Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2015 Apr 22;79(5):709–719. doi: 10.1111/bcp.12498

Rituximab in the treatment of autoimmune haemolytic anaemia

Chaturaka Rodrigo 1,✉, Senaka Rajapakse 1, Lallindra Gooneratne 2
PMCID: PMC4415708  PMID: 25139610

Abstract

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.

Keywords: autoimmune haemolytic anaemia, cold agglutinin disease, rituximab

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 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. A population-based study revealed the incidence of AIHA to be 0.8/100 000 year−1, but the prevalence is 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 (4°C). They may act merely as agglutinins (CAD) or as agglutinins and lysins. The first instance where rituximab had been tried for CAD 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 375 mg m−2 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 level improved to 12.3 g dl−1 from 8.4 g dl−1 6. In the same year Quartier et al. reported five 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 CAD and mixed type anaemias 15–18. This established its role as a potentially successful therapy for refractory autoimmune haemolytic anaemias and especially CAD where previously no specific therapy was available. This led to the design 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 1.

Table 1.

Summary of studies included in the review

Study Study design and sample size Definition of a response Response rates
Warm autoimmune haemolytic anaemia
Zecca et al. 2003 [19] Prospective single arm study of 15 children with refractory AIHA 1.5 g dl−1 increment in haemoglobin (Hb) with a 50% reduction in absolute reticulocyte count observed within 2 months of rituximab administration 87%, median follow-up; 14 months (range 7–28 months)
Median age 2 years (range 0.3 −14)
Rituximab 375 mg m−2
2–4 weekly doses
Narat et al. 2005 [20] Retrospective analysis of 11 adults with chronic wAIHA Complete response (CR): Hb level above 13 g dl−1 (for males) and 12 g dl−1 (for females) without further evidence of haemolysis while off all therapy for at least 4 weeks after rituximab Overall response rate: 63.6% (CR: 3/11, PR: 4/11)
Mean age 52 years (range 26–81) Median duration of response : 11 months (range 2.5–20)
Rituximab 375 mg m−2 four doses weekly
Partial response (PR): A stable Hb increment of 2 g dl−1 and discontinuation of other immunosuppression
D'Arena et al. 2006 [21] Prospective study of 14 adult patients with secondary AIHA to CLL C R: normalization of Hb levels, transfusion-free and absence of clinical and laboratory signs of haemolysis Overall response rate: 71.4% (CR: 3/14, PR: 7/14)
Mean age 68 years (range 48−87)
Rituximab 375 mg m−2 four doses weekly (as second line therapy after steroids) PR: rise in Hb levels >2 g dl−1, transfusion-free either without or reduced need for transfusion requirement, and improvement of clinical and laboratory signs of haemolysis
Bussone et al. 2009 [23] Retrospective analysis of 27 patients with wAIHA CR: Hb level >11 g dl−1 in women or 12 g dl−1 in men without haemolysis while off treatment Overall response rate: 93% (CR: 8/27, PR: 17/27)
Mean age ± SD 49.7 ± 21 years PR: Hb level >10 g dl−1 with at least a 2 g dl−1 increase from the pretreatment level with persistent features of haemolysis
Rituximab 375 mg m−2 weekly, four doses (as second line or later treatment)
Dierickx et al. 2009 [24] Retrospective analysis of 53 patients with AIHA (36 with wAIHA) CR: normalization of Hb level without further evidence of haemolysis, without immunosuppression Overall response rate for wAIHA group: 83.3% (75% in rituximab monotherapy group who received only rituximab without co-administered other immunosuppressants)
Median age 65 years, range 1–87 (for the entire group) PR: independence from further transfusions (in a previously transfusion dependent patient) or stable increment of Hb by 2 g dl−1 CR: 18/36, PR: 12/36
Rituximab 375 mg m−2 weekly, four doses (as second line or later treatment) Median follow-up: 15 months
