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Rituximab in autoimmune thrombotic thrombocytopenic purpura: A success story

  • Antoine Froissart
    Affiliations
    Service de médecine interne, CHI, Créteil, France

    Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, France
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  • Agnès Veyradier
    Affiliations
    Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, France

    Service d’hématologie biologique, Hôpital Lariboisière, Paris, France

    Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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  • Miguel Hié
    Affiliations
    Service de Médecine Interne, Hôpital la Pitié-Salpétrière, Paris, France
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  • Ygal Benhamou
    Affiliations
    Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, France

    Service de médecine interne, CHU Charles Nicolle, Rouen, France
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  • Paul Coppo
    Correspondence
    Corresponding author at: Centre de Référence des Microangiopathies Thrombotiques, Service d’Hématologie, Hôpital Saint Antoine, Université Pierre et Marie Curie, 184 rue du Faubourg Saint Antoine, Assistance Publique – Hôpitaux de Paris, 75012 Paris, France. Tel.: +33 1 49 28 26 21; fax: +33 1 49 28 33 75.
    Affiliations
    Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, France

    Service d’hématologie, Hôpital Saint Antoine, Paris, France

    Inserm U1009, Institut Gustave Roussy, Villejuif, France
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  • French Reference Center for Thrombotic Microangiopathies
Published:August 17, 2015DOI:https://doi.org/10.1016/j.ejim.2015.07.021

      Highlights

      • Rituximab is recommended in acquired TTP with a suboptimal response with standard management.
      • Rituximab should be considered in patients with severe ADAMTS13 deficiency during TTP remission.
      • Rituximab in acquired TTP is associated with acceptable side effects.

      Abstract

      Despite a significant improvement of thrombotic thrombocytopenic purpura (TTP) prognosis since the use of plasma exchange, morbidity and mortality remained significant because of poor response to standard treatment or exacerbations and relapses. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte CD20 antigen, has shown a particular interest in this indication. Recent studies also reported strong evidence for its efficiency in the prevention of relapses. This review addresses these recent progresses and still opened questions in this topic: should rituximab be proposed in all patients at the acute phase? Should all patients benefit from a preemptive treatment? Is the infectious risk acceptable in this context?

      Keywords

      1. Introduction

      Acquired, autoimmune thrombotic thrombocytopenic purpura (TTP) is a severe form of thrombotic microangiopathy (TMA) characterized by the association of a microangiopathic hemolytic anemia with a peripheral thrombocytopenia, organ failure of variable severity due to thrombi in microvasculature, and an antibody-mediated severe deficiency (<10% of normal activity) in the von Willebrand-factor (VWF) cleaving protease ADAMTS13 (A Disintegrin And Metalloproteinase with Thrombospondine type 1 repeats, 13rd member) [
      • Furlan M.
      • Robles R.
      • Galbusera M.
      • Remuzzi G.
      • Kyrle P.A.
      • Brenner B.
      • et al.
      Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
      ,
      • Tsai H.M.
      • Lian E.C.
      Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
      ]. The standard treatment consists mainly in daily therapeutic plasma exchange (TPE), which allows supplying ADAMTS13 deficiency and to a lesser extend removing serum anti-ADAMTS13 antibodies and possibly proaggregant substances. TPE transformed the historically fatal prognosis of TTP, allowing current overall survival rates of 80–85% [
      • Rock G.A.
      • Shumak K.H.
      • Buskard N.A.
      • Blanchette V.S.
      • Kelton J.G.
      • Nair R.C.
      • et al.
      Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group.
      ]. These last years, further significant changes occurred in the management of autoimmune TTP. The identification of a central role for anti-ADAMTS13 antibodies in acquired TTP pathophysiology, which is now considered as an autoimmune disease, led to a wider use of immunosuppressive treatments. In this context, the introduction of rituximab has probably been the second major breakthrough in the management of this disease. However, current knowledge about the use of rituximab in this indication is based on few studies with a limited number of patients and moderate levels of proof. Moreover, these studies raised many questions that remain unsolved so far: should rituximab be introduced frontline in all patients or in patients with a suboptimal response to TPE? Which schedules of rituximab administration can be proposed? Should rituximab be systematically proposed as a preemptive therapy? Which strategy one can propose when rituximab fails to improve ADAMTS13 activity? These topical points are addressed in this review.

      2. Methodology

      We conducted a literature review reporting the use of rituximab in autoimmune TTP. We searched via PubMed articles published until March 2015 using the terms thrombotic thrombocytopenic purpura [MesH] AND rituximab. We selected English-written articles reporting patients who received ≥1 rituximab infusion. We retained case reports and clinical studies, either retrospective or prospective as well as clinical trials. Studies reporting patients with an associated condition (an HIV infection, a neoplastic disease, drug intake, or transplantation) were subsequently excluded. We considered studies that included patients with a severe ADAMTS13 deficiency or at least a decreased enzyme activity. Studies where ADAMTS13 activity was normal or not specified were not included in this review.

