Pure red cell aplasia is an orphan disease without rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In all these, the pathogenetic mechanisms may involve autoreactive cytotoxic responses. We selected 62 uniformly diagnosed pure red cell aplasia patients and analyzed their pathophysiologic features and responsiveness to rationally applied first-line and salvage therapies to propose diagnostic and therapeutic algorithms that may help guide management of prospective patients. Of these, 52% were idiopathic; others involved large granular lymphocytic leukemia, thymoma, and B-cell dyscrasia. T-cell mediated responses ranged between a continuum from polyclonal to monoclonal (as seen in large granular lymphocytic leukemia). During a median observation period of 40mo., patients received on average 3 different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall RR (response rate) of 76% (53/70). Oral cyclophosphamide showed activity albeit lower than cyclosporine. Intravenous immunoglobulins were efficacious in parvovirus patients but also effective in hypogammaglobulinemia cases. In salvage settings, alemtuzumab is active, particularly in large granular lymphocytic leukemia associated cases. Other potentially useful salvage options include rituximab, anti-thymocyte globulin and bortezomib. The workup of acquired pure red cell aplasia should include investigations of common pathological associations. Most effective therapies are directed against T cell-mediated immunity and therapeutic choices need to account for associated conditions that may help in choosing alternative salvage agents such as intravenous immunoglobulin, alemtuzumab and bortezomib.
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