review
Inhibitor eradication with rituximab in haemophilia: where do we stand? Massimo Franchini1 and Pier Mannuccio Mannucci2 1
Department of Transfusion Medicine and Haematology, Carlo Poma Hospital, Mantova, and 2IRCCS Ca Granda Foundation Maggiore Hospital, Milan, Italy
Summary Rituximab is a humanized chimeric anti-CD20 monoclonal antibody initially developed for the treatment of some haematological malignancies. Thanks to its ability to rapidly and specifically deplete B cells, it has also been used in a variety of autoimmune disorders, haematological or not. In this context, during the last decade several small case series have documented successful inhibitor eradication with rituximab, alone or in combination with other immunosuppressive agents, in patients with acquired haemophilia A refractory to standard therapy. In addition, a number of investigators have recently used this agent in patients with congenital haemophilia A or B and alloantibodies refractory to first-line treatment. This article critically reviews the current knowledge on the use of rituximab in acquired haemophilia or congenital haemophilia complicated by alloantibodies, also providing treatment algorithms for the management of these conditions. Keywords: rituximab, inhibitors, acquired haemophilia, congenital haemophilia, autoantibodies, alloantibodies. Rituximab is a genetically engineered chimeric human/mouse monoclonal antibody, directed against CD20 (expressed on pre-mature and mature B lymphocytes but not on plasma cells or haematopoietic stem cells), which rapidly depletes B cells from the blood, lymph nodes and bone marrow (Reff et al, 1994). The suggested mechanisms of action of rituximab include antibody-dependent cell-mediated or complement-mediated cytotoxicity and a direct apoptotic activity (Smith, 2003). This agent was first developed for the treatment of oncohaematological disorders and numerous reports have documented that it is clinically effective alone or in combination with other chemotherapeutic drugs in indolent and aggressive non-Hodgkin lymphoma and in chronic
Correspondence: Pier Mannuccio Mannucci, IRCCS Ca Granda Foundation Maggiore Policlinico Hospital, Via Pace 9, 20122 Milan, Italy. E-mail: [email protected]
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
lymphocytic leukaemia (Maloney et al, 1994; Cvetkovic & Perry, 2006). Due to the central role of B cells in autoimmunity and the selective anti-CD20 activity of rituximab, a number of studies have been conducted to assess its effectiveness in various non-haematological (mainly rheumatoid arthritis, for which it is licensed in the USA and Europe) and haematological (idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, thrombotic thrombocytopenic purpura and acquired haemophilia A) autoimmune disorders (Edwards et al, 2004; Franchini, 2007; Franchini et al, 2010). Recently, there has been also increasing interest towards the use of rituximab for inhibitor eradication in patients with congenital haemophilia complicated by the occurrence of alloantibodies (Carcao et al, 2006). In this review, we examine the clinical evidence supporting the use of rituximab in the inhibitor eradication in patients with acquired or congenital haemophilia. A search of PubMed was performed up to December 2013 combining the word “rituximab” with each of the two diseases. In addition, further studies were retrieved from the reference list of the publications identified in PubMed.
