Accepted Article

Rituximab in the treatment of autoimmune haemolytic anaemia 1

1

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1

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2

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Chaturaka Rodrigo Senaka Rajapakse Lallindra Gooneratne

Affiliations: 1

Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka

2

Department of Pathology, Faculty of Medicine, University of Colombo, Sri Lanka

Corresponding author: Chaturaka Rodrigo Department of Clinical Medicine Faculty of Medicine, University of Colombo

Sri Lanka

Tel: +94 71 8130991 Fax: +94 112 689188 Email: [email protected] Keywords; Rituximab, Autoimmune haemolytic anaemia, Cold agglutinin disease Running title: Rituximab in autoimmune haemolytic anaemia This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/bcp.12498

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Accepted Article Summary

Rituximab is a B-cell depleting monoclonal antibody that is gaining popularity as an effective therapy for many autoimmune cytopenias. This article systematically evaluates its therapeutic efficacy in the treatment of different types of autoimmune haemolytic anaemia. We conclude that there is sufficient evidence to recommend it as a second line therapy for warm autoimmune haemolytic anaemia (wAIHA) either as monotherapy or combined therapy. Evidence from a single randomized controlled trial suggests that it may also be more efficacious as first-line therapy in combination with steroids than steroids alone. A fewer number of studies have assessed its role in cold autoimmune haemolytic anaemia (cAIHA) and cold agglutinin disease (CAD) with success rates varying from 45-66%. In the absence of alternative definitive therapy, rituximab should be considered for patients with symptomatic CAD and significant haemolysis. Case reports of its efficacy in mixed autoimmune haemolytic anaemias are available but evidence from case series or larger cohorts are nonexistent.

Introduction Rituximab is a B cell depleting monoclonal antibody with CD20 specificity that has proven efficacy in many autoimmune disorders [1]. Although it is licensed for the treatment of B-cell lymphomas and severe rheumatoid arthritis, its use in autoimmune haemolytic anaemia is “off label” and has been evaluated in only a small number of prospective as well as retrospective clinical studies. The data from these individual trials, case series and case reports are promising and some authors suggest the use of rituximab earlier than other traditionally accepted therapies (e.g. before splenectomy in primary warm autoimmune haemolytic anaemia) [2]. This is especially true when splenectomy has long term 2 This article is protected by copyright. All rights reserved.

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consequences on patients especially in children. However, rituximab is costly and not all patients respond favourably to its administration. In resource limited settings the cost effectiveness of rituximab for this indication is an ongoing debate. There are also different types of autoimmune haemolytic anaemias and response of rituximab to each type may vary. Therefore, it is important to have an exact efficacy estimate on rituximab for each type of haemolytic anaemia. As it remains an “off label” indication, this systematic review aims at critically evaluating the evidence for using rituximab in different types of haemolytic anaemia with the aim of identifying the strength of evidence for its use in each indication.

Methods

A MEDLINE and PUBMED search was performed for all articles with the key word ‘Rituximab’ and ‘autoimmune hemolytic anemia’ or ‘autoimmune haemolytic anaemia’ in any field. There were no time or language restrictions to the search. There were 378 abstracts in the original search with these search terms. The software Endnote X3 (Thomson Reuters, Carlsbad, CA 92011, USA) was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read independently by all authors, and key articles were identified based on a consensus. Forty one articles were selected for the final synthesis based on the relevance to the topic and after removing duplicate results. These included prospective and retrospective studies, case reports, opinion papers, treatment guidelines and cross sectional analyses of patients.

Review

Autoimmune haemolytic anaemias (AIHA) are rare and are characterized by autoantibodies directed against self red blood cells which results in severe anaemia [3]. Most have a positive Coombs or direct agglutination test (DAT) which detects antibody with or without complement, on the surface of red cells.

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A population-based study revealed the incidence of AIHA to be 0.8/100,000/year, but the prevalence 17/100,000 [4].Warm type autoimmune haemolytic anaemia (wAIHA) affects all age groups and account for 70-80% of all AIHA. About 30-40% of wAIHA are primary haemolytic anaemias whereas the rest are due to secondary causes such as drugs, autoimmune disorders and lymphoproliferative disorders. Other types of AIHA are cold autoimmune haemolytic anaemia (cAIHA) including cold agglutinin disease (CAD), paroxysmal cold haemoglobinuria (PCH) and mixed type autoimmune haemolytic anaemia. Cold-acting antibodies are predominantly IgM and bind with antigen in the cold (40C). They may act merely as agglutinins (CAD) or as agglutinins and lysins. The first instance where rituximab had been tried for cold agglutinin disease was in 1998 which was successful [5]. Following this Ahrens and colleagues used it for a patient with refractory AIHA (type not specified) who had not responded to steroids, azathioprine, mycophenolate mofetil (MMF) and cyclophosphamide. The dose used was 375mg/m2 once a week for 4 weeks with 15 mg of prednisolone daily. The patient was followed up for 6 months with good haematological response. The haemoglobin(Hb) level improved to 12.3 g/dl from 8.4 g/dl [6]. In the same year Quartier et al. reported 5 children recovering from wAIHA following rituximab therapy. They had maintained remission for a duration of 15-22 months with minimal or no side effects [7]. Soon there were many case reports and small case series where rituximab had been successfully used to treat AIHA [8-14]. Its successful use was also reported for cAIHA as well as cold agglutinin disease and mixed type anemias [15-18]. This established its role as a potentially successful therapy for refractory autoimmune haemolytic anaemias and especially the cold agglutinin disease where previously no specific therapy was available. This led to designing of prospective and retrospective observational studies and clinical trials on the efficacy of rituximab for these indications. A summary of all studies discussed in this review is given in table I. Rituximab for warm autoimmune haemolytic anaemia (wAIHA)