Penalver et al. 2010 [25] Retrospective analysis of 36 patients with AIHA (27 patients with wAIHA) CR: non-transfused Hb level >12 g dl−1 and Hb increase of at least >2 g dl−1 above their pretreatment Hb level with the discontinuation of concomitant immunosuppressive therapies CR rate for wAIHA: 61.5% (16/26)
Median age 64 years (range 20–86) Median follow-up : 15 months (range 6–86)
Rituximab 375 mg m−2 weekly, four doses (as second line or later treatment)
PR: non-transfused Hb level >10 g dl−1 and Hb increase of at least 2 g dl−1 above their pretreatment Hb levels
Maung et al. 2013 [26] Retrospective single arm study of 34 patients with wAIHA CR: normalization of Hb, bilirubin and/or LDH sustained for at least 6 months Overall response: 70.6%
Median age 59 years (range 14–83) PR: increase in Hb of 2 g dl−1 from baseline or maintenance of Hb above 10 g dl−1 for at least 6 months post-treatment CR: 9/34, PR: 15/34
Rituximab 375 mg m−2 weekly, four doses (as second line or later treatment)
Barcellini et al. 2012 [27] Prospective single arm study of 23 AIHA patients (14 wAIHA) CR: Hb >12 g dl−1 with normal markers of haemolysis Overall response for wAIHA was 100% at 12 months follow up for 13 patients
Mean age 46.5 years (range 25–75) PR: Hb 10–12 g dl−1 or at least 2 g dl−1 increase in Hb, and no transfusion requirement CR: 9/13, PR: 4/13 at 12 months
Rituximab weekly 100 mg infusions, four doses
Birgens et al. 2013 [31] Phase III randomized controlled trial of 64 patients with wAIHA CR: normalization of Hb levels without any ongoing haemolytic activity enabling stopping of immunosuppressants Only CR or non-responders observed at 12 months
Trial arm (n = 32): prednisolone and rituximab 375 mg m−2 weekly, four doses PR: similar to CR except that patients required a low dose of prednisolone (<10 mg day−1) to maintain the response (or tolerated a compensated state of haemolytic anaemia that did not require more than 10 mg of daily prednisolone to maintain a normal Hb level) CR in trial arm: 75%
Control arm (n = 32): prednisolone only
CR in test arm: 36%
P = 0.02
Cold autoimmune haemolytic anaemia including cold agglutinin disease (CAD)
Berentsen et al. 2004 [40] Prospective single arm study of 27 patients with CAD CR: absence of anaemia 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) Overall response rate: 54% (counted as total number of responses over number of rituximab courses given as some patients were retreated)
Mean age 71 years (range 51–91) CR: 1/27, PR: 19/27
Rituximab 375 mg m−2 weekly, four doses and retreated as necessary
PR: a stable increase of Hb >2 g dl−1, transfusion independence, and clinical improvement with at least 50% reduction in the monoclonal protein
Schollkopf et al. 2006 [41] Prospective single arm study of 20 patients with CAD CR: normalization of Hb, absence of clinical features of CAD and absence of features of haemolysis Overall response rate: 45%
Median age 75 years (range 54–86) CR: 1/20, PR: 8/20
Rituximab 375 mg m−2 weekly, four doses and retreated as necessary PR: increase in Hb levels >1.0 g dl−1 for a minimum of 1 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 Median duration of response: 6.5 months
Dierickx et al. 2009 [24] Retrospective analysis of 53 patients with AIHA (14 with cAIHA) Please see above Overall response rate for cAIHA: 64%
Other details described above CR: 4/14, PR: 5/14
Penalver et al. 2010 [25] Retrospective analysis of 36 patients with AIHA (nine patients with cAIHA) Please see above Overall response for cAIHA: 66.6%
Please see above for other details Median duration of response: 21 months (range 17–36 months)
Barcellini et al. 2012 [27] Prospective single arm study of 23 AIHA patients (nine with cAIHA) Please see above Relapse free maintained response rate at 2 years follow-up: 40%
Please see above for other details
Berentsen et al. 2010 [43] A prospective single arm study of combined therapy with rituximab and fludarabine for 29 patients with CAD As mentioned in Berentsen et al. 2004 40 Overall response rate: 76%
Dosing : four doses of 375 mg m−2 of rituximab at monthly intervals and 40 mg m−2 fludarabine for 4 days after each infusion of rituximab CR: 6/29, PR: 16/29
Open in a new tab

Rituximab for warm autoimmune haemolytic anaemia (wAIHA)

