Rational management approach to pure red cell aplasia

Abstract

Pure red cell aplasia is an orphan disease, and as such lacks rationally established standard therapies. Most cases are idiopathic; a subset is antibody-mediated. There is overlap between idiopathic cases and those with T-cell large granular lymphocytic leukemia, hypogammaglobulinemia, and low-grade lymphomas. In each of the aforementioned, 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 in order to propose diagnostic and therapeutic algorithms that may be helpful in guiding the management of prospective patients, 52% of whom were idiopathic, while the 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 40 months, patients received a median of two different therapies to achieve remission. Frequently used therapy included calcineurin-inhibitors with a steroid taper yielding a first-line overall response rate of 76% (53/70). Oral cyclophosphamide showed activity, albeit lower than that produced by cyclosporine. Intravenous immunoglobulins were effective both in parvovirus patients and 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.

Figure 1.

Pathogenesis of pure red cell aplasia (PRCA) in our cohort. (A) Different causes of PRCA affect red cell production in different ways. Parvovirus causes direct cytolysis of erythroid precursor cells. Several drugs are implicated in causing PRCA, probably through a direct toxic effect. EPO antibodies can recognize antigens at the erythroid burst forming unit (BFU-E) level and cause PRCA. There is a wide range of antigen recognition by CTL exhibiting a polyclonal response, seen as negative TCR (T-cell gene rearrangement) by testing, which, however, still causes PRCA, probably by direct cytotoxicity. At the other end of the spectrum are LGLs that are monoclonal with STAT3 mutations and can recognize antigens at the erythroid precursor level, and thus cause PRCA. (B) Flow cytometry Vβ analysis of the peripheral blood of individual representative patients from the cohort shows clonal skewing. Illustration shows a spectrum of polyclonal to oligoclonal to monoclonal response of CTL in individual patients with PRCA.

Figure 2.

Treatment algorithm for immune-mediated PRCA in our patient cohort. Cyclosporine or cyclophosphamide with a steroid taper is the first-line choice of treatment in both idiopathic and LGL- related PRCA. Maintenance treatment with immunosuppressive therapy is usually needed, and varies based on the sustainability of the response obtained (see text for details). Methotrexate is used in a salvage setting in LGL/PRCA, but has no role in idiopathic PRCA. Alemtuzumab is one of the commonly used salvage options in refractory PRCA.

Figure 3.

Response probabilities across various treatment options in aPRCA. (A) Cyclosporine and tacrolimus are the most effective drugs for PRCA in our cohort. The details of IVIG response rates are elaborated in Table 3. Rituximab is used only in the salvage setting when the front-line options have failed, including commonly used salvage treatments such as alemtuzumab. ATG is used purely as a salvage option, but only shows mediocre, but acceptable, response rates. The other salvage treatment options include danazol, mycophenolate mofetil, bortezomib, erythropoietin, abatacept (Orencia), and tofacitinib (Xeljanz) etc., all of which show good response rates when used in the right setting (see text for details). (B) Response proportion for different treatment options: comparison between LGL vs. non-LGL PRCA groups. Cyclosporine and tacrolimus show better RR in the non-LGL group, whereas campath (alemtuzumab), though not statistically significant, works better in LGL-PRCA. Patients with parvovirus PRCA, and those presenting with low immunoglobulin levels in PRCA show excellent RR with IVIG (see also Table 3).