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While there are several case reports and case series of successful use of rituximab in wAIHA, for the purpose of this review we have considered prospective and retrospective studies and case series that had more than ten patients. In this regard, the earliest case series that reported a significant benefit of rituximab for treatment refractory wAIHA was by Zecca et al.[19]. This prospective study enrolled 15 children with AIHA at a mean age of diagnosis of 2 years. Thirteen of them had warm reactive auto antibodies (IgG) and four of them had a diagnosis of Evans syndrome. All children had received at least two different immunosuppressive regimens (IV methylprednisolone, oral prednisolone, IV immunoglobulin, azathioprin and cyclosporine A) prior to enrolment and two had undergone splenectomy without success. Rituximab was administered in a dose of 375mg/m2 weekly with a total of 2-4 doses. The median follow up for all patients was 14 months (range 7-28 months). Authors concluded that of the total series, 13 out of 15 (87%) responded to treatment. Response was defined as a 1.5 g/dl rise in haemoglobin and a 50% reduction of the total reticulocyte count at two months follow up. Of those with warm reactive antibodies, 11 (84.6%) responded to treatment (both non responders in the series had wAIHA). Two patients with wAIHA who initially responded to rituximab later developed further episodes of haemolysis which again responded to further dosing. Others were eventually weaned off from other immunosuppressive drugs (predominantly steroids) after remission induction with rituximab. There were no serious adverse events directly attributable to rituximab. Narat and colleagues reported the course of eleven patients (mean age 52 years; range 26-81) with wAIHA treated with four doses of weekly 375mg/m2 rituximab [20]. The overall response rate was 64% with three complete responses and four partial responses for a mean duration of 11 months. A partial response was defined as a haemoglobin increment of 2g/dl and discontinuation of other immunosuppression while a complete response was a haemoglobin level above 13 g/dl (for males) or 12g/dl (females) without further episodes of haemolysis. At the time of rituximab administration the patients continued other means of immunosuppression (prednisolone, cyclophosphamide) but in 5 This article is protected by copyright. All rights reserved.

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responders they were tapered off. It is noted that one of the responders had died of sepsis 10 weeks following rituximab. He was not on any other immunosuppression during rituximab administration but has had steroids and splenectomy prior to that. His wAIHA was secondary to chronic lymphocytic leukaemia (CLL) indicating a primary immunosuppressive illness. Time to maximum response following therapy varied from 5-12 weeks. While it is plausible that the death in this series might have been contributed to by B cell depletion in an already immunocompromised patient, it is difficult to implicate rituximab as a significantly responsible agent for the death as he had many other alternative causes for immunosuppression. In a third case series of 14 patients having wAIHA secondary to chronic lymphocytic leukaemia (CLL), D’Arena and colleagues[21] report a response rate of 71.4% (12 out of 14) to four cycles of rituximab at a

weekly dose of 375mg/m2. The mean increment of haemoglobin was 3.6g/dl (range; 0.7 -10). Four

patients converted to direct antiglobulin test (DAT) negative status after the drug. Overall, rituximab infusions were associated with a decline in lymphocyte numbers and spleen volume. Again no significant side effects attributable to rituximab were observed in the sample. One of the first comparative studies of using rituximab for treatment resistant AIHA was carried out by Heidel et al [22]. Their series had 12 patients with AIHA (type not specified) who were non responsive to initial treatment with various immunosuppressive regimens that included steroids, azathioprine, cytotoxic agents and immunoglobulins. Three of these patients were administered rituximab (375mg/m2 weekly up to 8 doses). Response rate (defined as maintaining a Hb level above 10g/dl with a reduction in lactate dehydrogenase levels and a rise in serum haptoglobin levels > 0.3 g/l) was 100% in all three patients who received rituximab in addition to standard therapy (response rate was 66.7% for standard therapy without rituximab). No significant side effects were recorded other than transient episodes of skin rashes and fever at times of infusion.

