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Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, FranceService d’hématologie biologique, Hôpital Lariboisière, Paris, FranceUniversité Paris Diderot, Sorbonne Paris Cité, Paris, France
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.
Centre de Référence des Microangiopathies Thrombotiques, AP-HP, Paris, FranceService d’hématologie, Hôpital Saint Antoine, Paris, FranceInserm U1009, Institut Gustave Roussy, Villejuif, France
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?
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) [
]. 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% [
]. 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 [
]. 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 [
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.
]. 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%) [
]. 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) [
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.
]. 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 [
], 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 [
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.
]. Repeated relapses result from the persistence of a severe ADAMTS13 deficiency, due to the persistence or the recurrence of anti-ADAMTS13 antibodies [
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 [
], 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) [
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) [
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.
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.
] 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 [
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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
] 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 [
] 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) [
Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.
]. 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 [
]. It may be possible to extrapolate data from patients treated for lymphomas or autoimmune diseases to patients receiving preemptive treatment for TTP [
]. 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 [
]. 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 [
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.
]. 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 [
]. 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 [
], 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 [
]. 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 [
]. 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 [
]. The development of human antichimeric antibodies (HACA) could, in addition to being involved in the occurrence of serum sickness, reduce the efficacy of rituximab [
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
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 [
], 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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
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.
Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
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.
Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
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.
Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
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.
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 [
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 [
]. 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).
Fig. 1Schedule of rituximab administration for patients with autoimmune TTP experiencing a suboptimal response to TPE, according to the French study
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
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 [
] 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 [
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.
]. 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 [
]. 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 [
]. 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 [
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 [
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.
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 [
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.
Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to 2008.
]. 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 [
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 [
]. 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 [
]. 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 [
Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin.
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) [
]. 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 [
]. 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 [
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.
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.
Progressive multifocal leukoencephalopathy following treatment with rituximab in an HIV-negative patient with non-Hodgkin lymphoma. A case report and literature review.
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.
Concise reviews reported exhaustive side effects observed in patients treated with rituximab for various indications, including more specifically autoimmune diseases [
]. 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) [
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
] (in a context of preemptive rituximab treatment). One patient who received multiple preemptive infusions of rituximab developed an asymptomatic hypogammaglobulinemia [
]. 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 [
]. 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 ([
Twice-daily plasma exchange for patients with refractory thrombotic thrombocytopenic purpura: the experience of the Oklahoma Registry, 1989 through 2006.
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.
Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma.
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.
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.
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.
Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13.
Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.
Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia.
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.
Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: results of a Spanish multicenter study.
Complications of plasma exchange in patients treated for thrombotic thrombocytopenic purpura. IV. An additional study of 43 consecutive patients, 2005 to 2008.
Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin.
Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.
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.
Progressive multifocal leukoencephalopathy following treatment with rituximab in an HIV-negative patient with non-Hodgkin lymphoma. A case report and literature review.
Twice-daily plasma exchange for patients with refractory thrombotic thrombocytopenic purpura: the experience of the Oklahoma Registry, 1989 through 2006.
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