While there are several case reports and case series of the 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 10 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 (i.v. methylprednisolone, oral prednisolone, i.v. immunoglobulin, azathioprine and ciclosporin A) prior to enrolment and two had undergone splenectomy without success. Rituximab was administered in a dose of 375 mg m−2 weekly with a total of two to four doses. The median follow-up for all patients was 14 months (range 7–28 months). The authors concluded that of the total series, 13 out of 15 (87%) responded to treatment. Response was defined as a 1.5 g dl−1 rise in haemoglobin and a 50% reduction of the total reticulocyte count at 2 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 11 patients (mean age 52 years; range 26–81) with wAIHA treated with four doses of weekly 375 mg m−2 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 2 g dl−1 and discontinuation of other immunosuppressives while a complete response was a haemoglobin level above 13 g dl−1 (for males) or 12 g dl−1 (females) without further episodes of haemolysis. At the time of rituximab administration the patients continued other means of immunosuppression (prednisolone, cyclophosphamide) but in responders they were tapered off. It was 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 had steroids and a 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 with wAIHA secondary to CLL, D'Arena and colleagues21 reported a response rate of 71.4% (12 out of 14) to four cycles of rituximab at a weekly dose of 375 mg m−2. The mean increment of haemoglobin was 3.6 g dl−1 (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 (375 mg m−2 weekly up to eight doses). Response rate (defined as maintaining a haemoglobin level above 10 g dl−1 with a reduction in lactate dehydrogenase levels and a rise in serum haptoglobin levels >0.3 g l−1) 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.

In a retrospective analysis of 27 patients with wAIHA (primary 17, secondary 10, mean age 49 ± 21 years), Bussone and colleagues have demonstrated response in 25 (93%) patients 23. There were eight full (haemoglobin level >11 g dl−1 in women or 12 g dl−1 in men without haemolysis while off treatment) and 15 partial (haemoglobin level >10 g dl−1 with at least a 2 g dl−1 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 (375 mg m−2). 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 years) 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). 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 level without further episodes of haemolysis (complete response) or independence from further transfusions (in a previously transfusion dependent patient)/stable increment of haemoglobin by 2 g dl−1 (partial response). A similar retrospective analysis of treatment refractory AIHA in 36 (27 wAIHA and nine 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 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 375 mg m−2, four weekly doses) showed 71% response rate (24 out of 34 patients) 26. Among responders, 87% showed a response within 1 month of starting treatment while the remainder showed a response by 3 months. However, of all responders half had relapsed during follow-up but had a considerable period between initial treatment and relapse (mean 16.5 months). 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 years) response was assessed for four times weekly 100 mg infusions of rituximab. The median time of follow-up was 15 months (range 6–35 months). The response for wAIHA was 100% at 2 months (haemoglobin above 12 g dl–1 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 CAD as well, sustained response to rituximab at 6 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 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 the 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 haemoglobin levels was maintained at 24 and 36 months of follow-up 28. However it must be noted that data were only available for 12 and seven 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 (10 mg subcutaneously for 3 days) was shown to be effective for a 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 (four times weekly 100 mg 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 vs. combined therapy with rituximab (plus steroids) for patients with wAIHA 31. They prospectively recruited 64 patients with wAIHA and randomized them into the two treatment groups of equal size (n = 32). The enrolled patients were newly diagnosed patients with either primary or secondary wAIHA who might have received steroids at the time of enrolment for a duration not exceeding 1 week. All patients received a starting dose of oral prednisolone 1.5 mg kg−1 day−1 and the test group received four weekly infusions of rituximab at a dose of 375 mg m−2. 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 prednisolone (<10 mg day−1) to maintain the response (or tolerated a compensated state of haemolytic anaemia that did not require more than 10 mg 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 with the 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 3 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 the combined treatment group and 36% in the prednisolone only group, P = 0.02). The number of non-responders who 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 and an adequately powered clinical trial is needed for a better and accurate estimate. Heterogeneity of patients (primary wAIHA and secondary causes) and 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 were extensive and were beyond 6 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 who 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 375 mg m−2 doses while one group has demonstrated that four infusions of 100 mg 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 have been reported in patients receiving rituximab. There is no firm evidence to attribute the sepsis to rituximab. Except on one occasion, all other patients were on (or had been on) multiple immunosuppressive regimens and suffered from 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 10 patients followed up prospectively or retrospectively.