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In a retrospective analysis of 27 patients with wAIHA (primary; 17, secondary; 10, mean age; 49 years ± 21), Bussone and colleagues have demonstrated response in 25 (93%) patients [23]. There were eight full (Hb level >11 g/dL in women or 12 g/dL in men without haemolysis while off treatment) and fifteen partial (Hb level >10 g/dL with at least a 2 g/dL increase from the pre-treatment level with persistent features of haemolysis) responders. Of these patients, five were resistant to steroids and 16 had a steroid dependent wAIHA. Most patients had received four weekly doses of rituximab (375mg/m2). Of those responding, five had a relapse of AIHA and three of them were successfully re-treated with rituximab. Mild adverse events (urticaria and transient polyarthralgia) were observed in two patients. However, two other patients of the series had episodes of severe neutropenia and Pneumocystis jiroveci infection respectively. Both had secondary AIHA and were severely immunosuppressed (due to CLL, multicentric castleman disease and Kaposi sarcoma). The episode of Pneumocystis pneumonia was 2 months after rituximab. A Belgian retrospective study of 53 patients with AIHA (36, 68% with wAIHA, median age; 65 years, age range; 1-87) demonstrated that rituximab in the same dose as in the previous study was effective in inducing a remission in 83.3% of patients for a median follow up of 15 months [24]. Unfortunately, none of the pretreatment parameters helped to differentiate responders from non responders (e.g. age, gender, underlying disorder). It is noted that rituximab monotherapy was only given for 12 patients while all others received concomitant immunosuppressants, mainly steroids. The overall response rate of the rituximab monotherapy group was 75%. Response to rituximab was defined as follows; reaching a normal haemoglobin (Hb) level without further episodes of haemolysis (complete response) or independence from further transfusions (in a previously transfusion dependent patient) / stable increment of Hb by 2g/dl (partial response). A similar retrospective analysis of treatment refractory AIHA in 36 (27 wAIHA and 9 cAIHA) patients in Spain showed an overall response rate of 77% and wAIHA response rate of 61.5% to rituximab (majority receiving a dose similar to studies above)[25]. Again there 7 This article is protected by copyright. All rights reserved.

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were no statistically significant predictors of response to rituximab including the type of AIHA, previous first line therapies (including splenectomy), type of underlying disorder, age and gender. There was also no difference in response rates in those receiving monotherapy with rituximab and combined therapy with other immunosuppressants. The median time to response was also not significantly different between these two groups. Only one patient in this sample experienced a mild adverse event (urticaria). There were no serious adverse events or fatalities attributable to rituximab. Another retrospective analysis of patients with wAIHA treated with rituximab as second line therapy (at a dose of 375mg/m2, four weekly doses) showed 71% response rate (24 out of 34 patients) [26]. Among responders, 87% showed a response within one month of starting treatment while the reminder showed a response by three months. However, of all responders half had relapsed during follow up but had a considerable 16.5 months of a mean period between initial treatment and relapse. Again age, gender or duration between diagnosis and treatment were not predictors of clinical response to rituximab. Apart from a single episode of neutropenic sepsis (the patient was not on any other immunosuppressants); no significant adverse events were reported due to rituximab. Barcellini and colleagues attempted a phase II multicentre prospective study of efficacy of low dose rituximab in AIHA [27]. In their cohort of 23 patients with primary AHIA (wAIHA; 14, cAIHA; 9, mean age of wAIHA patients; 46.5 years, range 25-75) response was assessed for 4 X weekly 100mg infusions of rituximab. The median time of follow up was 15 months (range 6-35 months). The response for wAIHA was 100% at two months (Hb above 12g/dl and normalization of markers of haemolysis) since start of therapy and response was maintained at 6 and 12 months of follow up. There were no adverse effects attributable to rituximab in the cohort. When considering the overall cohort which included patients with cold agglutinin disease as well, sustained response to rituximab at six months was significantly associated with a diagnosis of wAIHA in the multivariate analysis (while univaraiate analysis also showed associations with a shorter time duration between diagnosis and treatment, higher weight and younger 8 This article is protected by copyright. All rights reserved.

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age). The patients were concurrently administered a dose of steroids and it was completely tailed off in nine (64%) patients with wAIHA following rituximab therapy. In others steroid dose was reduced while maintaining response. A later follow up of the same study (with four additional recruits to the wAIHA group) showed that improvement in overall Hb levels was maintained at 24 and 36 months of follow up [28]. However it must be noted that data was only available for 12 and 7 patients at these time points respectively. Two wAIHA patients had to be treated with cytotoxic drugs due to relapse and three had to undergo splenectomy. One patient with wAIHA had responded to a second dose of rituximab. Overall, the authors concluded that low dose rituximab is an effective form of therapy for wAIHA for a follow up of 36 months. In a separate study by Gomez-Almaguer et al. low dose rituximab in combination with alemtuzumab (10mg subcutaneously for 3 days) was shown to be effective for limited number of patients (n-9) with refractory autoimmune haemolytic anaemia [29]. A third study published recently

reported 66.7% (8/12) of patients having complete remission with low dose rituximab (4 X weekly 100mg infusions, without steroids) while a parallel group treated with steroids had only 20% (5/25) success in achieving complete remission [30]. Taking this further, Birgens et al conducted a phase III randomized trial comparing steroid monotherapy versus combined therapy with rituximab (plus steroids) for patients with wAIHA [31]. They prospectively recruited 64 patients with wAIHA and randomized them in to the two treatment groups of equal size (n32). The enrolled patients were newly diagnosed patients with either primary or secondary wAIHA who might have received steroids at time of enrolment for a duration not exceeding 1 week. All patients received a starting dose of oral prednisolone 1.5mg/kg day and the test group received four weekly infusions of rituximab at a dose of 375mg/m2. Responses were evaluated at intervals of 3, 6 and 12 months since initiation of treatment. A complete response was defined as a normalization of haemoglobin levels without any ongoing haemolytic activity enabling stopping of immunosuppressants. A partial response was similar to complete response except that patients required a low dose of 9 This article is protected by copyright. All rights reserved.