Acquired haemophilia A Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by circulating auto-antibodies that inhibit the coagulant activity of factor VIII (FVIII) (Delgado et al, 2003; Collins & Percy, 2010; Franchini & Lippi, 2011; Coppola et al, 2012). The incidence of AHA has been estimated to be 02–10 cases per 1 million persons per year, although epidemiological data are likely to be underestimated, especially in elderly patients (Delgado et al, 2003). The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years (postpartum inhibitors) and a major peak in patients aged 68–80 years. FVIII autoantibodies are distributed equally by sex, although females predominate in the younger age group because of the association with pregnancy while males constitute the majority of patients over the age of 60 years (Collins & Percy, 2010). In approximately 50% of cases, FVIII autoantibodies occur in patients apparently lacking relevant concomitant diseases
doi:10.1111/bjh.12829
Review Table I. Conditions associated with acquired haemophilia A. Category Idiopathic Pregnancy Autoimmune disorder Malignancy
Drug-induced Skin disease Other
Disease
Systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj€ ogren syndrome, Goodpasture syndrome, myasthenia gravis, Graves disease Haematological: chronic lymphocytic leukaemia, multiple myeloma, Waldenstr€ om macroglobulinemia, non-Hodgkin lymphoma Penicillin and its derivatives, sulfa antibiotics, phenytoin, methyldopa, chloramphenicol, interferon-alpha, fludarabine, clopidogrel Psoriasis, pemphigus Acute hepatitis B and C, chronic obstructive pulmonary disease, asthma, diabetes
(spontaneous antibodies), and in nearly 10% of cases autoantibodies to FVIII appear during the postpartum period, usually in primiparous women within 3 months of delivery (Delgado et al, 2003). However, several other conditions and diseases (i.e., autoimmune disorders, malignancies and drugs) have been associated with the development of FVIII inhibitors (Table I). AHA is usually recognized following the investigation of abnormal bleeding developing in subjects with negative family and personal bleeding history, although occasionally patients are diagnosed during routine blood tests with no prior clinical evidence of bleeding. The diagnosis is based on the detection of an isolated prolongation of activated partial thromboplastin time (APTT), which cannot be corrected by incubating equal volumes of patient and normal plasma (mixing study), associated with reduced FVIII levels and evidence of a FVIII inhibitor (measured using the Bethesda assay or the Nijmegen modification) (Verbruggen et al, 1995). The bleeding pattern of AHA is rather different from that of congenital haemophilia A. Thus, most patients with FVIII autoantibodies have haemorrhages into the skin, muscles or soft tissues and mucous membranes (e.g. epistaxis, gastrointestinal and urological bleeds), whereas haemarthroses, a typical feature of congenital FVIII deficiency, are uncommon. Frequently, the haemorrhages in AHA are serious or life-threatening, accounting for the high morbidity and mortality rates (up to 30%) reported in the literature (Knoebl et al, 2012).
Therapeutic approaches A prompt diagnosis and start of appropriate treatment is crucial in AHA for a favourable outcome, which also depends on the identification and treatment of possible concomitant diseases or triggering conditions that, if removed, in some cases may lead to the disappearance of the inhibitor (Franchini & Lippi, 2008). The treatment of AHA is directed to the control of bleeding episodes and the eradication of the autoantibody (Collins, 2011). While bypassing agents [i.e., activated prothrombin complex concentrates (APCC) and 2
Solid: prostate, lung, pancreas, colon, stomach, melanoma, breast, kidney, cervix, head, neck
recombinant activated factor VII (rFVIIa)] are recommended as first-line therapy for the control of bleeding (Franchini & Lippi, 2010; Baudo et al, 2012; Sborov & Rodgers, 2013), immunosuppressive therapy (i.e. corticosteroids alone or in association with cyclophosphamide) is effective in achieving complete inhibitor eradication in 70–80% of patients with a median time interval of approximately 5 weeks after starting therapy (Collins et al, 2012). There are also increasing reports in the literature regarding the efficacy of rituximab in the treatment of acquired autoantibodies to FVIII (Franchini & Lippi, 2011).