It was previously thought 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 prewarmed 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 the 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.

Berentsen and colleagues assessed the response to rituximab in 27 patients with chronic CAD prospectively 40. Patients received four weekly doses of rituximab at 375 mg m−2. The follow-up was for at least 6 months in each patient. A complete response (CR) was defined as absence of anaemia 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 haemoglobin >2 g dl−1, 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 six partial responses were observed. Median time to response was 1.5 months. The median increase of haemoglobin in responders was 4 g dl−1. The overall response rate was 54% in this sample. When variables such as age, pre-treatment haemoglobin, 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 1 g dl−1 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.

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, four with CR and five 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, six out of nine patients with CAD responded to rituximab therapy and this response was on a 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% (six out of nine patients) compared with a 100% response rate to wAIHA at 2 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 analogue) 43. Patients received four doses of 375 mg m−2 of rituximab at monthly intervals and 40 mg m−2 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 six CRs (21%) and 16 PRs (55%). This was a marked improvement compared with previous studies which used rituximab monotherapy. Median time to maximum response was 4 months and the median increment in haemoglobin was 3.1 g dl−1 43. It is interesting that in 10 patients who on an earlier occasion had received rituximab monotherapy and failed to respond, there was a 60% response rate to combined therapy (one CR and five PRs). The duration of follow-up ranged from 3–66 months and at the median follow-up point of 33 months, five 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, pretreatment haemoglobin level or cold agglutinin titre. 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 three episodes of significant haemolysis during therapy which had caused concern as fludarabine is known to induce a haemolysis. However, the authors attributed 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 10 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 with 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 it to be comparatively low for CAD. The studies reported 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 the 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 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 (375 mg m−2) four doses administered at weekly intervals. After two cycles of therapy (eight 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 (eight doses, same as in the case report by Morselli et al.) and remained in remission for 1 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 2 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 described a 64 year old woman with haemoglobin of 6 g dl−1 with biochemical evidence of haemolysis and Donath Landsteiner antibody positivity. She responded well to a course of four doses of weekly rituximab of 375 mg m−2 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 months follow-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 with 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

  1. For wAIHA; 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.

  2. For CAD treatment with rituximab has yielded an overall response rate of 45–66% 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.

  3. There are insufficient data to recommend rituximab for mixed autoimmune haemolytic anaemias and PCH. However, case reports suggest that it may be useful.

Competing Interests

All authors have completed the Unified Competing Interest form at http://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 organizations that might have an interest in the submitted work in the previous 3 years and 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 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.