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prednisolone (< 10mg/day) to maintain the response (or tolerated a compensated state of haemolytic anaemia that did not require more than 10mg of daily prednisolone to maintain a normal haemoglobin level). All other patients were considered as non responders. Therefore, the criteria for definition of response was stringent compared to other prospective studies mentioned above. There were no significant differences between the two groups in relation to gender, age, biochemical parameters and aetiology of wAIHA at recruitment. It was noted that at three months almost 50% of patients in each arm showed either a complete or a partial response. However at 6 months the number showing partial response was less. At 12 months there were either complete responders or non responders only. The difference of responders and non responders between the groups became apparent at 6 months and was shown to be more statistically significantly at 12 months in the combined treatment group (75% in combined treatment group and 36% in prednisolone only group, p = 0.02). The number of non responders that had to undergo splenectomy was equivalent in the two groups. An extended follow up for 36 months showed that of all responders in each treatment arm, 70% maintained their response without relapses in the rituximab + prednisolone group while only 45% of responders maintained continued remission in the prednisolone only group. There was no statistically significant difference reported for adverse events between the two groups. Overall, the evidence for using rituximab for wAIHA is mainly from retrospective or prospective single arm studies or case series. The evidence is mainly from cohorts of adult patients (apart from the trial by Zecca et al and exists for both primary as well as secondary wAIHA [19]. The definitions of complete and partial response vary and it is a major hindrance to compare or combine response rates recorded by each group of authors. The response rates reported for treatment with rituximab vary between 64 – 100% in different studies (we only considered studies which had more than 10 patients). The study which recorded the lowest response rate for rituximab had a stringent criterion to define a clinical response to rituximab [20]. Low numbers in each study may also account for variability in response rates 10 This article is protected by copyright. All rights reserved.

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and an adequately powered clinical trial is needed for a better and an accurate estimate. Heterogeneity of patients (primary wAIHA and secondary causes), other therapies given in combination and stage of disease at which rituximab was used (first, second or third line therapy) would all contribute to the variability of observed response rates between studies. The follow up periods of all these studies are extensive and were beyond six months (at least) and in many cases over 12 months. Relapses have been observed in a significant minority of responders but some of them had responded well to a second dose of rituximab. However, there had been non responders that required alternative therapy. Rituximab has been tried and proven to be effective in patients having failed splenectomy for wAIHA. Therefore it is a potentially spleen sparing strategy to consider. However, there is no evidence from a randomized clinical trial for this recommendation. The response to rituximab is slow and may take on average 1 month to manifest in a majority of responders while late responses extending up to 3-6 months have been observed. Most studies have used four weekly 375mg/m2 doses while one group has demonstrated that four infusions of 100mg of the drug can be equally effective. However, on assessing the available evidence, there is only one randomized trial that has assessed the efficacy of rituximab for wAIHA. That also has only assessed the efficacy of it as an add-on therapy to steroids and not as an independent comparison of an alternative therapeutic strategy. Still, given the rarity of the disease and the difficulty in recruiting newly diagnosed untreated patients, the evidence from this trial is very valuable to clearly point out that rituximab is efficacious as add on therapy for newly diagnosed patients. There are no other head to head comparisons of rituximab with other alternative second line therapies such as splenectomy and cytotoxic therapy. Overall, infusion of rituximab has had good safety data. Most reported adverse events were restricted to urticarial rashes and fever. However, it is noted that though very few in number, several episodes of sepsis had been reported in patients receiving rituximab. There is no firm evidence to attribute the sepsis to rituximab. Except in one occasion, all other patients were on (or had been on) multiple immunosuppressive regimens and suffered from

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underlying malignancies which would have contributed to the immunosuppression. However, this is a cautionary fact that treating physicians should remain vigilant about. The most severe potential long term complication of rituximab therapy remains progressive multifocal leukoencephalopathy (PML), which is very rare and was observed in two patients with AIHA by Carson et al [32]. Rituximab for cold autoimmune haemolytic anaemia (cAIHA) including cold agglutinin disease (CAD) The use of rituximab in the treatment of cAIHA has a special place as many strategies used for wAIHA such as steroids and splenectomy are unsuccessful for haemolysis induced by auto antibodies that bind to red cells at low temperatures. Successful use of rituximab for cAIHA and CAD is reported in several case reports and small case series [15, 16, 18, 33-38]. There are however very few case series or studies that had a cohort of more than ten patients followed up prospectively or retrospectively. It was previously opined that these patients had a “primary” immunological disorder that produced antibodies against red cell membrane receptors that binds at low temperatures. This group of patients which accounts for about 20-30% of all adult AIHA is now recognized to be secondary to a low grade lymphoproliferative disorder in approximately 90% of cases (associated with presence of monoclonal IgMk with anti-I specificity) [2]. Treatment of CAD has been restricted to supportive measures such as avoiding cold, prompt treatment of febrile illnesses and transfusion with pre warmed blood in severe cases of haemolysis. Steroids, immunosuppressive cytotoxic drugs, alkylating agents and splenectomy are largely ineffective in these patients [39]. Therefore, the traditional treatment strategy for CAD has been a “watch and wait” approach for non severe anaemia and supportive measures mentioned above

for those needing therapy. It is in this background that several recent studies have demonstrated a benefit of rituximab in transient cAIHA and CAD either administered alone or in combination with fludarabine.

