Review of PRCA. However, concern has centred around the precise number of patients treated with CsA who achieve a sustained remission and the number who relapse. In 1988, Dessypris pointed out that treatment of PRCA with CsA appeared to be very promising, but that such treatment should be considered still experimental, and that further studies were necessary to determine the effectiveness of this drug, the optimal and least toxic dosage, the minimum duration of therapy for induction of remission, and whether or not there was a need for maintenance treatment (Dessypris, 1988). An advantage of CsA therapy for PRCA has long remained unclear, as comparing one therapeutic approach to another has been almost impos- sible because the disease is so rare that controlled studies could not be performed. However, the number of patients treated with CsA has accumulated over two decades, which made it possible to conduct an analytical study. The present paper reviews the current status of CsA therapy, comparing it to other treatments for the diverse types of acquired PRCA except for transient erythroblastopenia of childhood. Diagnosis and initial evaluation Pure red cell aplasia in adults can be easily diagnosed when isolated anaemia, in the presence of normal white cell and platelet counts, is associated with a marrow of normal cellularity in which there is an almost complete absence of erythroblasts but normal myeloid cells and megakaryocytes (Dessypris & Lipton, 2004). The classiﬁcation of the clinical course (acute or chronic) and pathogenesis, such as secondary or idiopathic (no deﬁnite underlying disease) is essential to select the optimal therapeutic modality. Evaluations for the possible causes of PRCA should include a previous history of drug use and toxins or infections, liver and kidney functions, immunological examination including auto-antibodies, a bone marrow examination including morphology, chromosome and rearrangement of T cell receptor (TCR) analysis, peripheral- blood ﬂow cytometry, virological examination including parvovirus B19 DNA, and computed tomography and/or magnetic resonance imaging examinations to rule out the presence of thymoma and neoplasms. Today, a careful assessment of the increase of large granular lymphocytes (LGLs) is especially critical and an analysis of immunophenotype and TCR rearrangement of lymphocytes may be essential for ruling out LGL leukaemia, also referred to as granular lymphocyte proliferative disorders (GLPD) (Oshimi et al, 1993) or lymphoproliferative disease of gran- ular lymphocytes (LDGL) (Go et al, 2001). LGL leukaemia was the most common underlying disease of secondary PRCA in a single institutional study from the United States, and the second most common cause in Japan (Lacy et al, 1996; Mamiya et al, 1997; Sawada et al, 2007). Since the diagnosis of LGL leukemia is somewhat difﬁcult in patients without lymphocytosis, this group of patients can be misdiagnosed as idiopathic PRCA although LGL leukemia-associated PRCA may require a different treatment for the primary disease. It is a heterogeneous disorder characterized by a persistent increase in the number of peripheral blood LGLs, and the majority of patients have a clonal rearrangement of T-cell receptors (Oshimi et al, 1993; Semenzato et al, 1997; Chan et al, 2001). Clonal disorders of LGLs arise from either mature T lymphocytes or NK cells, and may be indolent or behave as an aggressive disease. T-cell LGL leukaemia is the most common form of clonal LGL disorders and most cases behave in an indolent fashion. Neutropenia is the most frequent cytopenia in T-cell LGL leukaemia, and anaemia occurs in 48% of the patients (Loughran, 1993; Lamy & Loughran, 1998, 2003). The evidence of a granular lymphocytosis greater than 2 · 109/l lasting for more than 6 months has been regarded as the criteria for deﬁning the disease (Loughran & Starkebaum, 1987; Semenzato et al, 1987; Oshimi, 1988). However, the normal range for peripheral blood LGL counts is 0Æ223 ± 0Æ099 · 109/l (Loughran et al, 1987) and clonal disease has been documented in 8% of patients when absolute LGL counts are between 0Æ6 to 1Æ0 · 109/l (Loughran, 1993). Thus, an expansion of a restricted LGL subset demonstrates the diagnosis of LGL-leukaemia and a 6-month follow-up criterion is not necessary when clonality is established (Semenzato et al, 1997). The characteristic ﬁnding is the presence of increased numbers of LGL, usually identiﬁed by a greater size than normal lymphocytes, abundant pale cytoplasm, and prominent azurophilic granules. However, these features may vary, even among cells from the same patient (Loughran, 1993). The granulation can range from ﬁne to coarse, and some cells may have otherwise characteristic features but lack granules (sometimes called large agranular lymphocytes) (Bassan et al, 1986). Occasionally, clonally expanded lymphocytes with a characteristic CD3+, CD57+ phenotype may not have LGL morphology on a peripheral smear (Ahern et al, 1990) but may represent in vivo antigen-activated cytotoxic effector T cells. An increase of CD3+/CD56) or CD3)/CD56+ cells by peripheral- blood ﬂow cytometry and/or an inverted CD4+/CD8+ cell ratio (<1Æ0) suggests the existence of LGL leukaemia (Gonzales- Chambers et al, 1992). Initial management During the initial evaluation, red cell transfusions can be given as necessary. In cases supposed to be primary idiopathic PRCA, it would be preferable to wait for at least a month before instituting speciﬁc treatment, with the rationale that 10–12% of PRCA patients run a short and self-limited course (Dessypris, 1988). If, after such a waiting period, no signs of recovery of erythropoiesis appear, speciﬁc treatment should be instituted. Many of the secondary PRCAs are due to drugs and disappear when the drug is stopped. Those secondary to parvovirus B19 can be treated with intravenous immunoglob- ulin. Secondary PRCA not responding to treatment of the underlying diseases and primary PRCA are treated as immu- nologically-mediated diseases. 506 ª 2008 The Authors Journal Compilation ª 2008 Blackwell Publishing Ltd, British Journal of Haematology, 142, 505–514