      3. Rationale for the use of rituximab in autoimmune TTP

      TTP results from an excessive systemic platelet aggregation caused by the accumulation of ultralarge multimers of VWF in plasma [
      • Moake J.L.
      • Rudy C.K.
      • Troll J.H.
      • Weinstein M.J.
      • Colannino N.M.
      • Azocar J.
      • et al.
      Unusually large plasma factor VIII: von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura.
      ,
      • Asada Y.
      • Sumiyoshi A.
      • Hayashi T.
      • Suzumiya J.
      • Kaketani K.
      Immunohistochemistry of vascular lesion in thrombotic thrombocytopenic purpura, with special reference to factor VIII related antigen.
      ]. A failure to degrade these endothelium-derived hyper-reactive ultralarge multimers of VWF into smaller, less adhesive forms is related to a severe deficiency in ADAMTS13. In the acquired, autoimmune form of the disease, this deficiency is due to the presence of autoantibodies directed against the enzyme [
      • Tsai H.M.
      • Lian E.C.
      Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
      ,
      • Furlan M.
      • Robles R.
      • Solenthaler M.
      • Lammle B.
      Acquired deficiency of von Willebrand factor-cleaving protease in a patient with thrombotic thrombocytopenic purpura.
      ,
      • Sadler J.E.
      Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.
      ,
      • Cataland S.R.
      • Wu H.M.
      Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic microangiopathies.
      ]. In most cases, anti-ADAMTS13 antibodies are of IgG type (rarely, IgM and/or IgA isotypes are associated) [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ,
      • Rieger M.
      • Mannucci P.M.
      • Kremer Hovinga J.A.
      • Herzog A.
      • Gerstenbauer G.
      • Konetschny C.
      • et al.
      ADAMTS13 autoantibodies in patients with thrombotic microangiopathies and other immunomediated diseases.
      ,
      • Scheiflinger F.
      • Knobl P.
      • Trattner B.
      • Plaimauer B.
      • Mohr G.
      • Dockal M.
      • et al.
      Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura.
      ,
      • Ferrari S.
      • Mudde G.C.
      • Rieger M.
      • Veyradier A.
      • Kremer Hovinga J.A.
      • Scheiflinger F.
      IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.
      ]. Several subtypes may be associated in the same patient. IgG4 seems to be the most prevalent IgG subclass of anti-ADAMTS13 antibodies in acquired TTP (90%), followed by IgG1 (52%), IgG2 (50%), and finally, IgG3 (33%) [
      • Ferrari S.
      • Mudde G.C.
      • Rieger M.
      • Veyradier A.
      • Kremer Hovinga J.A.
      • Scheiflinger F.
      IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.
      ]. Anti-ADAMTS13 antibodies decrease ADAMTS13 activity by directly inhibiting the catalytic activity of the enzyme or by decreasing its plasma concentrations through opsonization (i.e., an accelerated clearance of the enzyme by the formation of immune complexes) [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ,
      • Scheiflinger F.
      • Knobl P.
      • Trattner B.
      • Plaimauer B.
      • Mohr G.
      • Dockal M.
      • et al.
      Nonneutralizing IgM and IgG antibodies to von Willebrand factor-cleaving protease (ADAMTS-13) in a patient with thrombotic thrombocytopenic purpura.
      ,
      • Rieger M.
      • Ferrari S.
      • Kremer Hovinga J.A.
      • Konetschny C.
      • Herzog A.
      • Koller L.
      • et al.
      Relation between ADAMTS13 activity and ADAMTS13 antigen levels in healthy donors and patients with thrombotic microangiopathies (TMA).
      ]. The major involvement of ADAMTS13 in the occurrence of autoimmune TTP and the central role of anti-ADAMTS13 antibodies in the pathophysiology of the disease have been well demonstrated in an experimental primate model [
      • Feys H.B.
      • Roodt J.
      • Vandeputte N.
      • Pareyn I.
      • Lamprecht S.
      • van Rensburg W.J.
      • et al.
      Thrombotic thrombocytopenic purpura directly linked with ADAMTS13 inhibition in the baboon (Papio ursinus).
      ], which provides additional insights to consider acquired TTP as an autoimmune disease, and a strong rationale for the use of immunomodulators in this indication.
      Patients with autoimmune TTP can present a single episode; in 40% of cases, however, they experience one or multiple relapses [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ,
      • Kremer Hovinga J.A.
      • Vesely S.K.
      • Terrell D.R.
      • Lammle B.
      • George J.N.
      Survival and relapse in patients with thrombotic thrombocytopenic purpura.
      ,
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ,
      • Willis M.S.
      • Bandarenko N.
      Relapse of thrombotic thrombocytopenic purpura: is it a continuum of disease?.
      ] where episodes of TTP are separated by free intervals of variable duration, ranging from months to years [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ]. Repeated relapses result from the persistence of a severe ADAMTS13 deficiency, due to the persistence or the recurrence of anti-ADAMTS13 antibodies [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ]. It is therefore likely that the typical sequence of a TTP episode is the following: (re)occurrence of anti-ADAMTS13 antibodies in a patient with predisposing genetic factors [
      • Coppo P.
      • Busson M.
      • Veyradier A.
      • Wynckel A.
      • Poullin P.
      • Azoulay E.
      • et al.
      HLA-DRB1*11: a strong risk factor for acquired severe ADAMTS13 deficiency-related idiopathic thrombotic thrombocytopenic purpura in Caucasians.
      ,
      • Scully M.
      • Brown J.
      • Patel R.
      • McDonald V.
      • Brown C.J.
      • Machin S.
      Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link.
      ], a severe ADAMTS13 deficiency, thrombocytopenia and hemolytic anemia, and finally, clinical manifestations with organ(s) failure. These observations provided a rationale to evaluate the efficacy of rituximab in autoimmune TTP at the acute phase of the disease, and as a preemptive therapy in patients in clinical remission but with a persistent severe acquired ADAMTS13 deficiency.

