, and patients had previously received a median of 5.5 treatments (including splenectomy in nine cases). Median platelet count was 14 × 10⁹/1 (range 6-26 × 10⁹/1) at the onset of DXM and eight patients had bleeding symptoms. Eight patients received at least three cycles of DXM.
Five patients had a response (i.e. platelet count at least doubled and increased by >20 × 10⁹/1), including one almost complete remission and four minor responses (MR).
Of the MR, one was probably due to concurrent IVIg administration, and all four MR were transient, in spite of further cycles of DXM. In three patients DXM was a failure after three or four cycles. In two patients DXM had to be stopped after one course because of major side-effects (systemic hypertension with stroke and insulin-dependent diabetes, respectively).
In our experience, high-dose DXM had a relatively limited effect in chronic refractory ITP and was associated with severe side-effects in some cases.     

Interim evaluation of two cooperative studies assessing the effects of intravenous immunoglobulin (i.v. IgG) on childhood idiopathic thrombocytopenic purpura (ITP)

Summary Since in a pilot study i.v. IgG was shown to induce a rapid rise of thrombocytes in children with ITP two prospective multicenter ITP studies were started: one comparing i.v. IgG with oral corticosteroids in previously untreated acute ITP, the other investigating the response to i.v. IgG in pretreated acute or chronic ITP in childhood. In this report preliminary results of both studies are summarized. i.v. IgG treatment of acute and chronic ITP is at least as effective as corticosteroid therapy but is not associated with significant side effects. At least some patients with chronic ITP may benefit from i.v. IgG. Longer observation periods are required for further analysis.     

Splenectomy for the treatment of thrombotic thrombocytopenic purpura

Plasma exchange is the treatment of choice for patients with thrombotic thrombocytopenic purpura (TTP) and results in remission in >80% of the cases. Treatment of patients who are refractory to plasma therapy or have relapsing disease is difficult. Splenectomy has been a therapeutic option in these conditions but its value remains controversial. We report on a series of 33 patients with TTP who were splenectomised because they were plasma refractory (n = 9) or for relapsed disease (n = 24). Splenectomy generated prompt and unmaintained remissions in all except five patients, in whom remission was delayed (n = 4) or who died with progressive disease (n = 1). Four postoperative complications occurred: one pulmonary embolism and three surgical complications. Median follow-up after splenectomy was 109 months (range 28-230 months). The overall postsplenectomy relapse rate was 0.09 relapses/patient-year and the 10-year relapse-free survival (RFS) was 70% (95% CI 50-83%). In the patients with relapsing TTP, relapse rate fell from 0.74 relapses/patient-year before splenectomy to 0.10 after splenectomy (P < 0.00001). Two patients died from first postsplenectomy relapse. Although these results are based on retrospective data and that the relapse rate may spontaneously decrease with time, we conclude that splenectomy, when performed during stable disease, has an acceptable safety profile and should be considered in cases of plasma refractoriness or relapsing TTP to reach durable remissions and to reduce or prevent future relapses.     

Successful use of cyclosporine A in the treatment of refractory thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is, in most cases, treatable with plasma exchange therapy (PLEX). Rarely, patients do not respond to PLEX or develop refractory disease despite an initial remission. In these cases, treatment options are limited and the response to established alternative therapies is often disappointing. We report the case of a paediatric patient with TTP who developed refractory disease after an initial response to PLEX. She was subsequently treated with cyclosporine A and showed an immediate and sustained response. CSA may be a safe and effective therapy for patients with refractory TTP and should be studied in randomized, prospective clinical trials.     

Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune‐mediated severe ADAMTS13‐deficiency: a report of four cases and a systematic review of the literature

Thrombotic thrombocytopenic purpura (TTP) is a potentially life‐threatening disorder that in significant proportion of cases is related to the development of autoantibodies to, and resulting severe deficiency of, the ADAMTS13 protease. However, ADAMTS13 deficiency does not account for all cases. Response to plasma exchange (PE) is seen in TTP with and without ADAMTS13 deficiency and is therefore indicated for all with a clinical diagnosis of TTP, although the pathogenesis of the latter group remains to be defined. Although the majority of cases respond to PE, a significant percent are refractory or experience relapse. Rituximab is being increasingly used off‐label in this setting, but many reports do not define the pathogenesis of TTP so treated. We here report our experience with, and systematically review the published experience to date, of rituximab in management of refractory and or relapsing TTP specifically related to immune‐mediated severe ADAMTS13‐deficiency. In total, 73 patients met defined study inclusion criteria. The majority (～95%) achieved complete remission within weeks of the first application of rituximab. The reported relapse rate was low in this patient subgroup, which carry an anticipated relapse rate of up to 60%. However, caution in interpretation of this data is needed given the relatively short median duration of follow‐up of approximately 10 months. Rituximab was generally well tolerated, with few serious adverse events reported. However, three severe infectious complications were identified, including viral reactivation in keeping with black box warnings for this agent. Furthermore, reflecting the rarity of this disorder, only a relatively small number of patients have been treated and data with regards to long‐term follow‐up are largely based on individual case reports. Prospective studies are urgently needed to define the true efficacy and long‐term safety of rituximab.     

Rituximab induces remission of cerebral ischemia caused by thrombotic thrombocytopenic purpura

OBJECTIVE: This report describes the experience of a case of atypical thrombotic thrombocytopenic purpura (TTP) whose diagnosis was based on severe deficiency of the von Willebrand factor (vWF) cleaving metalloprotease ADAMTS13. METHODS: The level of ADAMTS13 activity, the titer of the inhibitors of this protease and the size distribution of vWF multimers in plasma samples were analysed in a patient with recurrent episodes of dizziness and blurred vision. RESULTS: In the absence of thrombocytopenia or microangiopathic hemolysis, diagnosis of TTP was established by demonstration of very low ADAMTS13 activity levels and the presence of inhibitors of this protease. After rituximab therapy decreased the inhibitor titer and increased the ADAMTS13 level, the patient has had no relapse of ischemic symptoms in the following 16 months. CONCLUSIONS: Acute neurological deficits may occur in TTP without concurrent thrombocytopenia or microangiopathic hemolysis. The role of rituximab for patients with TTP deserves further exploration.