References

  1. Abdulla NE, Ninan MJ, Markowitz AB. Rituximab: current status as therapy for malignant and benign hematologic disorders. BioDrugs. 2012;26:71–82. doi: 10.2165/11599500-000000000-00000. [DOI] [PubMed] [Google Scholar]
  2. Michel M. Classification and therapeutic approaches in autoimmune hemolytic anemia: an update. Expert Rev Hematol. 2011;4:607–618. doi: 10.1586/ehm.11.60. [DOI] [PubMed] [Google Scholar]
  3. Garvey B. Rituximab in the treatment of autoimmune haematological disorders. Br J Haematol. 2008;141:149–169. doi: 10.1111/j.1365-2141.2008.07054.x. [DOI] [PubMed] [Google Scholar]
  4. Lechner K, Jager U. How I treat autoimmune hemolytic anemias in adults. Blood. 2010;116:1831–1838. doi: 10.1182/blood-2010-03-259325. [DOI] [PubMed] [Google Scholar]
  5. Lee EJ, Kueck B. Rituxan in the treatment of cold agglutinin disease. Blood. 1998;92:3490–3491. [PubMed] [Google Scholar]
  6. Ahrens N, Kingreen D, Seltsam A, Salama A. Treatment of refractory autoimmune haemolytic anaemia with anti-CD20 (rituximab) Br J Haematol. 2001;114:244–245. doi: 10.1046/j.1365-2141.2001.02873-4.x. [DOI] [PubMed] [Google Scholar]
  7. Quartier P, Brethon B, Philippet P, Landman-Parker J, Le Deist F, Fischer A. Treatment of childhood autoimmune haemolytic anaemia with rituximab. Lancet. 2001;358:1511–1513. doi: 10.1016/s0140-6736(01)06573-4. [DOI] [PubMed] [Google Scholar]
  8. Zecca M, De Stefano P, Nobili B, Locatelli F. Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia. Blood. 2001;97:3995–3997. doi: 10.1182/blood.v97.12.3995. [DOI] [PubMed] [Google Scholar]
  9. Motto DG, Williams JA, Boxer LA. Rituximab for refractory childhood autoimmune hemolytic anemia. Isr Med Assoc J. 2002;4:1006–1008. [PubMed] [Google Scholar]
  10. Galor A, O'Brien T. Rituximab treatment for relapsed autoimmune hemolytic anemia in Evans syndrome. Int J Hematol. 2003;78:335–336. doi: 10.1007/BF02983558. [DOI] [PubMed] [Google Scholar]
  11. Gottardo NG, Baker DL, Willis FR. Successful induction and maintenance of long-term remission in a child with chronic relapsing autoimmune hemolytic anemia using rituximab. Pediatr Hematol Oncol. 2003;20:557–561. doi: 10.1080/08880010390232781. [DOI] [PubMed] [Google Scholar]
  12. Quinn JP, Gilligan OM, Horgan M. Evan's syndrome complicating multicentric Castleman's disease – dramatic response to rituximab. Eur J Haematol. 2004;73:384–385. doi: 10.1111/j.1600-0609.2004.00302.x. [DOI] [PubMed] [Google Scholar]
  13. Paydas S. Fludarabine-induced hemolytic anemia: successful treatment by rituximab. Hematol J. 2004;5:81–83. doi: 10.1038/sj.thj.6200339. [DOI] [PubMed] [Google Scholar]
  14. Gupta N, Kavuru S, Patel D, Janson D, Driscoll N, Ahmed S, Rai KR. Rituximab-based chemotherapy for steroid-refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia. Leukemia. 2002;16:2092–2095. doi: 10.1038/sj.leu.2402676. [DOI] [PubMed] [Google Scholar]
  15. Engelhardt M, Jakob A, Ruter B, Trepel M, Hirsch F, Lubbert M. Severe cold hemagglutinin disease (CHD) successfully treated with rituximab. Blood. 2002;100:1922–1923. doi: 10.1182/blood-2002-04-1213. [DOI] [PubMed] [Google Scholar]
  16. Mori A, Tamaru J, Sumi H, Kondo H. Beneficial effects of rituximab on primary cold agglutinin disease refractory to conventional therapy. Eur J Haematol. 2002;68:243–246. doi: 10.1034/j.1600-0609.2002.01667.x. [DOI] [PubMed] [Google Scholar]
  17. Morselli M, Luppi M, Potenza L, Tonelli S, Dini D, Leonardi G, Donelli A, Narni F, Torelli G. Mixed warm and cold autoimmune hemolytic anemia: complete recovery after 2 courses of rituximab treatment. Blood. 2002;99:3478–3479. doi: 10.1182/blood-2002-01-0018. [DOI] [PubMed] [Google Scholar]
  18. Zaja F, Iacona I, Masolini P, Russo D, Sperotto A, Prosdocimo S, Patriarca F, de Vita S, Regazzi M, Baccarani M, Fanin R. B-cell depletion with rituximab as treatment for immune hemolytic anemia and chronic thrombocytopenia. Haematologica. 2002;87:189–195. [PubMed] [Google Scholar]