      4. Rituximab: mode of action

      Rituximab is a human/murine chimeric monoclonal IgG1 antibody that specifically targets the transmembrane protein CD20 of B cells. With the exception of plasma cells, the CD20 molecule is present on all B cells after the pro-B cell state (before IgM expression) [
      • Pescovitz M.D.
      Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action.
      ,
      • Uchida J.
      • Lee Y.
      • Hasegawa M.
      • Liang Y.
      • Bradney A.
      • Oliver J.A.
      • et al.
      Mouse CD20 expression and function.
      ]. Rituximab causes a rapid (24–72 hours) and significant depletion of peripheral B cells [
      • Maloney D.G.
      • Liles T.M.
      • Czerwinski D.K.
      • Waldichuk C.
      • Rosenberg J.
      • Grillo-Lopez A.
      • et al.
      Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
      ] which frequently lasts for more than 6 months. The effector mechanisms leading to B cell depletion are multiple, non-exclusive, and include antibody-dependant cellular cytotoxicity (ADCC) [
      • Hamaguchi Y.
      • Uchida J.
      • Cain D.W.
      • Venturi G.M.
      • Poe J.C.
      • Haas K.M.
      • et al.
      The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice.
      ,
      • Cardarelli P.M.
      • Quinn M.
      • Buckman D.
      • Fang Y.
      • Colcher D.
      • King D.J.
      • et al.
      Binding to CD20 by anti-B1 antibody or F(ab')(2) is sufficient for induction of apoptosis in B-cell lines.
      ], phagocytosis by the reticulo-endothelial system of rituximab-coated B cells [
      • Lefebvre M.L.
      • Krause S.W.
      • Salcedo M.
      • Nardin A.
      Ex vivo-activated human macrophages kill chronic lymphocytic leukemia cells in the presence of rituximab: mechanism of antibody-dependent cellular cytotoxicity and impact of human serum.
      ], complement dependent cytotoxicity (CDC) [
      • Cardarelli P.M.
      • Quinn M.
      • Buckman D.
      • Fang Y.
      • Colcher D.
      • King D.J.
      • et al.
      Binding to CD20 by anti-B1 antibody or F(ab')(2) is sufficient for induction of apoptosis in B-cell lines.
      ,
      • Cragg M.S.
      • Glennie M.J.
      Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents.
      ], and B cells direct apoptosis by CD20 crosslinking [
      • Byrd J.C.
      • Kitada S.
      • Flinn I.W.
      • Aron J.L.
      • Pearson M.
      • Lucas D.
      • et al.
      The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction.
      ].
      The precise mechanisms of action of rituximab in autoimmune diseases are multiple [
      • Cooper N.
      • Arnold D.M.
      The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases.
      ] and only partially known to date and probably differ from one autoimmune disease to another. In autoimmune TTP, the striking parallelism between the rapid peripheral B cell depletion, anti-ADAMTS13 antibodies decrease, ADAMTS13 recovery, and disease remission [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ,
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ,
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      ] strongly suggests that the depletion of B cells at the origin of short-lived plasmocytes secreting anti-ADAMTS13 autoantibodies is the main mechanism of action of rituximab. Whether other immunoregulatory mechanisms as those reported in other autoimmune diseases [
      • Cooper N.
      • Arnold D.M.
      The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases.
      ,
      • Yanaba K.
      • Bouaziz J.D.
      • Matsushita T.
      • Magro C.M.
      • St Clair E.W.
      • Tedder T.F.
      B-lymphocyte contributions to human autoimmune disease.
      ,
      • Gurcan H.M.
      • Keskin D.B.
      • Stern J.N.
      • Nitzberg M.A.
      • Shekhani H.
      • Ahmed A.R.
      A review of the current use of rituximab in autoimmune diseases.
      ,
      • Townsend M.J.
      • Monroe J.G.
      • Chan A.C.
      B-cell targeted therapies in human autoimmune diseases: an updated perspective.
      ] also have a role in the control of the disease still remains to be established.
      The pharmacokinetics of rituximab has been studied in patients treated for lymphoid malignancies and in autoimmune diseases, especially rheumatoid arthritis (1000 mg on days 1 and 15) [
      • Berinstein N.L.
      • Grillo-Lopez A.J.
      • White C.A.
      • Bence-Bruckler I.
      • Maloney D.
      • Czuczman M.
      • et al.
      Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.
      ,
      • Breedveld F.
      • Agarwal S.
      • Yin M.
      • Ren S.
      • Li N.F.
      • Shaw T.M.
      • et al.
      Rituximab pharmacokinetics in patients with rheumatoid arthritis: B-cell levels do not correlate with clinical response.
      ]. In this latter case, rituximab had a mean terminal half-life of 19–22 days after the second infusion; systemic clearance of rituximab with monotherapy was slow (242 mL/d), and the volume of distribution at steady state was low (4.28–4.74 L) and similar to normal plasma volume. The half-life of rituximab varies with the dosage, interval between infusions, diffusion velocity, and kinetics of elimination [
      • Renaudineau Y.
      • Devauchelle-Pensec V.
      • Hanrotel C.
      • Pers J.O.
      • Saraux A.
      • Youinou P.
      Monoclonal anti-CD20 antibodies: mechanisms of action and monitoring of biological effects.
      ]. It may be possible to extrapolate data from patients treated for lymphomas or autoimmune diseases to patients receiving preemptive treatment for TTP [
      • McDonald V.
      • Manns K.
      • Mackie I.J.
      • Machin S.J.
      • Scully M.A.
      Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura.
      ]. On the opposite, in TTP at the acute phase, rituximab is performed in association with intensive (i.e., daily) TPE, which leads to the removal of part of the drug (up to 65%), particularly when performed less than 3 days after the infusion [
      • Puisset F.
      • White-Koning M.
      • Kamar N.
      • Huart A.
      • Haberer F.
      • Blasco H.
      • et al.
      Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease.
      ]. However, the remaining circulating rituximab is enough to provide an efficient and rapid peripheral B cell leading to a recovery of ADAMTS13 activity in most cases [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • McDonald V.
      • Manns K.
      • Mackie I.J.
      • Machin S.J.
      • Scully M.A.
      Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura.
      ]. Despite daily TPE, profound peripheral B cell depletion occurs rapidly, within 3–7 days after the first rituximab infusion, and peripheral B cell recovery variably occurs between 6 and 12 months [
      • McDonald V.
      • Manns K.
      • Mackie I.J.
      • Machin S.J.
      • Scully M.A.
      Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura.
      ]. Naive B cells (IgD+/CD27) recovery following treatment with rituximab and TPE predominates, whereas pre-switch (IgD+/CD27+) and post-switch (IgD/CD27+) memory B cells remain low. During follow-up, there is a gradual decrease of naive B cells with a progressive increase of CD27+ memory B cells. Although peripheral B cell depletion with rituximab is very efficient, B cells located in lymphoid organs have different sensitivities to the drug [
      • Gong Q.
      • Ou Q.
      • Ye S.
      • Lee W.P.
      • Cornelius J.
      • Diehl L.
      • et al.
      Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
      ,
      • Kamburova E.G.
      • Koenen H.J.
      • Borgman K.J.
      • ten Berge I.J.
      • Joosten I.
      • Hilbrands L.B.
      A single dose of rituximab does not deplete B cells in secondary lymphoid organs but alters phenotype and function.
      ]. Particularly, B cells in the spleen seem to be less sensitive to the treatment [
      • Ahuja A.
      • Shupe J.
      • Dunn R.
      • Kashgarian M.
      • Kehry M.R.
      • Shlomchik M.J.
      Depletion of B cells in murine lupus: efficacy and resistance.
      ], probably because of a low diffusion of anti-CD20 antibodies in extravascular areas. Moreover, it is likely that tissue microenvironment provides pro-survival signals (including signals from the B cell-activating factor of the TNF family/BAFF-BlyS [B lymphocyte signal] survival factor and integrin-regulated homeostasis) counteracting the proapoptotic signals of rituximab [
      • Gong Q.
      • Ou Q.
      • Ye S.
      • Lee W.P.
      • Cornelius J.
      • Diehl L.
      • et al.
      Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
      ]. In this regard, median BAFF levels at presentation of idiopathic TTP are higher than in normal controls; moreover, these levels increase significantly after rituximab administration perhaps partly due to BAFF receptor loss as B cell numbers fell, whereas they decrease again at B cell recovery [
      • Thomas M.R.
      • Machin S.J.
      • Mackie I.
      • Scully M.A.
      B cell activating factor is elevated in acute idiopathic thrombotic thrombocytopenic purpura.
      ,
      • Becerra E.
      • Scully M.A.
      • Leandro M.J.
      • Heelas E.O.
      • Westwood J.P.
      • De La Torre I.
      • et al.
      Effect of rituximab on B cell phenotype and serum B cell-activating factor levels in patients with thrombotic thrombocytopenic purpura.
      ]. Also, some non-circulating B cells binding rituximab may not be depleted; this may result from microenvironment factors, cellular competition, or differential expression of inhibitory proteins, that could contribute to a decreased sensitivity of B cells to the proapoptotic effect of the drug [
      • Gong Q.
      • Ou Q.
      • Ye S.
      • Lee W.P.
      • Cornelius J.
      • Diehl L.
      • et al.
      Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
      ,
      • Martin F.
      • Chan A.C.
      B cell immunobiology in disease: evolving concepts from the clinic.
      ,
      • Di Gaetano N.
      • Cittera E.
      • Nota R.
      • Vecchi A.
      • Grieco V.
      • Scanziani E.
      • et al.
      Complement activation determines the therapeutic activity of rituximab in vivo.
      ]. The development of human antichimeric antibodies (HACA) could, in addition to being involved in the occurrence of serum sickness, reduce the efficacy of rituximab [
      • Looney R.J.
      • Anolik J.H.
      • Campbell D.
      • Felgar R.E.
      • Young F.
      • Arend L.J.
      • et al.
      B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab.
      ]. To date, however, they have not been reported in patients with TTP.