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Berentsen and colleagues assessed the response to rituximab in 27 patients with chronic CAD prospectively [40]. Patients received four weekly doses of rituximab at 375mg/m2. The follow up was for at least 6 months in each patient. A complete response (CR) was defined as absence of anemia and absence of biochemical or haematological evidence of haemolysis, clinical features of CAD plus absence of a monoclonal band or clonal lymphoproliferative expansion (as assessed by bone marrow histology and flow cytometry). A partial response (PR) was defined as a stable increase of Hb > 2g/dl, transfusion independence, and clinical improvement with at least 50% reduction in the monoclonal protein. After a single round of therapy, a remission was observed in 14 patients (CR; 1, PR; 13). Ten further patients, who were either non responders or those who had a relapse after initial response, were re-treated with rituximab and another 6 partial responses were observed. Median time to response was 1.5 months. The median increase of Hb in responders was 4 g/dl. The overall response rate was 54% in this sample. When variables such as age, pre-treatment Hb, serum levels of IgM, complement proteins C3 and C4 levels, CD 20+ cell percentage in bone marrow aspirates and κ/λ light chain ratio were compared in

responders and non responders, it did not help to differentiate between the two groups. There were no adverse reactions attributable to rituximab and it was observed to be safe. A similar study by Schollkopf et al [41] which followed up 20 patients with CAD after treatment with a similar dosing regimen with rituximab showed an overall response rate of 45% (eight partial remissions and one complete remission). However, eight of these patients relapsed and only one maintained a remission (median duration of response was 6.5 months). The criteria for complete and partial remission were similar to the criteria of the study above except that an improvement of 1g/dl in haemoglobin was considered adequate to define a partial response in this study. Median time to maximal response was 3 months (range 1-5 months). Again there were no severe side effects thought to be due to rituximab and minor reactions such as transient fever, nausea, diarrhoea and dizziness occurred in some patients.

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The previously mentioned study in the section on wAIHA by Dierickx et al[24] also had 14 patients with CAD and they demonstrated an overall response rate of 64% (9/14, 4 with CR and 5 with PR). The overall response for the subgroup with wAIHA was 83%. Still in this study the diagnosis of CAD or wAIHA did not predict a response to rituximab. Also in the previously mentioned study by Penalvar et al[25], 6 out of 9 patients with CAD responded to rituximab therapy and this response was in par with the response patients with wAIHA had to rituximab. In the already mentioned trial by Barcellini and colleagues of low dose rituximab infusions for AIHA, the response to cAIHA was 60% (6 out of 9 patients) compared to a 100% response rate to wAIHA at two months [27, 42]. The estimated relapse free survival at 2 years was 40% for CAD while it was 81% for wAIHA. Follow up of this cohort with later recruitments (a total of 14 patients with CAD) showed that response to rituximab in CAD was less impressive than that for wAIHA and the relapse risk was greater though not statistically significant [28]. A more recently published study has assessed the place of combined therapy with rituximab and fludarabine (a purine analog) [43]. Patients received four doses of 375mg/m2 of rituximab at monthly intervals and 40mg/m2 fludarabine for 4 days after each infusion of rituximab (four courses altogether). The definitions of partial and complete responses were as indicated above [40]. The overall response rate in this cohort was 76% with 6 CRs (21%) and 16 PRs (55%). This was a marked improvement compared to previous studies which used rituximab monotherapy. Median time to maximum response was 4 months and the median increment in Hb was 3.1 g/dl [43]. It is interesting that in ten patients who on an earlier occasion had received rituximab monotherapy and failed to respond, there was a 60% response rate to combined therapy (1 CR and 5 PRs). The duration of follow up ranged from 3-66 months and at the median follow up point of 33 months, 5 patients had relapsed while 17 patients maintained remission. A marginal negative correlation was observed between responders and non responders with regard to their age and κ/λ light chain ratio of bone marrow at the beginning. There

was no correlation for IgM levels, complement protein C4 level, pre treatment Hb level or cold 14

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agglutinin titer. The addition of fludarabine to the treatment regimen warrants a closer look at reported adverse events in this cohort. There were a substantial number of cytopenias that were asymptomatic. However, 14% of participants had a severe cytopenia attributable to fludarabine therapy. Overall, fludarabine therapy was reduced or discontinued in 13 (45%) patients. There were 3 episodes of significant haemolysis during therapy which had caused concern as fludarabine is known to induce a haemolysis. However, the authors attribute it to concurrent infections (high CRP and haemolysis responding to antimicrobial therapy) rather than fludarabine[43].