The role of rituximab The first report of successful inhibitor eradication in all three patients with AHA treated with rituximab, given at the traditional dose of 375 mg/m2 weekly for 4 weeks, was from Karwal et al (2001). The following year, Wiestner et al (2002) published four additional AHA cases with high-titre inhibitors refractory to standard therapy. The administration of rituximab weekly for up to four infusions resulted within 3–12 weeks in the resolution of bleeding in all cases and normalization of FVIII activity with no detectable inhibitor in three cases. Interestingly, in the fourth patient with mild haemophilia A as underlying disorder, FVIII levels changed from unmeasurable to low but measurable values (15% of normal) after autoantibody eradication. Stasi et al (2004) published an open label trial reporting 10 AHA cases treated with rituximab. Eight patients with an inhibitor titre less than 100 Bethesda units (BU)/ml achieved a complete response. Three relapsed patients obtained a new sustained response following retreatment with rituximab at the same dosage. The remaining two patients with inhibitor titres higher than 100 BU/ml, who had experienced only a partial and transient decrease of the inhibitor following rituximab alone, obtained a complete and sustained response following a combination therapy with rituximab plus pulsed intravenous cyclophosphamide. Thus, on the basis of these results, the authors suggested that in high titre inhibitor patients, rituximab treatment should be reinforced with the addition of ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review cyclophosphamide. The need for a combination of rituximab with other immunosuppressive therapies in order to obtain sustained responses in very high-titre inhibitors (>100 BU/ ml) was subsequently confirmed in two case series on 4 and 15 AHA patients, respectively (Field et al, 2007; Boles et al, 2011). In particular, Boles et al (2011) observed that patients who achieved a complete or partial response on rituximab alone had a median baseline FVIII inhibitor titre of 22 BU/ ml, whereas those who achieved a complete response with the addition of immunosuppressive agents had a median of initial titre of 834 BU/ml (P = 00283), suggesting that rituximab is most effective in the treatment of AHA when the patient’s initial inhibitor titre is 100 BU/ml) being a negative prognostic factor for response to rituximab (Franchini, 2007). Other positive experiences were those of Aggarwal et al (2005) and Onitilo et al (2006). Interestingly, Onitilo et al (2006) observed a rapid reduction of inhibitor titres in all six AHA patients treated with rituximab, with very little requirement for costly bypassing therapy (rFVIIa) and no need for long-term immunosuppressive maintenance. However, because a sustained rebound marked rise in FVIII level (up to 420%) was observed following rituximab in three cases, the authors advised monitoring those patients for the risk of thrombotic complications. However, the most important publication in this field, accounting for nearly half of all the published AHA cases treated with rituximab, is that reporting the final results of the prospective European Acquired Haemophilia Registry (EACH2): 30 of 51 (59%) patients treated with a first-line regimen that included rituximab achieved a sustained eradication (Collins et al, 2012). The 12 patients treated with rituximab alone had only a 42% response rate, whereas those treated with rituximab and another agent had a 64% sustained inhibitor eradication, similar to the 70% rate observed for patients treated with corticosteroids and cyclophosphamide. Interestingly, the rituximab-based regimens were associated with a longer median time to achieve a complete response than other agents (65 days vs. 32 days), thus exposing the patients for a longer period to an increased bleeding risk (Collins et al, 2012). The adverse event rate for rituximab was 37%, similar to that for treatment with corticosteroids and cyclophosphamide. Thus, on the basis of these results, which documented that rituximab does not produce a higher probability of complete or more rapid response than standard immunosuppressive therapy, the authors concluded that there is actually no evidence to support the use of this agent as first-line therapy in AHA patients. Table II, which summarizes the characteristics of the main studies, features 108 AHA cases treated with rituximab. Apart ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
from the high overall response (complete and partial) rate of 80% (86/108), these data are difficult to interpret, mostly because they are derived from small case reports, raising the suspicion of a positive reporting bias (Garvey, 2008; Barcellini & Zanella, 2011; Collins, 2012). On the other hand, the limited follow-up of these cases and the concomitance of many immunosuppressive therapies hinder a clear evaluation of the net role of rituximab in inhibitor eradication. Nevertheless, although the most crucial questions about this agent (i.e. whether or not it gives advantages towards standard immunosuppressive therapy in terms of sustained response, adverse event rate and overall survival) are still far from being answered, we propose a diagnostic and therapeutic algorithm based on actual knowledge (Fig 1). In accordance with the recent international recommendations made by a panel of experts (Huth-K€ uhne et al, 2009) we suggest that rituximab should be used only as a second-line therapy if first-line immunosuppressive therapy fails or is contraindicated. An earlier use of rituximab as first line therapy for high-titre inhibitor patients requires additional clinical evidence before it can be recommended.