  19. Zecca M, Nobili B, Ramenghi U, Perrotta S, Amendola G, Rosito P, Jankovic M, Pierani P, De Stefano P, Bonora MR, Locatelli F. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood. 2003;101:3857–3861. doi: 10.1182/blood-2002-11-3547. [DOI] [PubMed] [Google Scholar]
  20. Narat S, Gandla J, Hoffbrand AV, Hughes RG, Mehta AB. Rituximab in the treatment of refractory autoimmune cytopenias in adults. Haematologica. 2005;90:1273–1274. [PubMed] [Google Scholar]
  21. D'Arena G, Laurenti L, Capalbo S, D'Arco AM, De Filippi R, Marcacci G, Di Renzo N, Storti S, Califano C, Vigliotti ML, Tarnani M, Ferrara F, Pinto A. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol. 2006;81:598–602. doi: 10.1002/ajh.20665. [DOI] [PubMed] [Google Scholar]
  22. Heidel F, Lipka DB, von Auer C, Huber C, Scharrer I, Hess G. Addition of rituximab to standard therapy improves response rate and progression-free survival in relapsed or refractory thrombotic thrombocytopenic purpura and autoimmune haemolytic anaemia. Thromb Haemost. 2007;97:228–233. doi: 10.1160/th06-09-0499. [DOI] [PubMed] [Google Scholar]
  23. Bussone G, Ribeiro E, Dechartres A, Viallard JF, Bonnotte B, Fain O, Godeau B, Michel M. Efficacy and safety of rituximab in adults' warm antibody autoimmune haemolytic anemia: retrospective analysis of 27 cases. Am J Hematol. 2009;84:153–157. doi: 10.1002/ajh.21341. [DOI] [PubMed] [Google Scholar]
  24. Dierickx D, Verhoef G, Van Hoof A, Mineur P, Roest A, Triffet A, Kentos A, Pierre P, Boulet D, Bries G, Le PQ, Janssens A, Delannoy A. Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study. J Intern Med. 2009;266:484–491. doi: 10.1111/j.1365-2796.2009.02126.x. [DOI] [PubMed] [Google Scholar]
  25. Penalver FJ, Alvarez-Larran A, Diez-Martin JL, Gallur L, Jarque I, Caballero D, Diaz-Mediavilla J, Bustelos R, Fernandez-Acenero MJ, Cabrera JR. Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia. Ann Hematol. 2010;89:1073–1080. doi: 10.1007/s00277-010-0997-y. [DOI] [PubMed] [Google Scholar]
  26. Maung SW, Leahy M, O'Leary HM, Khan I, Cahill MR, Gilligan O, Murphy P, McPherson S, Jackson F, Ryan M, Hennessy B, McHugh J, Goodyer M, Bacon L, O'Gorman P, Nee A, O'Dwyer M, Enright H, Saunders J, O'Keeffe D. A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia. Br J Haematol. 2013;163:118–122. doi: 10.1111/bjh.12486. [DOI] [PubMed] [Google Scholar]
  27. Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Battista ML, Di Bona E, Fattizzo B, Consonni D, Cortelezzi A, Fanin R, Zanella A. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood. 2012;119:3691–3697. doi: 10.1182/blood-2011-06-363556. [DOI] [PubMed] [Google Scholar]
  28. Barcellini W, Zaja F, Zaninoni A, Imperiali FG, Di Bona E, Fattizzo B, Consonni D, Cortelezzi A, Zanella A. Sustained response to low-dose rituximab in idiopathic autoimmune hemolytic anemia. Eur J Haematol. 2013;91:546–551. doi: 10.1111/ejh.12199. [DOI] [PubMed] [Google Scholar]
  29. Gomez-Almaguer D, Solano-Genesta M, Tarin-Arzaga L, Herrera-Garza JL, Cantu-Rodriguez OG, Gutierrez-Aguirre CH, Jaime-Perez JC. Low-dose rituximab and alemtuzumab combination therapy for patients with steroid-refractory autoimmune cytopenias. Blood. 2010;116:4783–4785. doi: 10.1182/blood-2010-06-291831. [DOI] [PubMed] [Google Scholar]
  30. Zhang X, Sun J. Lower dose of rituximab in the treatment of elderly autoimmune hemolytic anemia. Zhonghua Xue Ye Xue Za Zhi. 2014;35:236–238. doi: 10.3760/cma.j.issn.0253-2727.2014.03.012. [DOI] [PubMed] [Google Scholar]
  31. Birgens H, Frederiksen H, Hasselbalch HC, Rasmussen IH, Nielsen OJ, Kjeldsen L, Larsen H, Mourits-Andersen T, Plesner T, Ronnov-Jessen D, Vestergaard H, Klausen TW, Schollkopf C. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol. 2013;163:393–399. doi: 10.1111/bjh.12541. [DOI] [PubMed] [Google Scholar]
