Short- and long-term effects of rituximab for the treatment of thrombotic thrombocytopenic purpura: four case reports

We report four cases of thrombotic thrombocytopenic purpura (TTP) successfully treated with rituximab in combination with plasma exchange and other immunosuppressive agents. All four cases fulfilled the diagnostic criteria of TTP with severe deficiencies in ADAMTS13 activity and a detectable anti-ADAMTS13 inhibitor. Four weekly doses of 375?mg/m² rituximab were initiated on day 3?C29 of presentation as a salvage treatment for relapsing/refractory disease in three patients and as a first-line treatment in one. Resolution of clinical symptoms and hematological abnormalities occurred as early as the second dose and, after the completion of treatment, all four patients achieved complete response (CR). They are currently free from relapse and the duration of CR has been 13?C72?months. During the treatment course, the level of ADAMTS13 activity and the titer of the inhibitor correlated well with resolution or exacerbation of the disease. This report suggests that rituximab exhibits short- and long-term favorable effects for the treatment of TTP and that a severe ADAMTS13 deficiency and ADAMTS13 inhibitor positivity may support early administration of rituximab in both acute/refractory and relapsing cases.     

Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.     

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.     

Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura

Discoveries during the past decade have revolutionized our understanding of idiopathic thrombotic thrombocytopenic purpura (TTP). Most cases in adults are caused by acquired autoantibodies that inhibit ADAMTS13, a metalloprotease that cleaves von Willebrand factor within nascent platelet-rich thrombi to prevent hemolysis, thrombocytopenia, and tissue infarction. Although approximately 80% of patients respond to plasma exchange, which removes autoantibody and replenishes ADAMTS13, one third to one half of survivors develop refractory or relapsing disease. Intensive immunosuppressive therapy with rituximab appears to be effective as salvage therapy, and ongoing clinical trials should determine whether adjuvant rituximab with plasma exchange also is beneficial at first diagnosis. A major unanswered question is whether plasma exchange is effective for the subset of patients with idiopathic TTP who do not have severe ADAMTS13 deficiency.     

Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura

Therapeutic plasma exchange is an effective empiric treatment for thrombotic thrombocytopenic purpura (TTP), but how therapy affects the level of a disintegrin and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) or inhibitor has not been reported in many patients. We prospectively analyzed ADAMTS13 activity and inhibitor levels in 37 adults with TTP. ADAMTS13 level at presentation was lower than 5% in 16 of 20 patients with idiopathic TTP and in none of 17 patients with TTP associated with hematopoietic stem cell transplantation, cancer, drugs, or pregnancy (P <.00001). Seven of the 16 patients with ADAMTS13 activity lower than 5% ( approximately 44%) had inhibitors. For 8 patients followed serially with ADAMTS13 activity lower than 5% but no inhibitor at presentation, plasma exchange led to complete clinical remission and a rise in ADAMTS13 level. In contrast, 4 patients with low ADAMTS13 activity but high-titer inhibitor (> 5 units/mL) had neither a rise in ADAMTS13 activity nor a reduction in the inhibitor titer: 3 had recurrent disease and 1 died. Among 17 patients with AD-AMTS13 activity at presentation higher than 25%, 10 died. Mortality rate for idiopathic TTP was 15%, whereas mortality for nonidiopathic TTP was 59% (P <.02). We conclude that assays of ADAMTS13 activity and inhibitors in addition to the clinical categories (idiopathic TTP and nonidiopathic TTP) are predictive of outcome and may be useful to tailor patient treatment.     

Pediatric thrombotic thrombocytopenic purpura

Child‐onset thrombotic thrombocytopenic purpura (TTP) is a rare entity of thrombotic microangiopathy (TMA). The pathophysiology of the disease is based on a severe functional deficiency of ADAMTS13 (activity <10%), the specific von Willebrand factor (VWF)‐cleavage protease. This deficiency may be either acquired (associated anti‐ADAMTS13 autoantibodies) or congenital (resulting from biallelic mutations of ADAMTS13 gene). ADAMTS13 deficiency is responsible for the accumulation of high molecular weight multimers of VWF and the formation of platelet thrombi in the microcirculation. Consequently, microangiopathic hemolytic anemia and consumption thrombocytopenia are associated with organ ischemia. The differential diagnosis with other TMAs, autoimmune cytopenias or hematological malignancies may be challenging. The exploration of ADAMTS13 (activity, antibodies, antigen, ADAMTS13 gene) supports the diagnosis of TTP. The first‐line treatment of the acute phase of TTP is based on plasmatherapy. In congenital TTP, patients with a chronic disease benefit from a prophylactic plasmatherapy. In autoimmune TTP, steroids and B‐cells depleting therapies increasingly are used together with plasma exchange. Long‐term follow‐up including the monitoring of ADAMTS13 activity is mandatory. A severe decrease in ADAMTS13 activity (<10%) may predict relapses and preemptive B‐cell depletion with rituximab can be used to prevent relapses.     