Congenital haemophilia The most challenging complication of replacement therapy for haemophilia A and B is actually the occurrence of alloantibodies inhibiting the coagulant activity of FVIII or FIX (Franchini & Mannucci, 2011, 2013). These inhibitors, which develop in approximately 25–30% of severe haemophilia A patients and in 3–5% of those with haemophilia B, render replacement therapies ineffective, limit patient access to a safe and effective standard of care and predispose them to an increased risk of morbidity and mortality (Plug et al, 2006). In addition, patients with haemophilia complicated by inhibitors require very high amounts of resources for management (about €220000 per year per patient) (Gringeri et al, 2003). A number of studies have revealed the importance of genetic [e.g. ethnicity, FVIII gene (F8) mutations, major histocompatibility complex genotype, polymorphisms of immune-response genes] and acquired (e.g. number of FVIII exposure-days, age at first exposure to FVIII concentrate, type of FVIII concentrate administered and modality of treatment) risk factors in the development of inhibitors, confirming that inhibitor formation in haemophilia is a multifactorial process (Astermark, 2006). While the available data indicate that the bypassing agents APCC and rFVIIa are equally safe and effective in the control of bleeding in haemophilia patients with inhibitors (Franchini et al, 2013), immune tolerance induction (ITI) through the long-term intensive treatment of patients with large doses of coagulation factors is actually the best method to eradicate inhibitors, with rates of success varying between 60% and 90% (Collins et al, 2013). With this background, some investigators have also explored the role of rituximab in haemophilia patients who had failed conventional ITI (Kruse-Jarres, 2011) 3
4
5–78
23/30
2/6
8/7
0/3
1/3
2/4
2/2
5/5
3/1
1/2
Sex (M/F)
27 Idiopathic, 7 AD, 7 Cancers, 1 PP
5 Idiopathic, 7 Cancer, 1 AD, 1 PP, 1 Infection 7 Idiopathic, 1 RA
2 Idiopathic, 3 Cancer, 1 PP 1 Diabetes, 1 PU, 1 CAD, 1 BP 3 PP
1 CRF, 1 LA, 1 PM, 1 MHA 6 Idiopathic, 1 NHL, 1 RA, 1 Cancer, 1 PP 4 Idiopathic
NR
Associated conditions
2 None; 3 PDN; 1 CPM; 1 AZA + PDN; 1 CVP + IVIG + CS NR
NR
None
4
4–6
4
1–4
4
2 None; 3 PDN; 1 CPM; 1 AZA + PDN; 1 CVP + IVIG + CS 12 None; 3 CPM; 28 PDN; 8 PDN + CPM
2 PDN + IVIG; 1 PDN 8 None; 3 PDN; 1 PDN + CPM
11–3075
1 AZA + VCP; 1 PDN; 4 CPM + PDN 1 None; 3 CPM
3–9
7–525
1 None; 3 PDN
4–8
1 None; 1 PDN; 2 PDN + CPM 1 AZA + CVP; 1 PDN; 4 CPM + PDN 3 CVP; 1 CVP + CPM
6–62
4–770
7 CR
31 CR
Inhibitor eradication with rituximab in haemophilia: where do we stand? Massimo Franchini1 and Pier Mannuccio Mannucci2 1
Department of Transfusion Medicine and Haematology, Carlo Poma Hospital, Mantova, and 2IRCCS Ca Granda Foundation Maggiore Hospital, Milan, Italy
Summary Rituximab is a humanized chimeric anti-CD20 monoclonal antibody initially developed for the treatment of some haematological malignancies. Thanks to its ability to rapidly and specifically deplete B cells, it has also been used in a variety of autoimmune disorders, haematological or not. In this context, during the last decade several small case series have documented successful inhibitor eradication with rituximab, alone or in combination with other immunosuppressive agents, in patients with acquired haemophilia A refractory to standard therapy. In addition, a number of investigators have recently used this agent in patients with congenital haemophilia A or B and alloantibodies refractory to first-line treatment. This article critically reviews the current knowledge on the use of rituximab in acquired haemophilia or congenital haemophilia complicated by alloantibodies, also providing treatment algorithms for the management of these conditions. Keywords: rituximab, inhibitors, acquired haemophilia, congenital haemophilia, autoantibodies, alloantibodies. Rituximab is a genetically engineered chimeric human/mouse monoclonal antibody, directed against CD20 (expressed on pre-mature and mature B lymphocytes but not on plasma cells or haematopoietic stem cells), which rapidly depletes B cells from the blood, lymph nodes and bone marrow (Reff et al, 1994). The suggested mechanisms of action of rituximab include antibody-dependent cell-mediated or complement-mediated cytotoxicity and a direct apoptotic activity (Smith, 2003). This agent was first developed for the treatment of oncohaematological disorders and numerous reports have documented that it is clinically effective alone or in combination with other chemotherapeutic drugs in indolent and aggressive non-Hodgkin lymphoma and in chronic
Correspondence: Pier Mannuccio Mannucci, IRCCS Ca Granda Foundation Maggiore Policlinico Hospital, Via Pace 9, 20122 Milan, Italy. E-mail: [email protected]
ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
lymphocytic leukaemia (Maloney et al, 1994; Cvetkovic & Perry, 2006). Due to the central role of B cells in autoimmunity and the selective anti-CD20 activity of rituximab, a number of studies have been conducted to assess its effectiveness in various non-haematological (mainly rheumatoid arthritis, for which it is licensed in the USA and Europe) and haematological (idiopathic thrombocytopenic purpura, autoimmune haemolytic anaemia, thrombotic thrombocytopenic purpura and acquired haemophilia A) autoimmune disorders (Edwards et al, 2004; Franchini, 2007; Franchini et al, 2010). Recently, there has been also increasing interest towards the use of rituximab for inhibitor eradication in patients with congenital haemophilia complicated by the occurrence of alloantibodies (Carcao et al, 2006). In this review, we examine the clinical evidence supporting the use of rituximab in the inhibitor eradication in patients with acquired or congenital haemophilia. A search of PubMed was performed up to December 2013 combining the word “rituximab” with each of the two diseases. In addition, further studies were retrieved from the reference list of the publications identified in PubMed.