  32. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL. 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. Blood. 2009;113:4834–4840. doi: 10.1182/blood-2008-10-186999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Etienne A, Gayet S, Vidal F, Poullin P, Brunet C, Harle JR, Kaplanski G. Severe hemolytic anemia due to cold agglutinin complicating untreated chronic hepatitis C: efficacy and safety of anti-CD20 (rituximab) treatment. Am J Hematol. 2004;75:243–245. doi: 10.1002/ajh.20004. [DOI] [PubMed] [Google Scholar]
  34. Palombi M, Niscola P, Perrotti AP, de Fabritiis P. Cold autoimmune hemolytic anemia resolved by rituximab. Asian J Transfus Sci. 2010;4:136–137. doi: 10.4103/0973-6247.67027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Palombi M, Niscola P, Trawinska MM, Scaramucci L, Giovannini M, Perrotti A, de Fabritiis P. Long-lasting remission induced by rituximab in two cases of refractory autoimmune haemolytic anaemia due to cold agglutinins. Blood Transfus. 2009;7:235–236. doi: 10.2450/2008.0066-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Glaser M, Glaser A, Skalicky M. Long lasting remission by rituximab in a patient with primary cold agglutinin autoimmune haemolytic anaemia. Wien Klin Wochenschr. 2011;123:680–683. doi: 10.1007/s00508-011-0060-6. [DOI] [PubMed] [Google Scholar]
  37. Simms-Waldrip T, Ikeda A, Goldfinger D, Moore T, Yuan S. Dramatic response to rituximab in a child with severe cold autoimmune hemolytic anemia arising after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2010;45:201–202. doi: 10.1038/bmt.2009.108. [DOI] [PubMed] [Google Scholar]
  38. Sekkach Y, Hammi S, Elqatni M, Fatihi J, Elomri N, Mekouar F, Badaoui M, Jira M, Smaali J, El Khattabi A, Amezyane T, Abouzahir A, Ghafir D. Efficacity of rituximab in hemolytic anemia with cold autoantibodies case. Ann Pharm Fr. 2011;69:205–208. doi: 10.1016/j.pharma.2011.06.002. [DOI] [PubMed] [Google Scholar]
  39. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev. 2008;22:1–15. doi: 10.1016/j.blre.2007.08.002. [DOI] [PubMed] [Google Scholar]
  40. Berentsen S, Ulvestad E, Gjertsen BT, Hjorth-Hansen H, Langholm R, Knutsen H, Ghanima W, Shammas FV, Tjonnfjord GE. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. 2004;103:2925–2928. doi: 10.1182/blood-2003-10-3597. [DOI] [PubMed] [Google Scholar]
  41. Schollkopf C, Kjeldsen L, Bjerrum OW, Mourits-Andersen HT, Nielsen JL, Christensen BE, Jensen BA, Pedersen BB, Taaning EB, Klausen TW, Birgens H. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma. 2006;47:253–260. doi: 10.1080/10428190500286481. [DOI] [PubMed] [Google Scholar]
  42. Barcellini W, Zanella A. Rituximab therapy for autoimmune haematological diseases. Eur J Intern Med. 2011;22:220–229. doi: 10.1016/j.ejim.2010.12.016. [DOI] [PubMed] [Google Scholar]
  43. Berentsen S, Randen U, Vagan AM, Hjorth-Hansen H, Vik A, Dalgaard J, Jacobsen EM, Thoresen AS, Beiske K, Tjonnfjord GE. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010;116:3180–3184. doi: 10.1182/blood-2010-06-288647. [DOI] [PubMed] [Google Scholar]
  44. Granel B, Rossi P, Bernard F, Dettori I, Costello R, Demoux AL, Bagneres D, Lafforgue P, Frances Y. Good outcome after rituximab treatment for a mixed warm and cold autoimmune haemolytic anaemia. BMJ Case Rep. 2009;2009 doi: 10.1136/bcr.09.2008.0857. doi: 10.1136/bcr.09.2008.0857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Gupta S, Szerszen A, Nakhl F, Varma S, Gottesman A, Forte F, Dhar M. Severe refractory autoimmune hemolytic anemia with both warm and cold autoantibodies that responded completely to a single cycle of rituximab: a case report. J Med Case Rep. 2011;5:156. doi: 10.1186/1752-1947-5-156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Koppel A, Lim S, Osby M, Garratty G, Goldfinger D. Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria. Transfusion. 2007;47:1902–1904. doi: 10.1111/j.1537-2995.2007.01414.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES