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 | ||