Overall, there are only a few prospective studies that have evaluated a cohort of patients over ten in number with regard to rituximab treatment in cAIHA/CAD. All of these studies have considered patients with CAD which is now identified as being secondary to a clonal lymphoproliferative disorder. The response to rituximab is less impressive compared to that of wAIHA and this fact is highlighted in three studies that had two cohorts of CAD and wAIHA patients followed up in parallel. Only one study reported that there was no significant difference in response rates while others suggested that it to be comparatively low for CAD. The studies report an overall response rate of 45 – 66% with a median time to response exceeding 1.5 months at least. Complete remissions were rare with rituximab monotherapy and most responses were classified as partial responses. It must be noted that the criteria for defining a complete and a partial response showed better uniformity than that of the studies assessing wAIHA (partly due to the fact that two studies involving the biggest cohorts to date were carried out by the same group) [40, 43]. The addition of fludarabine to rituximab treatment regimen in one study has

markedly improved the overall response rate to 76% and managed to induce remissions in patients who did not initially respond to monotherapy with rituximab. However, the toxicity of the combined regimen may cause concern as a significant proportion developed severe cytopenias. There are no randomized trials using rituximab for CAD but evidence from these single arm studies may be adequate to

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recommend it as an effective therapy for CAD as there is no effective therapy other than rituximab for comparison. Rituximab for mixed AIHA and paroxysmal cold haemoglobinuria (PCH) The use of rituximab for these rare entities has only been reported in individual cases. Usually patients

with mixed AIHA have auto antibodies of both IgG and IgM subclasses which are reactive in a wide thermal range. The disease responds to steroids but has a long protracted clinical course. Morselli et al.[17] described a 68 year old woman with mixed AIHA (primary) who responded well to steroids but relapsed when prednisolone was tapered off. She responded well to rituximab (375mg/m2) four doses administered at weekly intervals. After two cycles of therapy (8 doses) she remained in remission for a follow up of 7 months at the time of reporting the case. Granel and colleagues have also reported a case of successful treatment with rituximab for a 19 year old woman with mixed AIHA in a background of mixed connective tissue disorder [44]. This patient showed a good response to steroids but relapsed when the dose was tapered. She responded fully to two courses of rituximab (8 doses, same as in the case report by Morselli et al.) and remained in remission for one year (with low dose steroids) at the time of reporting the case. Gupta and colleagues have also reported a case of complete remission of mixed AIHA (unresponsive to steroids) with a single course (four doses at weekly intervals) of rituximab [45]. The patient remained in remission for two years at the time of reporting the case. Use of rituximab in PCH has only been reported in a single case report by Koppel et al [46]. PCH is also a difficult disease to treat with steroids and splenectomy being ineffective in general. This case report describes a 64 year old woman with haemoglobin of 6 g/dl with biochemical evidence of haemolysis and Donath Landsteiner antibody positivity. She responded well to a course of four doses of weekly rituximab of 375mg/m2 and remained in remission for 8 months. A second episode of haemolysis was

treated with another course of rituximab. The patient remained in remission during a 19 month follow 16 This article is protected by copyright. All rights reserved.

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up with normalized haemoglobin, DAT negativity and Donath Landsteiner antibody negativity. There are no other reports to assess the efficacy of rituximab in this rare haematological disorder. Scope for randomized controlled trials on rituximab The evidence from “off- label” use of rituximab for AIHA seems promising. However, designing clinical trials to establish the efficacy of rituximab with better quality evidence is a challenge for several reasons. AIHA are a diverse group of diseases with considerable heterogeneity among patients with “primary” and secondary causes. Certain secondary causes such as haematological malignancies may increase the theoretical risk of sepsis with B cell depleting therapy though in practice it has not been observed convincingly. Rituximab therapy is considerably expensive compared to standard glucocorticoid therapy which is the common first line therapy in wAIHA. Therefore, trials designed to observe a potential benefit of rituximab as first line therapy will have ethical issues in trying to justify a reasonably efficacious and cheap therapy (steroids) against a relatively untested expensive treatment option if a head to head comparison is planned. However, designing a clinical trial for using rituximab as a second line therapy in patients who have failed to respond to steroids and as primary therapy in patients with cAIHA should be less of an ethical dilemma as effective alternative treatment strategies are limited. Especially in the case of wAIHA, the efficacy of rituximab vs. splenectomy should be evaluated as the latter is invasive, costly and leaves the patient with life-time vulnerability to overwhelming sepsis. Designing a randomized controlled trial with an adequate sample size (allowing better statistical power) will be difficult as refractory wAIHA / cAIHA are rare. It is also important that future clinical trials compare low dose rituximab vs. standard dose therapy as several studies have shown that low doses (less than one third of the standard dose) are as effective as standard doses for wAIHA.

