Review most important therapeutic index should be trough CsA levels. Caucasian patients with anti-EPO antibody-related PRCA have been successfully treated with CsA alone at a dose of 200 mg/d (or 100 mg twice daily) (Verhelst et al, 2004; Rossert et al, 2005). Since organ transplantations have shown that long-term immunosuppression is associated with post-transplant malignancies (Cattran et al, 1995; Young et al, 2006), contin- uous and careful follow-up is required for patients receiving long-term CsA therapy. Cytotoxic immunosuppressive drugs Patients with an absolute contraindication for CsA or patients refractory to CsA may be treated with CS or a combination of CS and other immunosuppressives. Cyclophosphamide (CY) has been the principal alkylating agent utilized as an immuno- suppressive drug in PRCA. The details of CY therapy are described elsewhere (Dessypris, 1988; Dessypris & Lipton, 2004). The initial dosage of CY is 50 mg/d p.o. and PSL at a dose of 20–30 mg/d is added in the absence of any contrain- dication. If the white blood cell and platelet counts allow, it is increased by 50 mg weekly or biweekly to a maximum of 150 mg daily until remission occurs or bone marrow suppres- sion develops. The mean time to response is approximately 11 to 12 weeks with an overall response rate of 40 to 60%. When response occurs, the dose of PSL is tapered, and then the dose of CY is progressively decreased and eventually discontinued after 3–4 months from the time of normalization of haematocrit. The duration of remission induced by CY seems to be prolonged as compared to remissions induced by CS (Clark et al, 1984; Firkin & Maher, 1988; Go et al, 2001). LGL leukaemia-associated PRCA has been primarily treated with chemotherapy, such as CY with or without CS, CsA, CS or methotrexate (Dhodapkar et al, 1994; Loughran et al, 1994; Lacy et al, 1996; Yamada et al, 1997; Sood et al, 1998; Hamidou et al, 2000; Go et al, 2001; Battiwalla et al, 2003; Osuji et al, 2006). The combination of CY plus CS is associated with a longer duration of response than CS alone (Dhodapkar et al, 1994; Lacy et al, 1996; Go et al, 2001). The overall response to initial CY ± CS therapy has been reported to be 66 to 100 % (Yamada et al, 1997; Go et al, 2003) and the median duration of response is 32 months (Go et al, 2003). In one study, none of the patients with a response to cytotoxic agents had relapses (Lacy et al, 1996), but the other studies reported that a substantial number of patients relapsed when the CY was withdrawn (Zaentz et al, 1976; Clark et al, 1984). Maintenance CY therapy may prevent relapse, however, recognition of a variety of toxicities, particularly concerns about the long-term risk of malignancy and gonadal toxicity, often lead clinicians to consider less toxic alternative medica- tions whenever possible (Csuka et al, 1986; Hoffman et al, 1992). These toxicity risks from alkylating agents are related to the cumulative dose of the medication (Reinhold-Keller et al, 2000) and the duration of therapy (Radis et al, 1995). Thus, the best role of CY therapy for PRCA might be to induce remissions using oral treatment lasting not longer than six months, with a switch to less toxic medication, such as CsA, for maintenance, but no controlled studies exist and this is purely speculative. It has been reported that crossover to azathioprine was effective in patients initially unresponsive to CY and vice versa (Firkin & Maher, 1988). Anti-thymocyte globulin In the largest series of nine PRCA patients treated with anti- thymocyte globulin (ATG) at a dose of 15 mg/kg per day for 10 d, six responded to therapy, ﬁve with normal haematocrits and one with a stable haematocrit of 32% (Abkowitz et al, 1986). Three remained in complete remission and two relapsed, which suggests that ATG is an effective form of treatment. However, this is an expensive and conﬁning therapy that requires hospitalization because of a possible anaphylactic reaction. Alemtuzumab The anti-CD52 monoclonal antibody alemtuzumab (Cam- path-1H) is a humanized IgG1j monoclonal antibody directed against the CD52 antigen, present on B and T lymphocytes, NK cells, monocytes/macrophages, dendritic cells and eosino- phils but not on human haemopoietic stem cells (Hale, 2001). The rationale behind the use of alemtuzumab in refractory cytopenias is that T-lymphocytes are thought to play an important role in the pathogenesis of autoimmune cytopenias, as they are involved in the control of expansion of immuno- globulin-producing, auto-reactive B-lymphocyte clones (Willis et al, 2001). Willis et al (2001) reported the effect of treatment with alemtuzumab followed by CsA administration in 21 patients with severe and life-threatening autoimmune cytope- nias including four patients with PRCA. A response was seen in 2/4 patients with PRCA, although one patient relapsed at 7 months when the CsA blood level was suboptimal. One patient with PRCA in association with low-grade non-Hodg- kin lymphoma died from high-grade transformation at 16 months while still in remission from the PRCA. Ru and Liebman (2003) reported two patients with chronic lympho- cytic leukaemia (CLL) and a CD8 T-LGL leukaemia who were refractory to multiple treatments for PRCA. When both patients were treated with alemtuzumab, there was a rapid increase in the reticulocyte count that occurred as early as the third infusion. At the time reporting, both patients had been in PRCA remission for 9 and 5 months, respectively. These results indicated that alemtuzumab is an alternative option in the treatment of patients with refractory PRCA, however, relapse can occur and a signiﬁcant number of patients need maintenance therapy with CsA after alemtuzumab treatment. Therefore, it remains uncertain whether alemtuzumab can induce a maintenance-free haematological response in PRCA. The use of alemutuzumab should be limited to patients with PRCA who are refractory to conventional immunosuppressive 508 ª 2008 The Authors Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 142, 505–514