Acquired haemophilia A Acquired haemophilia A (AHA) is a rare autoimmune disorder caused by circulating auto-antibodies that inhibit the coagulant activity of factor VIII (FVIII) (Delgado et al, 2003; Collins & Percy, 2010; Franchini & Lippi, 2011; Coppola et al, 2012). The incidence of AHA has been estimated to be 02–10 cases per 1 million persons per year, although epidemiological data are likely to be underestimated, especially in elderly patients (Delgado et al, 2003). The age distribution of autoantibodies is typically biphasic with a small peak between 20 and 30 years (postpartum inhibitors) and a major peak in patients aged 68–80 years. FVIII autoantibodies are distributed equally by sex, although females predominate in the younger age group because of the association with pregnancy while males constitute the majority of patients over the age of 60 years (Collins & Percy, 2010). In approximately 50% of cases, FVIII autoantibodies occur in patients apparently lacking relevant concomitant diseases
doi:10.1111/bjh.12829
Review Table I. Conditions associated with acquired haemophilia A. Category Idiopathic Pregnancy Autoimmune disorder Malignancy
Drug-induced Skin disease Other
Disease
Systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sj€ ogren syndrome, Goodpasture syndrome, myasthenia gravis, Graves disease Haematological: chronic lymphocytic leukaemia, multiple myeloma, Waldenstr€ om macroglobulinemia, non-Hodgkin lymphoma Penicillin and its derivatives, sulfa antibiotics, phenytoin, methyldopa, chloramphenicol, interferon-alpha, fludarabine, clopidogrel Psoriasis, pemphigus Acute hepatitis B and C, chronic obstructive pulmonary disease, asthma, diabetes
(spontaneous antibodies), and in nearly 10% of cases autoantibodies to FVIII appear during the postpartum period, usually in primiparous women within 3 months of delivery (Delgado et al, 2003). However, several other conditions and diseases (i.e., autoimmune disorders, malignancies and drugs) have been associated with the development of FVIII inhibitors (Table I). AHA is usually recognized following the investigation of abnormal bleeding developing in subjects with negative family and personal bleeding history, although occasionally patients are diagnosed during routine blood tests with no prior clinical evidence of bleeding. The diagnosis is based on the detection of an isolated prolongation of activated partial thromboplastin time (APTT), which cannot be corrected by incubating equal volumes of patient and normal plasma (mixing study), associated with reduced FVIII levels and evidence of a FVIII inhibitor (measured using the Bethesda assay or the Nijmegen modification) (Verbruggen et al, 1995). The bleeding pattern of AHA is rather different from that of congenital haemophilia A. Thus, most patients with FVIII autoantibodies have haemorrhages into the skin, muscles or soft tissues and mucous membranes (e.g. epistaxis, gastrointestinal and urological bleeds), whereas haemarthroses, a typical feature of congenital FVIII deficiency, are uncommon. Frequently, the haemorrhages in AHA are serious or life-threatening, accounting for the high morbidity and mortality rates (up to 30%) reported in the literature (Knoebl et al, 2012).
