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

Abstract

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 (approximately 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.

Persistence of circulating ADAMTS13-specific immune complexes in patients with acquired thrombotic thrombocytopenic purpura

“…Over the last years, rituximab, a humanized antibody that targets CD20 expressed on mature and memory B cells but not on plasma cells, 39 has successfully been administered as an adjuvant therapy for refractory and relapsing acquired TTP, and treated patients seem to benefit through long-lasting remission. [40][41][42][43] In our study, we found that the ten patients treated with rituximab during the acute event still had detectable free and/or complexed anti-ADAMTS13 antibodies in remission; in some of the patients with long-term remission, ADAMTS13-specific immune complexes were detectable even after years. Moreover, there was no significant difference in free and complexed anti-ADAMTS13 antibody titers in these patients compared to those in patients not treated with rituximab.…”

Treatment of thrombotic thrombocytopenic purpura beyond therapeutic plasma exchange

“…Rituximab was first introduced with encouraging results (Table 1) in the acute phase of autoimmune TTP, [6][7][8] typically in patients with a suboptimal response to conventional first-line treatment (ie, disease exacerbation or refractoriness, as defined by no improvement of the clinical features and/or lack of doubling of the platelet count from baseline after 4 full days of standard treatment). In these trials, TPE was usually continued daily and rituximab was administered immediately after a TPE.…”

Thrombotic Thrombocytopenic Purpura: A Hematological Emergency

“…A 2009 meta-analysis found that 95% of patients with autoimmune-mediated TTP who either failed plasma exchange therapy or encountered frequent relapses responded to rituximab within weeks of the first rituximab dose (39). A study done the same year noted that rituximab decreased ADAMTS13 antibody inhibitor activity and elevated ADAMTS13 activity in 5 out of 5 patients with autoimmune TTP (40).…”