Clinical presentation and management of acquired thrombotic thrombocytopenic purpura: A case series of 55 patients

The aim of this study was to explore the clinical characteristics and treatment of acquired thrombotic thrombocytopenic purpura (TTP). The clinical manifestations, laboratory findings, differential diagnoses, therapeutic methods, and prognosis of 55 patients with acquired TTP were retrospectively analyzed. Among the 55 TTP patients, 17 were males and 38 were females, with a mean age of 40 ± 15 years. Twenty‐one patients had the Triad syndrome, which included neurological syndromes, microangiopathic hemolytic anemia, and thrombocytopenia. Twenty‐three patients had the Quinary syndrome, which included fever, microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and neurological symptoms. Twenty‐eight patients received the measurement for a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and 23 patients had <10% of the normal range. ADAMTS13 inhibitor was tested in 20 patients and was positive in 18 patients. Both ADAMTS13 activity and ADAMTS13 inhibitor were examined in 20 patients and 90% of the patients showed double positive results. The treatment methods included plasma exchange, glucocorticoids, rituximab, immunosuppressants, and intravenous immunoglobulin. Thirty‐three patients survived, and 22 patients died. Plasma exchange improved the remission rate from 16.7% to 65.3% (P = .022). The combined immunosuppressive therapy based on plasma exchange and glucocorticoids raised the remission rate from 43.8% to 75.8%. Most of acquired TTP patients had the Triad syndrome or the Quinary syndrome. A high proportion of TTP patients had ADAMTS13 activity reduction and ADAMTS13 inhibitor positivity. Plasma exchange and immunosuppressive therapy may improve the prognosis of this disease.     

Rituximab therapy for refractory thrombotic thrombocytopenic purpura

While most patients of thrombotic thrombocytopenic purpura (TTP) respond to plasma exchange and achieve remission, a subset of the patients experience multiple relapses or develop a persistent disease that may be debilitating and life threatening. We report the experience of rituximab treatment in three consecutive patients who had required periodic plasma exchange for greater than 50-180 days after failing other modalities of treatments. Two patients each received eight doses of rituximab infusion and had clinical remissions that have lasted for 23 months and ongoing in one patient and for 17 months before relapse in the other. The third patient received four doses of rituximab infusion and had improvement of disease for 60 days until her death from unrelated causes. Analysis of the von Willebrand factor-cleaving metalloprotease activity (ADAMTS13) and its inhibitor in two patients showed that rituximab treatment was associated with a rise of the protease level and a decrease of the inhibitor titers in one patient who achieved clinical remission and a decrease of the inhibitor titer but no increase in protease level in the other patient who had a partial response. Based on the responses to rituximab and its mild toxicity in these three patients, and the lack of effective alternative treatments, additional exploration of the role of rituximab in the treatment of refractory TTP is warranted.     

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.     

von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome

Whether measurement of ADAMTS13 activity may enable physicians to distinguish thrombotic thrombocytopenic purpura (TTP) from hemolytic uremic syndrome (HUS) is still a controversial issue. Our aim was to clarify whether patients with normal or deficient ADAMTS13 activity could be distinguished in terms of disease manifestations and multimeric patterns of plasma von Willebrand factor (VWF). ADAMTS13 activity, VWF antigen, and multimeric pattern were evaluated in patients with recurrent and familial TTP (n = 20) and HUS (n = 29). Results of the collagen-binding assay of ADAMTS13 activity were confirmed in selected samples by testing the capacity of plasma to cleave recombinant VWF A1-A2-A3. Most patients with TTP had complete or partial deficiency of ADAMTS13 activity during the acute phase, and in some the defect persisted at remission. However, complete ADAMTS13 deficiency was also found in 5 of 9 patients with HUS during the acute phase and in 5 patients during remission. HUS patients with ADAMTS13 deficiency could not be distinguished clinically from those with normal ADAMTS13. In a subgroup of patients with TTP or HUS, the ADAMTS13 defect was inherited, as documented by half-normal levels of ADAMTS13 in their asymptomatic parents, consistent with the heterozygous carrier state. In patients with TTP and HUS there was indirect evidence of increased VWF fragmentation, and this occurred also in patients with ADAMTS13 deficiency. In conclusion, deficient ADAMTS13 activity does not distinguish TTP from HUS, at least in the recurrent and familial forms, and it is not the only determinant of VWF abnormalities in these conditions.     

Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin

Severe ADAMTS13 deficiency in thrombotic thrombocytopenic purpura (TTP) is either constitutional and caused by ADAMTS13 mutations, or acquired and most often due to ADAMTS13 inhibitory autoantibodies. In strongly hemolytic serum of a pediatric patient, diagnosed with TTP postmortem, ADAMTS13 activity was less than 3%. Both parents had an ADAMTS13 activity of approximately 50%. Sequencing of the ADAMTS13 gene revealed an intronic 687-2A>G substitution affecting exon 7, homozygous in the propositus and heterozygous in both parents, confirming constitutional ADAMTS13 deficiency. ADAMTS13 activity of normal plasma was inhibited by incubation with the propositus' serum, suggesting alloantibody formation to ADAMTS13. However, immunoglobulin purified from serum had no ADAMTS13 inhibitory effect, whereas the immunoglobulin-depleted hemolytic serum inhibited ADAMTS13 activity of normal plasma, suggesting an inhibitory effect of hemolysis products. Incubation of hemoglobin, recombinant and from lysed erythrocytes, with normal plasma revealed an ADAMTS13 inhibitory effect at hemoglobin concentrations of 2 g/L or higher.     

Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that occurs mainly in young adults. Acquired cases are usually a result of antibodies directed against ADAMTS13 (a disintegrin-like and metalloprotease [reprolysin type] with thrombospondin type 1 motif 13), a protease that cleaves the von Willebrand factor multimers. Prognosis has been improved by plasma therapy, but some acute severe forms are refractory to this treatment and achieving a sustained remission is still a challenge in chronic relapsing forms. We therefore conducted a multicentric open-label prospective trial to test the efficacy of rituximab, an anti-B-cell monoclonal antibody, as a curative and prophylactic treatment in patients with TTP as a result of anti-ADAMTS13 antibodies. Six patients were included during an acute refractory TTP episode. Five patients with severe relapsing TTP and persistent anti-ADAMTS13 antibodies were prophylactically treated during remission. All patients received 4 weekly infusions of rituximab. The target of treatment was to restore a significant ADAMTS13 plasma activity (> 10%). Treatment with rituximab led to clinical remission in all cases of acute refractory TTP. In all patients, anti-ADAMTS13 antibodies disappeared, and a significant (18%-75%) plasma ADAMTS13 activity was detected following treatment. Tolerance of rituximab was good. Rituximab is a promising first-line immunosuppressive treatment in patients with acute refractory and severe relapsing TTP related to anti-ADAMTS13 antibodies.     

Rituximab in a child with autoimmune thrombotic thrombocytopenic purpura refractory to plasma exchange

A nine-year-old girl presented with headache, purpura and mild left hemiparesis. Laboratory evaluation revealed thrombotic microangiopathy with ADAMTS13 deficiency, with auto-antibodies to ADAMTS13. She was treated with plasma exchange and steroids, following which she improved transiently, relapsing within 2?months. The relapse was refractory to conventional therapy and rituximab was tried. She had good response to rituximab and has been in remission for the past 12?months. Rituximab may be a promising option for children with acquired TTP refractory to plasma exchange and steroids.     

Von Willebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura

A severe deficiency in von Willebrand factor-cleaving protease (ADAMTS13) activity (< 5% that in normal plasma) has been observed in most patients with a diagnosis of thrombotic thrombocytopenic purpura (TTP) but not in those with a diagnosis of hemolytic uremic syndrome. However, ADAMTS13 deficiency has been claimed not to be specific for TTP, since it was observed in various thrombocytopenic and other conditions. We studied 68 patients with thrombocytopenia due to severe sepsis or septic shock (n = 17), heparin-induced thrombocytopenia (n = 16), idiopathic thrombocytopenic purpura (n = 10), or other hematologic (n = 15) or miscellaneous conditions (n = 10). Twelve of the 68 patients had subnormal levels of ADAMTS13 activity (相似文献   

Presence of ADAMTS13 activity in a patient with metastatic cancer and thrombotic microangiopathy

Patients with metastatic cancers occasionally present with microangiopathic hemolysis and thrombocytopenia. A patient with metastatic adenocarcinoma of the colon and microangiopathic hemolysis was treated with plasma exchange for a presumptive diagnosis of thrombotic thrombocytopenic purpura (TTP). However, her condition continued to deteriorate and a determination of ADAMTS13 activity revealed that she did not have TTP. Despite similarity in clinical manifestation, microangiopathic hemolysis in patients with metastatic cancers may not be caused by ADAMTS13 deficiency and the role of plasma exchange in such patients should be reevaluated.     

Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.

OBJECTIVES: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP). BACKGROUND: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA). METHODS: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals. RESULTS: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without. CONCLUSIONS: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.     

Thrombotic microangiopathy in malignant hypertension and hemolytic uremic syndrome (HUS)/ thrombotic thrombocytopenic purpura (TTP): can we differentiate one from the other?

Patients with malignant hypertension sometimes exhibit microangiopathic hemolytic anemia/thrombocytopenia known as thrombotic microangiopathy (TMA). On the other hand, severe hypertension is sometimes associated with hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP). Because the clinical features of the two entities overlap significantly, it is sometimes difficult to distinguish one from the other. However, such differentiation is indispensable, since early performance of plasmapheresis is critical in HUS/TTP. It has been suggested that severe thrombocytopenia is one of the most useful differential points in diagnosing HUS/TTP from malignant hypertension caused by other etiologies. Early performance of plasmapheresis can be justified in the presence of both TMA and thrombocytopenia. However, thrombocytopenia can be seen in the cases with malignant hypertension from etiologies other than HUS/TTP, and in these particular cases, plasmapheresis is useless and can be harmful. Recently, the plasma level of ADAMTS13 (a disintegrin and metalloprotease domain, with thrombospondin type 1 motif 13), which is a von Willebrand Factor cleaving protease, has been shown to be very low in familial or some of the sporadic cases of TTP, and a low level of ADAMTS13 is very specific to TTP. Some reports have shown that patients with a very low plasma level of ADAMTS13 respond very well to plasmapheresis. We recently experienced two cases with TMA. Although both of our patients had severe hypertension with TMA, different therapeutic strategies ameliorated their illness: symptomatic treatment was effective in case 1, which showed normal ADAMTS13 activity, whereas plasma infusion was necessary to save case 2, which showed low ADAMTS13 activity. Thus, patients with a low level of ADAMTS13 activity might respond well to plasmapheresis or plasma infusion. When presented with patients with severe hypertension and thrombotic microangiopathy, ADAMTS13 activity may prove to be a promising adjunctive tool in differentiating TTP from TMA due to other etiologies, but in the meantime, we should make the choice of whether or not to perform plasmapheresis based on the degree of thrombocytopenia.     

Bortezomib in the treatment of refractory thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare, life‐threatening condition caused by autoantibody‐mediated inhibition of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type‐1 motif, 13). Therapeutic plasma exchange (TPE) improves survival, but disease may be refractory despite therapy. Management and treatment response of refractory TTP is variable, with rituximab and other immunosuppression often being used. Case reports have suggested a benefit of the proteasome inhibitor, bortezomib, possibly due to elimination of the autoreactive plasma cells producing anti‐ADAMTS13 antibodies. We evaluated the effect of bortezomib in a series of primary refractory TTP patients unresponsive to intensive therapy. Bortezomib‐treated patients were identified from consecutive cases managed at two UK referral centres. Demographic and clinical data were extracted from hospital records. ADAMTS13 activity was measured using a fluorescence resonance energy transfer VWF73 assay, and anti‐ADAMTS13 IgG using enzyme‐linked immunosorbent asssay. We identified six bortezomib‐treated patients out of 51 consecutive cases of acute, acquired TTP. All patients received TPE, methylprednisolone and rituximab. Five of the six achieved complete remission with bortezomib, and one died of cardiac arrest due to underlying disease. No treatment‐related adverse events were observed. Mean follow‐up time after hospital discharge was 17 months (range: 3–33). Bortezomib appears effective in the treatment of a subgroup of cases with severe, refractory TTP. Prospective trials are required to further investigate this effect.     

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II,multicenter noncomparative study

The standard four‐rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti‐ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange‐based regimen received two infusions of rituximab 375 mg m^?2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell‐driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti‐ADAMTS13 depletion in a similar manner to the standard four‐rituximab infusions schedule. The 1‐year relapse‐free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four‐rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246–1251, 2016. © 2016 Wiley Periodicals, Inc.