      5. Rituximab at the acute phase

      In patients with autoimmune TTP, rituximab was first introduced at the acute phase, in the more severe cases [
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ,
      • Chemnitz J.
      • Draube A.
      • Scheid C.
      • Staib P.
      • Schulz A.
      • Diehl V.
      • et al.
      Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab.
      ], and in patients with an insufficient (or suboptimal) response to conventional, TPE-based, treatment. Many single cases [
      • Zheng X.
      • Pallera A.M.
      • Goodnough L.T.
      • Sadler J.E.
      • Blinder M.A.
      Remission of chronic thrombotic thrombocytopenic purpura after treatment with cyclophosphamide and rituximab.
      ,
      • Tsai H.M.
      Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes.
      ,
      • Yomtovian R.
      • Niklinski W.
      • Silver B.
      • Sarode R.
      • Tsai H.M.
      Rituximab for chronic recurring thrombotic thrombocytopenic purpura: a case report and review of the literature.
      ,
      • van der Straaten M.
      • Jamart S.
      • Wens R.
      • Gottignies P.
      • Dratwa M.
      • Devriendt J.
      Treatment of thrombotic thrombocytopenic purpura.
      ,
      • Scott S.M.
      • Szczepiorkowski Z.M.
      Rituximab for TTP.
      ,
      • Kosugi S.
      • Matsumoto M.
      • Ohtani Y.
      • Take H.
      • Ishizashi H.
      • Fujimura Y.
      • et al.
      Rituximab provided long-term remission in a patient with refractory relapsing thrombotic thrombocytopenic purpura.
      ,
      • Hull M.J.
      • Eichbaum Q.G.
      Efficacy of rituximab and concurrent plasma exchange in the treatment of thrombotic thrombocytopenic purpura.
      ,
      • Illoh O.C.
      Infection as a cause of early relapse in patients recovering from thrombotic thrombocytopenic purpura.
      ,
      • Rufer A.
      • Brodmann D.
      • Gregor M.
      • Kremer Hovinga J.A.
      • Lammle B.
      • Wuillemin W.A.
      Rituximab for acute plasma-refractory thrombotic thrombocytopenic purpura. A case report and concise review of the literature.
      ,
      • Basquiera A.L.
      • Damonte J.C.
      • Abichain P.
      • Sturich A.G.
      • Garcia J.J.
      Long-term remission in a patient with refractory thrombotic thrombocytopenic purpura treated with rituximab and plasma exchange.
      ,
      • Hagel S.
      • Jantsch J.
      • Budde U.
      • Kalden J.R.
      • Eckardt K.U.
      • Veelken R.
      Treatment of acquired thrombotic thrombocytopenic purpura (TTP) with plasma infusion plus rituximab.
      ,
      • Limal N.
      • Cacoub P.
      • Sene D.
      • Guichard I.
      • Piette J.C.
      Rituximab for the treatment of thrombotic thrombocytopenic purpura in systemic lupus erythematosus.
      ,
      • Gupta D.
      • Roppelt H.
      • Bowers B.
      • Kunz D.
      • Natarajan M.
      • Gruber B.
      Successful remission of thrombotic thrombocytopenic purpura with rituximab in a patient with undifferentiated connective tissue disorder.
      ,
      • Lalmuanpuii J.
      • Yalamanchili K.
      • Fircanis S.
      • Nelson J.C.
      Hypersensitivity to plasma exchange in a patient with thrombotic thrombocytopenic purpura.
      ,
      • Knobl P.
      • Jilma B.
      • Gilbert J.C.
      • Hutabarat R.M.
      • Wagner P.G.
      • Jilma-Stohlawetz P.
      Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura.
      ,
      • Stein G.Y.
      • Blickstein D.
      • Orlin J.
      • Sarig G.
      • Inbal A.
      Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura.
      ,
      • Bhagirath V.C.
      • Kelton J.G.
      • Moore J.
      • Arnold D.M.
      Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura.
      ,
      • Prasad A.
      • Shah D.
      • Asija A.
      • Nelson J.
      Acquired thrombotic thrombocytopenic purpura associated with reversible severe renal failure requiring hemodialysis.
      ,
      • Magalini F.
      • Stella A.
      • Basaglia M.
      • Vescovini R.
      • Sassi M.
      • Maria Lombardi A.
      • et al.
      Thrombotic thrombocytopenic purpura with severe neurological impairment: remission after Rituximab.
      ] and small series [
      • Chemnitz J.
      • Draube A.
      • Scheid C.
      • Staib P.
      • Schulz A.
      • Diehl V.
      • et al.
      Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab.
      ,
      • Gutterman L.A.
      • Kloster B.
      • Tsai H.M.
      Rituximab therapy for refractory thrombotic thrombocytopenic purpura.
      ,
      • Ahmad A.
      • Aggarwal A.
      • Sharma D.
      • Dave H.P.
      • Kinsella V.
      • Rick M.E.
      • et al.
      Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP).
      ,
      • Sallah S.
      • Husain A.
      • Wan J.Y.
      • Nguyen N.P.
      Rituximab in patients with refractory thrombotic thrombocytopenic purpura.
      ,
      • Fakhouri F.
      • Vernant J.P.
      • Veyradier A.
      • Wolf M.
      • Kaplanski G.
      • Binaut R.
      • et al.
      Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.
      ,
      • Reddy P.S.
      • Deauna-Limayo D.
      • Cook J.D.
      • Ganguly S.S.
      • Blecke C.
      • Bodensteiner D.C.
      • et al.
      Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura.
      ,
      • Darabi K.
      • Berg A.H.
      Rituximab can be combined with daily plasma exchange to achieve effective B-cell depletion and clinical improvement in acute autoimmune TTP.
      ,
      • Niewold T.B.
      • Alpert D.
      • Scanzello C.R.
      • Paget S.A.
      Rituximab treatment of thrombotic thrombocytopenic purpura in the setting of connective tissue disease.
      ,
      • Patino W.
      • Sarode R.
      Successful repeat therapy with rituximab for relapsed thrombotic thrombocytopenic purpura.
      ,
      • Heidel F.
      • Lipka D.B.
      • von Auer C.
      • Huber C.
      • Scharrer I.
      • Hess G.
      Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
      ,
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      ,
      • Jhaveri K.D.
      • Scheuer A.
      • Cohen J.
      • Gordon B.
      Treatment of refractory thrombotic thrombocytopenic purpura using multimodality therapy including splenectomy and cyclosporine.
      ,
      • Scaramucci L.
      • Niscola P.
      • Palumbo R.
      • Giovannini M.
      • Ales M.
      • Tendas A.
      • et al.
      Rapid response and sustained remission by rituximab in four cases of plasma-exchange-failed acute thrombotic thrombocytopenic purpura.
      ,
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      ,
      • Caramazza D.
      • Quintini G.
      • Abbene I.
      • Coco L.L.
      • Malato A.
      • Di Trapani R.
      • et al.
      Rituximab for managing relapsing or refractory patients with idiopathic thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome.
      ,
      • Thomas M.R.
      • McDonald V.
      • Machin S.J.
      • Scully M.A.
      Thrombotic thrombocytopenic purpura associated with statin therapy.
      ,
      • Imanirad I.
      • Rajasekhar A.
      • Zumberg M.
      A case series of atypical presentations of thrombotic thrombocytopenic purpura.
      ,
      • Elliott M.A.
      • Heit J.A.
      • Pruthi R.K.
      • Gastineau D.A.
      • Winters J.L.
      • Hook C.C.
      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.
      ], most often from patients with a refractory disease or experiencing multiple relapses, reported encouraging results (Table 1). TPE were continued daily and rituximab was administered immediately after a TPE (except in one study [
      • Fakhouri F.
      • Vernant J.P.
      • Veyradier A.
      • Wolf M.
      • Kaplanski G.
      • Binaut R.
      • et al.
      Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.
      ], in which TPE were suspended). These studies were not randomized, non-controlled, usually retrospective, and displayed many confounding factors. Moreover, an accurate evaluation of the therapeutical response to rituximab was initially rendered challenging given the variability in the indications and in the schedules of drug administration, and the lack of consensual definitions in treatment responses. Moreover, rituximab was usually associated with other salvage therapies, making accountability uncertain. However, they provided the first line of evidence that rituximab allowed obtaining remission in most cases, and deserved further evaluation.