Summary and conclusions

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a) For warm autoimmune haemolytic anaemia; rituximab therapy has been proven effective as second line therapy in prospective and retrospective single arm studies with response rates varying from 64 – 100% in individual cohorts. A single randomized controlled trial has demonstrated that rituximab in combination with steroids is superior to monotherapy with steroids. Recommendation; Rituximab may be considered as a second-line option as monotherapy or combined therapy in wAIHA. It can also be used as a first line therapy in combination with steroids for newly diagnosed patients.

b) For cold agglutinin disease treatment with rituximab has yielded an overall response rate of 4566% in different cohorts. This is a significant response in the absence of alternative therapy for symptomatic patients. Combination with fludarabine is likely to improve the response rate but may cause significant cytopenias. Recommendation; treatment with rituximab should be considered in symptomatic patients with CAD and those with significant haemolysis.

c) There is insufficient data to recommend Rituximab for mixed autoimmune haemolytic anaemias and PCH. However, case reports suggest that it may be useful.

List of abbreviations Abbreviations are explained where they are first used in text

Competing interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organization for the submitted work; no financial relationships with any

18 This article is protected by copyright. All rights reserved.

Accepted Article

organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work

Author contributions LG conceptualized the review. CR did the initial literature search. All authors assessed the abstracts for suitability and contributed to data extraction. CR wrote the initial draft. All authors approved the read, corrected and approved the final draft.

Author information CR (MBBS, MD) is a lecturer in Medicine, Department of Clinical Medicine, Faculty of Medicine, University of Colombo. LG ( MBBS, MD, FRCPath) is Senior Lecturer and Consultant Haematologist attached to the Department of Pathology, Faculty of Medicine, University of Colombo. . SR (MBBS, MD, FACP, FRCP, FRCPE, FCCP) is Professor in Medicine, Faculty of Medicine, University of Colombo.

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Accepted Article Tables

Table 1. Summary of studies included in the review Study

Study design and

Definition of a

sample size

response

Response rates

Warm autoimmune haemolytic anaemia Zecca et al. 2003[19]

Narat et al. 2005[20]

Prospective single arm

1.5 g/dl increment in

87%, median follow up;

study of 15 children

haemoglobin (Hb) with

14 months (range 7-28

with refractory AIHA

a 50% reduction in

months)

absolute reticulocyte

Median age; 2 years

count observed within 2

(range: 0.3 -14)

months of rituximab Rituximab 375mg/m2

administration

2-4 weekly doses Retrospective analysis

Complete response

Overall response rate:

of 11 adults with

(CR): Hb level above 13

63.6% (CR: 3/11, PR:

chronic wAIHA

g/dl (for males) and 12

4/11)

g/dl (for females)

Mean age 52 years;

without further

range 26-81

evidence of haemolysis Rituximab 375mg/m

2

Median duration of response : 11 months (range 2.5 – 20)

while off all therapy for

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Accepted Article

D’Arena et al. 2006[21]

four doses weekly

at least 4 weeks after rituximab Partial response (PR): A stable haemoglobin increment of 2g/dl and discontinuation of other immunosuppression

Prospective study of 14

C R: normalization of

Overall response rate:

adult patients with

hemoglobin levels,

71.4% (CR: 3/14, PR:

secondary AIHA to CLL

transfusion-free and

7/14)

Mean age: 68 years (range 48 -87)

absence of clinical and laboratory signs of haemolysis

Rituximab 375mg/m2 four doses weekly (as second line therapy after steroids)

PR: rise in hemoglobin levels > 2 g/dl, transfusion-free either without or reduced need for transfusion requirement, and improvement of clinical and laboratory

26 This article is protected by copyright. All rights reserved.

Accepted Article

Bussone et al. 2009[23]

Dierickx et al. 2009[24]

signs of haemolysis Retrospective analysis

CR: Hb level >11 g/dL in

Overall response rate:

of 27 patients with

women or 12 g/dL in

93% (CR: 8/27, PR:

wAIHA

men without

17/27)

Mean age ± SD; 49.7 ± 21 years Rituximab 375mg/m2 weekly, four doses (as second line or later treatment)

haemolysis while off treatment PR: Hb level >10 g/dL with at least a 2 g/dL increase from the pretreatment level with persistent features of haemolysis

Retrospective analysis

CR: normalization of Hb

Overall response rate

of 53 patients with

level without further

for wAIHA group: 83.3%

AIHA (36 with wAIHA)

evidence of haemolysis,

(75% in rituximab

without

monotherapy group

immunosuppression

who received only

Median age; 65 years, range 1-87 (for the entire group) Rituximab 375mg/m2 weekly, four doses (as second line or later

PR: independence from further transfusions (in a previously transfusion dependent patient) or stable increment of Hb

rituximab without coadministered other immunosuppressants) CR: 18/36, PR: 12/36 Median follow up : 15

27 This article is protected by copyright. All rights reserved.

Accepted Article

Penalver et al. 2010[25]

Maung et al. 2013[26]

treatment)

by 2g/dl

months

Retrospective analysis

CR: nontransfused

CR rate for wAIHA:

of 36 patients with

haemoglobin level >12

61.5% (16/26)

AIHA (27 patients with

g/dl and hemoglobin

wAIHA)

increase of at least >2

Median age; 64 years (range 20-86)