Therapeutic approaches A prompt diagnosis and start of appropriate treatment is crucial in AHA for a favourable outcome, which also depends on the identification and treatment of possible concomitant diseases or triggering conditions that, if removed, in some cases may lead to the disappearance of the inhibitor (Franchini & Lippi, 2008). The treatment of AHA is directed to the control of bleeding episodes and the eradication of the autoantibody (Collins, 2011). While bypassing agents [i.e., activated prothrombin complex concentrates (APCC) and 2
Solid: prostate, lung, pancreas, colon, stomach, melanoma, breast, kidney, cervix, head, neck
recombinant activated factor VII (rFVIIa)] are recommended as first-line therapy for the control of bleeding (Franchini & Lippi, 2010; Baudo et al, 2012; Sborov & Rodgers, 2013), immunosuppressive therapy (i.e. corticosteroids alone or in association with cyclophosphamide) is effective in achieving complete inhibitor eradication in 70–80% of patients with a median time interval of approximately 5 weeks after starting therapy (Collins et al, 2012). There are also increasing reports in the literature regarding the efficacy of rituximab in the treatment of acquired autoantibodies to FVIII (Franchini & Lippi, 2011).
The role of rituximab The first report of successful inhibitor eradication in all three patients with AHA treated with rituximab, given at the traditional dose of 375 mg/m2 weekly for 4 weeks, was from Karwal et al (2001). The following year, Wiestner et al (2002) published four additional AHA cases with high-titre inhibitors refractory to standard therapy. The administration of rituximab weekly for up to four infusions resulted within 3–12 weeks in the resolution of bleeding in all cases and normalization of FVIII activity with no detectable inhibitor in three cases. Interestingly, in the fourth patient with mild haemophilia A as underlying disorder, FVIII levels changed from unmeasurable to low but measurable values (15% of normal) after autoantibody eradication. Stasi et al (2004) published an open label trial reporting 10 AHA cases treated with rituximab. Eight patients with an inhibitor titre less than 100 Bethesda units (BU)/ml achieved a complete response. Three relapsed patients obtained a new sustained response following retreatment with rituximab at the same dosage. The remaining two patients with inhibitor titres higher than 100 BU/ml, who had experienced only a partial and transient decrease of the inhibitor following rituximab alone, obtained a complete and sustained response following a combination therapy with rituximab plus pulsed intravenous cyclophosphamide. Thus, on the basis of these results, the authors suggested that in high titre inhibitor patients, rituximab treatment should be reinforced with the addition of ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
Review cyclophosphamide. The need for a combination of rituximab with other immunosuppressive therapies in order to obtain sustained responses in very high-titre inhibitors (>100 BU/ ml) was subsequently confirmed in two case series on 4 and 15 AHA patients, respectively (Field et al, 2007; Boles et al, 2011). In particular, Boles et al (2011) observed that patients who achieved a complete or partial response on rituximab alone had a median baseline FVIII inhibitor titre of 22 BU/ ml, whereas those who achieved a complete response with the addition of immunosuppressive agents had a median of initial titre of 834 BU/ml (P = 00283), suggesting that rituximab is most effective in the treatment of AHA when the patient’s initial inhibitor titre is 100 BU/ml) being a negative prognostic factor for response to rituximab (Franchini, 2007). Other positive experiences were those of Aggarwal et al (2005) and Onitilo et al (2006). Interestingly, Onitilo et al (2006) observed a rapid reduction of inhibitor titres in all six AHA patients treated with rituximab, with very little requirement for costly bypassing therapy (rFVIIa) and no need for long-term immunosuppressive maintenance. However, because a sustained rebound marked rise in FVIII level (up to 420%) was observed following rituximab in three cases, the authors advised monitoring those patients for the risk of thrombotic complications. However, the most important publication in this field, accounting for nearly half of all the published AHA cases treated with rituximab, is that reporting the final results of the prospective European Acquired Haemophilia Registry (EACH2): 30 of 51 (59%) patients treated with a first-line regimen that included rituximab achieved a sustained eradication (Collins et al, 2012). The 12 patients treated with rituximab alone had only a 42% response rate, whereas those treated with rituximab and another agent had a 64% sustained inhibitor eradication, similar to the 70% rate observed for patients treated with corticosteroids and cyclophosphamide. Interestingly, the rituximab-based regimens were associated with a longer median time to achieve a complete response than other agents (65 days vs. 32 days), thus exposing the patients for a longer period to an increased bleeding risk (Collins et al, 2012). The adverse event rate for rituximab was 37%, similar to that for treatment with corticosteroids and cyclophosphamide. Thus, on the basis of these results, which documented that rituximab does not produce a higher probability of complete or more rapid response than standard immunosuppressive therapy, the authors concluded that there is actually no evidence to support the use of this agent as first-line therapy in AHA patients. Table II, which summarizes the characteristics of the main studies, features 108 AHA cases treated with rituximab. Apart ª 2014 John Wiley & Sons Ltd, British Journal of Haematology
from the high overall response (complete and partial) rate of 80% (86/108), these data are difficult to interpret, mostly because they are derived from small case reports, raising the suspicion of a positive reporting bias (Garvey, 2008; Barcellini & Zanella, 2011; Collins, 2012). On the other hand, the limited follow-up of these cases and the concomitance of many immunosuppressive therapies hinder a clear evaluation of the net role of rituximab in inhibitor eradication. Nevertheless, although the most crucial questions about this agent (i.e. whether or not it gives advantages towards standard immunosuppressive therapy in terms of sustained response, adverse event rate and overall survival) are still far from being answered, we propose a diagnostic and therapeutic algorithm based on actual knowledge (Fig 1). In accordance with the recent international recommendations made by a panel of experts (Huth-K€ uhne et al, 2009) we suggest that rituximab should be used only as a second-line therapy if first-line immunosuppressive therapy fails or is contraindicated. An earlier use of rituximab as first line therapy for high-titre inhibitor patients requires additional clinical evidence before it can be recommended.