      Table 1Series of patients treated with rituximab at the acute phase of autoimmune TTP.
      Series (year)NAge (year) median (range)% F% RNumber of rituximab infusions, median (range)CR (%)Days to CR median (range)
      Gutterman et al. (2002)
      • Gutterman L.A.
      • Kloster B.
      • Tsai H.M.
      Rituximab therapy for refractory thrombotic thrombocytopenic purpura.
      354 (40–62)1001008 (4–8)33NA
      Ahmad et al. (2004)
      • Ahmad A.
      • Aggarwal A.
      • Sharma D.
      • Dave H.P.
      • Kinsella V.
      • Rick M.E.
      • et al.
      Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP).
      456.5 (53–61)501004 (2–8)759 (7–14)
      Sallah et al. (2004)
      • Sallah S.
      • Husain A.
      • Wan J.Y.
      • Nguyen N.P.
      Rituximab in patients with refractory thrombotic thrombocytopenic purpura.
      532 (31–52)NA10048031 (range NA)
      Fakhouri et al. (2005)
      • Fakhouri F.
      • Vernant J.P.
      • Veyradier A.
      • Wolf M.
      • Kaplanski G.
      • Binaut R.
      • et al.
      Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.
      638 (21–58)6767410026–35
      Reddy et al. (2005)
      • Reddy P.S.
      • Deauna-Limayo D.
      • Cook J.D.
      • Ganguly S.S.
      • Blecke C.
      • Bodensteiner D.C.
      • et al.
      Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura.
      537 (27–70)60NA410035 (21–63)
      Scully et al. (2007)
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      2543 (17–67)76444 (2–8)10011
      Heidel et al. (2007)
      • Heidel F.
      • Lipka D.B.
      • von Auer C.
      • Huber C.
      • Scharrer I.
      • Hess G.
      Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
      846 (21–77)88NA4 (1–8)10022 (3–82)
      Jasti et al. (2008)
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      1243 (19–59)838(1–13)8318 (14–41)
      Elliott et al. (2009)
      • Elliott M.A.
      • Heit J.A.
      • Pruthi R.K.
      • Gastineau D.A.
      • Winters J.L.
      • Hook C.C.
      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.
      431.5 (24–44)7525NA10017.5 (5–74)
      Scaramucci et al. (2009)
      • Scaramucci L.
      • Niscola P.
      • Palumbo R.
      • Giovannini M.
      • Ales M.
      • Tendas A.
      • et al.
      Rapid response and sustained remission by rituximab in four cases of plasma-exchange-failed acute thrombotic thrombocytopenic purpura.
      432 (26–50)100NA410010 (5–24)
      Ling et al. (2009)
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      1342 (23–71)6954NA92NA
      Caramazza et al. (2010)
      • Caramazza D.
      • Quintini G.
      • Abbene I.
      • Coco L.L.
      • Malato A.
      • Di Trapani R.
      • et al.
      Rituximab for managing relapsing or refractory patients with idiopathic thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome.
      440 (16–53)2525410014 (7–30)
      de la Rubia et al. (2010)
      • de la Rubia J.
      • Moscardo F.
      • Gomez M.J.
      • Guardia R.
      • Rodriguez P.
      • Sebrango A.
      • et al.
      Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
      24(24–72)71424 (1–8)87.514 (7–35)
      Scully et al. (2011)
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      4042 (21–76)65154 (2–8)82.512
      Imanirad et al. (2012)
      • Imanirad I.
      • Rajasekhar A.
      • Zumberg M.
      A case series of atypical presentations of thrombotic thrombocytopenic purpura.
      449 (25–68)10075450NA
      Froissart et al. (2012)
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      2236.8 ± 11671448212 ± 6.7
      N: number of patients; F: female; R: relapsing patients; CR: complete remission; NA: data not available
      Series (year)Clinical relapse (%)Months to relapse median (range)Clinical RFS (months) median (range)Serious adverse events
      Gutterman et al. (2002)
      • Gutterman L.A.
      • Kloster B.
      • Tsai H.M.
      Rituximab therapy for refractory thrombotic thrombocytopenic purpura.
      6612.5 (2–17)20 (17–23)0
      Ahmad et al. (2004)
      • Ahmad A.
      • Aggarwal A.
      • Sharma D.
      • Dave H.P.
      • Kinsella V.
      • Rick M.E.
      • et al.
      Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP).
      0/13 (6–14)0
      Sallah et al. (2004)
      • Sallah S.
      • Husain A.
      • Wan J.Y.
      • Nguyen N.P.
      Rituximab in patients with refractory thrombotic thrombocytopenic purpura.
      0/11 (range NA)0
      Fakhouri et al. (2005)
      • Fakhouri F.
      • Vernant J.P.
      • Veyradier A.
      • Wolf M.
      • Kaplanski G.
      • Binaut R.
      • et al.
      Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.
      0/9 (6–11)0
      Reddy et al. (2005)
      • Reddy P.S.
      • Deauna-Limayo D.
      • Cook J.D.
      • Ganguly S.S.
      • Blecke C.
      • Bodensteiner D.C.
      • et al.
      Rituximab in the treatment of relapsed thrombotic thrombocytopenic purpura.
      0/15 (range NA)0
      Scully et al. (2007)
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      0/10 (1–33)1 fatal pneumonia, 1 morbiliform rash
      Heidel et al. (2007)
      • Heidel F.
      • Lipka D.B.
      • von Auer C.
      • Huber C.
      • Scharrer I.
      • Hess G.
      Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
      37.523.5 (13.3–48.5)45.8 (2.4–51)Cytomegalovirus reactivation
      Jasti et al. (2008)
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      82348.5 (1–79)1 VZV transverse myelitis and encephalitis
      Elliott et al. (2009)
      • Elliott M.A.
      • Heit J.A.
      • Pruthi R.K.
      • Gastineau D.A.
      • Winters J.L.
      • Hook C.C.
      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.
      0/12.5 (4–41)0
      Scaramucci et al. (2009)
      • Scaramucci L.
      • Niscola P.
      • Palumbo R.
      • Giovannini M.
      • Ales M.
      • Tendas A.
      • et al.
      Rapid response and sustained remission by rituximab in four cases of plasma-exchange-failed acute thrombotic thrombocytopenic purpura.
      0/10 (4–12)0
      Ling et al. (2009)
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      0/24 (13–84)0
      Caramazza et al. (2010)
      • Caramazza D.
      • Quintini G.
      • Abbene I.
      • Coco L.L.
      • Malato A.
      • Di Trapani R.
      • et al.
      Rituximab for managing relapsing or refractory patients with idiopathic thrombotic thrombocytopenic purpura--haemolytic uraemic syndrome.
      0/7 (3–11)0
      de la Rubia et al. (2010)
      • de la Rubia J.
      • Moscardo F.
      • Gomez M.J.
      • Guardia R.
      • Rodriguez P.
      • Sebrango A.
      • et al.
      Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
      12.529 (7–29)30 (7.5–64)0
      Scully et al. (2011)
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      1027 (17–31)120
      Imanirad et al. (2012)
      • Imanirad I.
      • Rajasekhar A.
      • Zumberg M.
      A case series of atypical presentations of thrombotic thrombocytopenic purpura.
      5028 (22–34)10.5 (9–12)1 patient presented multiple infections
      Froissart et al. (2012)
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      1424 (20–36)33 ± 17.40
      RFS: relapse free survival; VZV; varicella zoster virus.
      To date, six studies (3 retrospective [
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      ,
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      ,
      • de la Rubia J.
      • Moscardo F.
      • Gomez M.J.
      • Guardia R.
      • Rodriguez P.
      • Sebrango A.
      • et al.
      Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
      ] and 3 prospective [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ,
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      ]) reported each more than 10 adult patients with an autoimmune TTP and treated with rituximab for a suboptimal response to standard treatment [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ,
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      ,
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      ,
      • de la Rubia J.
      • Moscardo F.
      • Gomez M.J.
      • Guardia R.
      • Rodriguez P.
      • Sebrango A.
      • et al.
      Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
      ] or frontline [
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      ] (Table 1).