Median follow up : 15 months (range 6-86)

g/dl above their pretreatment haemoglobin level with

Rituximab 375mg/m2 weekly, four doses (as second line or later treatment)

the discontinuation of concomitant immunosuppressive therapies PR: nontransfused hemoglobin level >10 g/dL and hemoglobin increase of at least 2 g/dL above their pretreatment hemoglobin levels

Retrospective single

CR: normalization of Hb, Overall response: 70.6%

arm study of 34

bilirubin and/or LDH

patients with wAIHA

sustained for at least 6

CR: 9/34, PR: 15/34

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Accepted Article

Median age: 59 years (range 14-83)

PR: increase in Hb of 2

Rituximab 375mg/m2

g/dl from baseline or

weekly, four doses (as

maintenance of Hb

second line or later

above 10 g/dl for at

treatment)

least 6 months posttreatment

Barcellini et al. 2012[27] Prospective single arm

Birgens et al. 2013[31]

months

CR: Hb > 12g/dl with

Overall response for

study of 23 AIHA

normal markers of

wAIHA was 100% at 12

patients (14 wAIHA)

haemolysis

months follow up for 13

Mean age: 46.5 years

PR: Hb 10-12 g/dl or at

(range 25-75)

least 2 g/dl increase in

CR: 9/13, PR: 4/13 at 12

Hb, and no transfusion

months

Rituximab weekly 100mg infusions, four

patients

requirement

doses Phase III randomized

CR: normalization of

Only CR or non

controlled trial of 64

haemoglobin levels

responders observed at

patients with wAIHA

without any ongoing

12 months

haemolytic activity

Trial arm (n-32):

enabling stopping of

prednisolone and rituximab 375mg/m

CR in trial arm: 75%

2

immunosuppressants

CR in test arm: 36%

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Accepted Article

weekly, four doses Control arm (n-32): prednisolone only

PR: similar to CR except

P = 0.02

that patients required a low dose of prednisolone (< 10mg/day) to maintain the response (or tolerated a compensated state of haemolytic anaemia that did not require more than 10mg of daily prednisolone to maintain a normal haemoglobin level)

Cold autoimmune haemolytic anaemia including cold agglutinin disease (CAD) Berentsen et al.

Prospective single arm

CR: absence of anemia

Overall response rate:

2004[40]

study of 27 patients

and absence of

54% (counted as total

with CAD

biochemical or

number of responses

haematological

over number of

evidence of haemolysis,

rituximab courses given

clinical features of CAD

as some patients were

plus absence of a

retreated)

Mean age: 71 years (range: 51-91) Rituximab 375mg/m2 weekly, four doses and

30 This article is protected by copyright. All rights reserved.

Accepted Article

retreated as necessary

monoclonal band or

CR: 1/27, PR: 19/27

clonal lymphoproliferative expansion (as assessed by bone marrow histology and flow cytometry) PR: a stable increase of Hb > 2g/dl, transfusion independence, and clinical improvement with at least 50% reduction in the monoclonal protein

Schollkopf et al.

Prospective single arm

CR: normalization of Hb, Overall response rate:

2006[41]

study of 20 patients

absence of clinical

with CAD

features of CAD and

Median age: 75 years (range 54-86) Rituximab 375mg/m2 weekly, four doses and retreated as necessary

45% CR: 1/20, PR: 8/20

absence of features of haemolysis

Median duration of response: 6.5 months

PR: increase in haemoglobin levels >1.0 g/dl for a minimum of 1

31 This article is protected by copyright. All rights reserved.

Accepted Article

Dierickx et al. 2009[24]

Penalver et al. 2010[25]

month, no need of erythrocyte transfusions, improvement of clinical CAD-related symptoms and, in the case of an elevated serum IgM concentration, at least a 50% reduction Retrospective analysis

Please see above

of 53 patients with

Overall response rate for cAIHA : 64%

AIHA (14 with cAIHA)

CR: 4/14, PR: 5/14

Other details described above Retrospective analysis

Please see above

of 36 patients with

Overall response for cAIHA: 66.6%

AIHA (9 patients with

Median duration of

cAIHA)

response: 21 months

Please see above for

(range 17-36 months)

other details

Barcellini et al. 2012[27] Prospective single arm study of 23 AIHA

Please see above

Relapse free maintained response rate at 2 year

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Accepted Article

patients (9 with cAIHA)

follow up: 40%

Please see above for other details

Berentsen et al.

A prospective single

As mentioned in

Overall response rate:

2010[43]

arm study of combined

Berentsen et al.

76%

therapy with rituximab

2004[40]

CR: 6/29, PR: 16/29

and fludarabine for 29 patients with CAD Dosing : four doses of 375mg/m2 of rituximab at monthly intervals and 40mg/m2 fludarabine for 4 days after each infusion of rituximab

33 This article is protected by copyright. All rights reserved.

Rituximab in the treatment of autoimmune haemolytic anaemia.

Rituximab is a B-cell depleting monoclonal antibody that is gaining popularity as an effective therapy for many autoimmune cytopenias. This article sy...
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