Congenital haemophilia The most challenging complication of replacement therapy for haemophilia A and B is actually the occurrence of alloantibodies inhibiting the coagulant activity of FVIII or FIX (Franchini & Mannucci, 2011, 2013). These inhibitors, which develop in approximately 25–30% of severe haemophilia A patients and in 3–5% of those with haemophilia B, render replacement therapies ineffective, limit patient access to a safe and effective standard of care and predispose them to an increased risk of morbidity and mortality (Plug et al, 2006). In addition, patients with haemophilia complicated by inhibitors require very high amounts of resources for management (about €220000 per year per patient) (Gringeri et al, 2003). A number of studies have revealed the importance of genetic [e.g. ethnicity, FVIII gene (F8) mutations, major histocompatibility complex genotype, polymorphisms of immune-response genes] and acquired (e.g. number of FVIII exposure-days, age at first exposure to FVIII concentrate, type of FVIII concentrate administered and modality of treatment) risk factors in the development of inhibitors, confirming that inhibitor formation in haemophilia is a multifactorial process (Astermark, 2006). While the available data indicate that the bypassing agents APCC and rFVIIa are equally safe and effective in the control of bleeding in haemophilia patients with inhibitors (Franchini et al, 2013), immune tolerance induction (ITI) through the long-term intensive treatment of patients with large doses of coagulation factors is actually the best method to eradicate inhibitors, with rates of success varying between 60% and 90% (Collins et al, 2013). With this background, some investigators have also explored the role of rituximab in haemophilia patients who had failed conventional ITI (Kruse-Jarres, 2011) 3
4
5–78
23/30
2/6
8/7
0/3
1/3
2/4
2/2
5/5
3/1
1/2
Sex (M/F)
27 Idiopathic, 7 AD, 7 Cancers, 1 PP
5 Idiopathic, 7 Cancer, 1 AD, 1 PP, 1 Infection 7 Idiopathic, 1 RA
2 Idiopathic, 3 Cancer, 1 PP 1 Diabetes, 1 PU, 1 CAD, 1 BP 3 PP
1 CRF, 1 LA, 1 PM, 1 MHA 6 Idiopathic, 1 NHL, 1 RA, 1 Cancer, 1 PP 4 Idiopathic
NR
Associated conditions
2 None; 3 PDN; 1 CPM; 1 AZA + PDN; 1 CVP + IVIG + CS NR
NR
None
4
4–6
4
1–4
4
2 None; 3 PDN; 1 CPM; 1 AZA + PDN; 1 CVP + IVIG + CS 12 None; 3 CPM; 28 PDN; 8 PDN + CPM
2 PDN + IVIG; 1 PDN 8 None; 3 PDN; 1 PDN + CPM
11–3075
1 AZA + VCP; 1 PDN; 4 CPM + PDN 1 None; 3 CPM
3–9
7–525
1 None; 3 PDN
4–8
1 None; 1 PDN; 2 PDN + CPM 1 AZA + CVP; 1 PDN; 4 CPM + PDN 3 CVP; 1 CVP + CPM
6–62
4–770
7 CR
31 CR