      In the three retrospective studies, 39 TTP patients with poor response to standard treatment were treated with rituximab [
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      ,
      • Ling H.T.
      • Field J.J.
      • Blinder M.A.
      Sustained response with rituximab in patients with thrombotic thrombocytopenic purpura: a report of 13 cases and review of the literature.
      ,
      • de la Rubia J.
      • Moscardo F.
      • Gomez M.J.
      • Guardia R.
      • Rodriguez P.
      • Sebrango A.
      • et al.
      Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
      ]. The schedule of administration was variable (most frequently 375 mg/m2 weekly, with a variable number of doses). Remission was obtained in 35/39 cases within 7–41 days. Four patients did not respond to treatment; one of these experienced a fatal outcome. Two patients relapsed and responded again to retreatment. In all but two explored cases, ADAMTS13 activity recovered.
      In 2007, Scully et al. [
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ] reported a study involving 25 patients treated with rituximab for a refractory or a recurrent disease (14 and 11 cases, respectively). Rituximab was given 375 mg/m2/week for 4 weeks. Remission was achieved in all patients within a median of 11 days (between 7 and 21 days). No relapse was observed after a median follow-up of 10 months (1–33 months). At 3 months post-rituximab, 21 patients achieved a normal ADAMTS13 activity and 23 patients had no detectable inhibitor. In 2012, our group reported a prospective study to evaluate the efficacy of rituximab in patients with autoimmune TTP experiencing a suboptimal response to TPE [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ]. A suboptimal response was defined as an exacerbation of the disease, or a refractory disease, as defined by no improvement of clinical features and/or a lack of doubling of platelet count from baseline following four full days of standard treatment to conventional first-line treatment. Patients received empirically 4 infusions of rituximab 375 mg/m2 on a tight schedule, i.e., within 15 days (day 1, 4, 8, and 15) (Fig. 1) given the large amounts of rituximab that are removed with TPE [
      • McDonald V.
      • Manns K.
      • Mackie I.J.
      • Machin S.J.
      • Scully M.A.
      Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura.
      ]. Rituximab was started on the day a suboptimal response was diagnosed (day 1), immediately after the TPE session. In the rituximab-treated patients, time to durable remission was significantly shorter, and platelet count normalized within 35 days in all 21 survivors, as compared to only 78% in a historical group. One additional patient died despite 2 rituximab infusions. No relapse occurred during the first year; however, relapses occurred beyond 1 year. Rituximab was associated with a rapid and profound peripheral B cell depletion, a higher increase in ADAMTS13 activity, a more frequent ADAMTS13 recovery, and a more profound depletion in anti-ADAMTS13 antibodies. This study emphasized the striking correlation between peripheral B cell count, ADAMTS13 activity, and response to treatment. In both studies, rituximab was associated with no significant side effect. From these results, we recently conducted a phase 2 trial in which we performed 2–3 rituximab infusions according to residual B cell count, in order to define the minimal number of rituximab infusions required to obtain an undetectable peripheral B cell count (www.clinicaltrials.gov no. NCT00907751) (Benhamou et al., in preparation).
      Figure thumbnail gr1
      Fig. 1Schedule of rituximab administration for patients with autoimmune TTP experiencing a suboptimal response to TPE, according to the French study
      [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ]
      . TPE: therapeutic plasma exchange; RTX: rituximab administration. Follow-up included the assessment of clinical features, peripheral B cell count, ADAMTS13 activity, and anti-ADAMTS13 antibodies
      [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ]
      .
      Whether rituximab should be introduced in patients who experience a suboptimal response to standard treatment, or frontline in all patients with a diagnosis of acquired TTP still remains an opened question. In 2011, the UK group [
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      ] reported a phase 2 study evaluating rituximab frontline in association with daily TPE in acute acquired TTP. Forty patients received rituximab 375 mg/m2/week for 4 weeks in the first 3 days following the diagnosis of TTP. The median time to sustained platelet count recovery was 12 days. The duration of hospitalization for the less severe patients was lower when compared to a historical group. A relapse occurred in only 10% of patients after a median time of 27 months, whereas in the historical control group, 57% of patients relapsed after a median time of 18 months. Rituximab was associated with a more sustained increase in ADAMTS13 activity and a decrease in anti-ADAMTS13 antibodies. Rituximab was well tolerated. These results could therefore encourage the use of rituximab frontline in acquired TTP; on the other hand, it is important to consider that ~50% of patients may recover from their TTP episode with standard TPE/steroids-based treatment without the need of rituximab; consequently, the systematic addition of rituximab frontline may lead to over-treat a large number of patients. Moreover, it is unclear as to whether rituximab performed at the acute phase decreases the incidence of long-term relapses [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • Scully M.
      • McDonald V.
      • Cavenagh J.
      • Hunt B.J.
      • Longair I.
      • Cohen H.
      • et al.
      A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura.
      ]. The rapid identification of a severe acquired ADAMTS13 deficiency in a patient with features of TMA represents the main limitation for the systematic use of rituximab frontline in these patients, since not all centers are able to assess ADAMTS13 activity in emergency. Moreover, it is also important in these patients to rule out other associated conditions that may impact the decision to treat or not with rituximab, such as an HIV infection or a history of infection with the hepatitis B virus [
      • Hanbali A.
      • Khaled Y.
      Incidence of hepatitis B reactivation following Rituximab therapy.
      ]. An additional study from the UK group in 2013 reported that apparently patients treated with rituximab frontline within the first 3 days following diagnosis achieved remission faster than those who received rituximab for a suboptimal response [
      • Westwood J.P.
      • Webster H.
      • McGuckin S.
      • McDonald V.
      • Machin S.J.
      • Scully M.
      Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse.
      ]. However, the study was not randomized, and the decision to treat patients with rituximab frontline or only if the response was suboptimal was not clearly specified. Therefore, one cannot totally exclude that patients with a suboptimal response represented a group of worse prognosis than those treated frontline, which included in part patients who may have recovered without rituximab [
      • Westwood J.P.
      • Webster H.
      • McGuckin S.
      • McDonald V.
      • Machin S.J.
      • Scully M.
      Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse.
      ].
      No randomized studies evaluated rituximab in autoimmune TTP. The main reason is the rarity of TTP, which precludes the inclusion of a sufficient number of patients in a trial within a reasonable period of time. The other reason is that the studies detailed above rapidly provided strong evidence that rituximab improves TTP patients who experience a suboptimal response to standard treatment, with a sufficient level of proof to propose this treatment in an increasing number of cases in this life-threatening disease [
      • Froissart A.
      • Buffet M.
      • Veyradier A.
      • Poullin P.
      • Provot F.
      • Malot S.
      • et al.
      Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.
      ,
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ]. In line with this statement, a randomized study aimed at evaluating rituximab in this indication (STAR: Study of TTP and Rituximab) was prematurely interrupted given the slow enrollment rhythm.

      6. Preemptive therapy with rituximab: how far to prevent relapses?

      At least 40% of patients experience a recurrence of TTP [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ,
      • Kremer Hovinga J.A.
      • Vesely S.K.
      • Terrell D.R.
      • Lammle B.
      • George J.N.
      Survival and relapse in patients with thrombotic thrombocytopenic purpura.
      ,
      • Willis M.S.
      • Bandarenko N.
      Relapse of thrombotic thrombocytopenic purpura: is it a continuum of disease?.
      ]. Each relapse exposes the patient to a risk of death and to complications related to TPE procedure or to intensive care unit hospitalization [
      • Howard M.A.
      • Williams L.A.
      • Terrell D.R.
      • Duvall D.
      • Vesely S.K.
      • George J.N.
      Complications of plasma exchange in patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.
      ,
      • Nguyen L.
      • Terrell D.R.
      • Duvall D.
      • Vesely S.K.
      • George J.N.
      Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to 2008.
      ]. Moreover, relapses also raise cost concerns [
      • Sadler J.E.
      Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.
      ]. Therefore, the prevention of relapses in autoimmune TTP represents a major goal that needs to be addressed. In autoimmune TTP, ADAMTS13 activity represents a reliable marker of disease activity, since patients who remain with a severe enzyme deficiency are at high risk of relapse [
      • Ferrari S.
      • Scheiflinger F.
      • Rieger M.
      • Mudde G.
      • Wolf M.
      • Coppo P.
      • et al.
      Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.
      ]. Preliminary reports suggested that infusions of rituximab in patients with a severe persistent ADAMTS13 deficiency and otherwise in clinical and hematological remission (i.e., preemptive infusions of rituximab) could efficiently prevent TTP relapses [
      • Stein G.Y.
      • Blickstein D.
      • Orlin J.
      • Sarig G.
      • Inbal A.
      Long-term response to rituximab in patients with relapsing thrombotic thrombocytopenic purpura.
      ,
      • Fakhouri F.
      • Vernant J.P.
      • Veyradier A.
      • Wolf M.
      • Kaplanski G.
      • Binaut R.
      • et al.
      Efficiency of curative and prophylactic treatment with rituximab in ADAMTS13-deficient thrombotic thrombocytopenic purpura: a study of 11 cases.
      ,
      • Imanirad I.
      • Rajasekhar A.
      • Zumberg M.
      A case series of atypical presentations of thrombotic thrombocytopenic purpura.
      ,
      • Galbusera M.
      • Bresin E.
      • Noris M.
      • Gastoldi S.
      • Belotti D.
      • Capoferri C.
      • et al.
      Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report.
      ,
      • Benetatos L.
      • Vassou A.
      • Bourantas K.L.
      Effectiveness of rituximab as prophylaxis in thrombotic thrombocytopenic purpura.
      ,
      • Schleinitz N.
      • Ebbo M.
      • Mazodier K.
      • Poullin P.
      • Bernit E.
      • Veit V.
      • et al.
      Rituximab as preventive therapy of a clinical relapse in TTP with ADAMTS13 inhibitor.
      ,
      • Bresin E.
      • Gastoldi S.
      • Daina E.
      • Belotti D.
      • Pogliani E.
      • Perseghin P.
      • et al.
      Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies.
      ,
      • Montoya R.C.
      • Poiesz B.J.
      Rituximab as prophylaxis in chronic relapsing thrombotic thrombocytopenic purpura: a case report and review of the literature.
      ]. Recently, a study reported thirty patients who received preemptive infusions of rituximab [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ]. Rituximab remarkably reduced the incidence of TTP relapse by diminishing the production of anti-ADAMTS13 antibodies and restoring ADAMTS13 activity, which paralleled B cell depletion. Of note, in 30% of patients, ADAMTS13 recovery was not sustained and further cycles of rituximab were required to maintain a detectable enzyme activity. Moreover, 16% of patients failed to improve ADAMTS13 activity and required other immunomodulatory drugs and/or a splenectomy [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ]. So far, manageable side effects were observed during follow-up, even in patients who required multiple cycles of rituximab.
      These findings argue for regular systematic assessments of ADAMTS13 activity during follow-up, in order to identify at an early step patients at risk of relapse. Preemptive rituximab represents a promising strategy that could significantly modify the epidemiology of autoimmune TTP by dramatically reducing relapses and the associated complications. However, this strategy may lead in the administration of multiple infusions of rituximab to maintain a detectable ADAMTS13 activity, exposing patients to infections or other long-term complications. On the other hand, to leave a patient for an undetermined period with a severe ADAMTS13 deficiency may expose him to a potentially sudden and fatal, unanticipated relapse. In line with this statement, an update of our data provided evidence that when we consider our 18 patients with a persistent chronic severe acquired ADAMTS13 deficiency from 2000 (the year our National Registry was set-up) to 2013 (the year we started to perform rituximab preemptively in most patients) the relapse rate is dramatically elevated, reaching 70% (unpublished data). Therefore, it is likely that most patients with a persistently severe ADAMTS13 deficiency are at risk of relapse.

      7. Side effects

      Although rituximab induces a profound and prolonged peripheral B cell depletion, immunoglobulins level usually remains normal (possibly because of the persistence of long-lived plasma cells, that do not express CD20). However, cases of hypogammaglobulinemia were reported in patients treated with repeated infusions or in patients receiving an associated chemotherapy or immunosuppressive therapies [
      • Casulo C.
      • Maragulia J.
      • Zelenetz A.D.
      Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections.
      ,
      • Cooper N.
      • Davies E.G.
      • Thrasher A.J.
      Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin.
      ,
      • Isvy A.
      • Meunier M.
      • Gobeaux-Chenevier C.
      • Maury E.
      • Wipff J.
      • Job-Deslandre C.
      • et al.
      Safety of rituximab in rheumatoid arthritis: a long-term prospective single-center study of gammaglobulin concentrations and infections.
      ,
      • Keystone E.
      • Fleischmann R.
      • Emery P.
      • Furst D.E.
      • van Vollenhoven R.
      • Bathon J.
      • et al.
      Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis.
      ]. It is uncertain, however, as to whether hypogammaglobulinemia is directly related to rituximab treatment [
      • Marco H.
      • Smith R.M.
      • Jones R.B.
      • Guerry M.J.
      • Catapano F.
      • Burns S.
      • et al.
      The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease.
      ,
      • Roberts D.M.
      • Jones R.B.
      • Smith R.M.
      • Alberici F.
      • Kumaratne D.S.
      • Burns S.
      • et al.
      Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease.
      ]. Moreover, hypogammaglobulinemia may not lead to an excess of infections [
      • Keystone E.
      • Fleischmann R.
      • Emery P.
      • Furst D.E.
      • van Vollenhoven R.
      • Bathon J.
      • et al.
      Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis.
      ]. A recent review of the literature [
      • Levy R.
      • Mahevas M.
      • Galicier L.
      • Boutboul D.
      • Moroch J.
      • Loustau V.
      • et al.
      Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.
      ] dealing with the occurrence of hypogammaglobulinemia for patients treated with rituximab (and steroids) for an immune thrombocytopenic purpura (ITP) concluded that this side effect is rare, usually transient and does not require immunoglobulin substitution. However, the follow-up of these patients is usually still limited, so definitive conclusions cannot be drawn at this time. It is therefore recommended to monitor serum immunoglobulin level before and repeatedly after rituximab initiation during long-term follow-up.
      The most important risk to consider in clinical practice is the reactivation of hepatitis B virus (HBV) [
      • Hanbali A.
      • Khaled Y.
      Incidence of hepatitis B reactivation following Rituximab therapy.
      ]. HBV reactivation may be delayed and can lead to fulminant liver failure. Although this complication has been reported primarily in patients treated for hematological malignancies, the potentially serious evolution is a reason to recommend routine serologic screening of patients before initiation of rituximab (and/or other immunosuppressive therapy) and to start a preventive antiviral therapy if required [
      • Lalazar G.
      • Rund D.
      • Shouval D.
      Screening, prevention and treatment of viral hepatitis B reactivation in patients with haematological malignancies.
      ]. There are also increasing evidences of a possible association between rituximab use and the occurrence of progressive multifocal leucoencephalopathy (PML), an almost systematically fatal viral encephalitis caused by JC polyomavirus [
      • Carson K.R.
      • Evens A.M.
      • Richey E.A.
      • Habermann T.M.
      • Focosi D.
      • Seymour J.F.
      • et al.
      Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.
      ,
      • Ram R.
      • Ben-Bassat I.
      • Shpilberg O.
      • Polliack A.
      • Raanani P.
      The late adverse events of rituximab therapy--rare but there!.
      ,
      • Keene D.L.
      • Legare C.
      • Taylor E.
      • Gallivan J.
      • Cawthorn G.M.
      • Vu D.
      Monoclonal antibodies and progressive multifocal leukoencephalopathy.
      ,
      • Morrison V.A.
      Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies.
      ]. Here again, most of the reported cases involved patients receiving rituximab in association with chemotherapy [
      • Carson K.R.
      • Evens A.M.
      • Richey E.A.
      • Habermann T.M.
      • Focosi D.
      • Seymour J.F.
      • et al.
      Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.
      ,
      • Bennett C.L.
      Pharmacovigilance and PML in the oncology setting.
      ,
      • Felli V.
      • Di Sibio A.
      • Anselmi M.
      • Gennarelli A.
      • Sucapane P.
      • Splendiani A.
      • et al.
      Progressive multifocal leukoencephalopathy following treatment with rituximab in an HIV-negative patient with non-Hodgkin lymphoma. A case report and literature review.
      ,
      • Al-Tawfiq J.A.
      • Banda R.W.
      • Daabil R.A.
      • Dawamneh M.F.
      Progressive multifocal leukoencephalopathy (PML) in a patient with lymphoma treated with rituximab: a case report and literature review.
      ]; however, cases have been described in the treatment of autoimmune diseases [
      • Carson K.R.
      • Evens A.M.
      • Richey E.A.
      • Habermann T.M.
      • Focosi D.
      • Seymour J.F.
      • et al.
      Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.
      ,
      • Tavazzi E.
      • Ferrante P.
      • Khalili K.
      Progressive multifocal leukoencephalopathy: an unexpected complication of modern therapeutic monoclonal antibody therapies.
      ,
      • Palazzo E.
      • Yahia S.A.
      Progressive multifocal leukoencephalopathy in autoimmune diseases.
      ,
      • Toussirot E.
      • Bereau M.
      The risk of progressive multifocal leukoencephalopathy under biological agents used in the treatment of chronic inflammatory diseases.
      ].
      Concise reviews reported exhaustive side effects observed in patients treated with rituximab for various indications, including more specifically autoimmune diseases [
      • Gea-Banacloche J.C.
      Rituximab-associated infections.
      ]. In the specific context of TTP treated with rituximab, only few side effects were reported so far. Usual infusion reactions (fever, chills, skin rash, pruritus, mild joint pain, tachycardia, hypotension) are generally mild and occur mainly during the first infusion. Four cases of severe infections were reported: a CMV reactivation (in a patient who received long-term steroid treatment) [
      • Heidel F.
      • Lipka D.B.
      • von Auer C.
      • Huber C.
      • Scharrer I.
      • Hess G.
      Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
      ], a fatal pneumonia [
      • Scully M.
      • Cohen H.
      • Cavenagh J.
      • Benjamin S.
      • Starke R.
      • Killick S.
      • et al.
      Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
      ], a herpes zoster transverse myelitis, and encephalitis (after a second course of treatment with rituximab and prednisone) [
      • Jasti S.
      • Coyle T.
      • Gentile T.
      • Rosales L.
      • Poiesz B.
      Rituximab as an adjunct to plasma exchange in TTP: a report of 12 cases and review of literature.
      ] and one erysipelas [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ] (in a context of preemptive rituximab treatment). One patient who received multiple preemptive infusions of rituximab developed an asymptomatic hypogammaglobulinemia [
      • Hie M.
      • Gay J.
      • Galicier L.
      • Provot F.
      • Presne C.
      • Poullin P.
      • et al.
      Preemptive rituximab infusions after remission efficiently prevent relapses in acquired thrombotic thrombocytopenic purpura.
      ]. Since an increasing number of patients may be treated with rituximab at the acute phase as well as preemptively, it is now crucial to plan a long-term follow-up for these patients to better specify the spectrum of side effects associated with this strategy.

      8. Learning points

      • Rituximab is recommended in patients with acquired TTP who experience a suboptimal response (refractoriness or an exacerbation of the disease) with standard management.
      • Rituximab may be considered frontline with therapeutic plasma exchange and steroids in patients with acquired TTP.
      • A persistent severe acquired ADAMTS13 deficiency during TTP remission should prompt consideration of preemptive rituximab to prevent relapses.
      • Rituximab in acquired TTP is associated with acceptable side effects.

      9. Conclusion

      Rituximab allowed a significant improvement in the management of autoimmune TTP by limiting the duration of treatment with TPE in slow responders and by preventing relapses in patients with a persistent severe ADAMTS13 deficiency during clinical remission. So far, studies converge to state that rituximab is generally well tolerated, even in patients who receive multiple infusions. Rituximab is now routinely recommended at the acute phase of the disease in patients with a suboptimal response to treatment, with typically remarkably high response rates. In contrast, the value of routine use of rituximab frontline in association with TPE/steroids remains uncertain [
      • Lim W.
      • Vesely S.K.
      • George J.N.
      The role of rituximab in the management of patients with acquired thrombotic thrombocytopenic purpura.
      ]. A persistently severe ADAMTS13 deficiency during remission exposes patients to a significant risk of relapse and clearly, a preemptive treatment with rituximab may be considered in this indication. Therefore, preemptive rituximab represents a promising strategy that could significantly modify the epidemiology of autoimmune TTP by dramatically reducing relapses and the associated complications. New anti-CD20 monoclonal antibodies (obinutuzumab, ofatumumab) may have a potential interest in this indication and also deserve evaluation. Intensification regimens in the more severe patients for whom rituximab was started remain to be defined. These may include twice daily TPE ([
      • Nguyen L.
      • Li X.
      • Duvall D.
      • Terrell D.R.
      • Vesely S.K.
      • George J.N.
      Twice-daily plasma exchange for patients with refractory thrombotic thrombocytopenic purpura: the experience of the Oklahoma Registry, 1989 through 2006.
      ] and CNR-MAT, manuscript in preparation), as well as pulses of cyclophosphamide and splenectomy [
      • Beloncle F.
      • Buffet M.
      • Coindre J.P.
      • Munoz-Bongrand N.
      • Malot S.
      • Pene F.
      • et al.
      Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.
      ].

      Conflict of interest

      Rituximab in thrombotic thrombocytopenic purpura (TTP) is discussed as an off-label drug.

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