Acquired Pure Red Cell Aplasia Associated with Alemtuzumab, Mycophenolate, and Daclizumab Immunosuppression after Pancreas Transplant.

Abstract

Acquired pure red cell aplasia (PRCA) is a rare disorder that may be associated with malignancy, infections, connective tissue disorders, pregnancy and drugs. Recently, we observed PRCA in pancreas transplant patients treated with a new immunosuppressive regimen. Since 1966, the University of Minnesota Medical Center (UMMC) has performed 1577 pancreas transplants. Since February 2003, 280 pancreas transplants were treated with a new immunosuppressive protocol involving induction and maintenance with (n=190) or conversion to (n=90) alemtuzumab (humanized anti-CD52) and mycophenolate mofetil (MMF). Daclizumab (humanized anti-CD25, IL-2 receptor) was added when MMF dosing was limited by neutropenia. Between September 2004 and July 2005, 12 patients receiving the triple drug combination were diagnosed with PRCA. All 12 had prolonged exposure to MMF and/or a calcineurin inhibitor (cyclosporine, tacrolimus) prior to induction with [n=8] or conversion to [n=4] the above protocol. Eight subjects had bone marrow biopsies performed and reviewed at UMMC, and 4 additional patients received the diagnosis of PRCA at other institutions. All cases showed similar morphologic features, including dysgranulopoiesis, erythroid aplasia or marked hypoplasia with evidence of maturation, megakaryocytic hyperplasia with normal or low peripheral platelet counts, and atypical lymphoid aggregates in bone marrow trephine sections. Cytogenetic studies showed normal karyotypes. Severe reticulocytopenia was present in all subjects. In one subject, an extramedullary post-transplant lymphoproliferative disorder was diagnosed simultaneously. Another patient developed atypical reactive lymphadenopathy. Acute parvovirus infection was excluded by serology or polymerase chain reaction in 11 cases. Erythropoietin, when used, was started after the diagnosis or maintained through recovery of PRCA. Two patients died, one (post conversion) of PRCA associated with autoimmune hemolytic anemia and one (post induction) of ischemic heart disease. MMF was either discontinued (n=8) or dose reduced (n=2) in the remaining 10 subjects, with improvement in hemoglobin or decreased transfusion requirements in 8 patients. The single patient in whom a follow-up bone marrow biopsy was obtained after clinical recovery showed normal erythropoiesis. Ten patients developed infections with cytomegalovirus (n=7), BK virus (n=3), Zygomyces (n=1), Aspergillus versicolor (n=1), and Mycobacteria Simiae/Interjectum (n= 1). Hypogammaglobulinemia was a common finding. We conclude that reversible PRCA is associated with the immunosuppressive protocol including alemtuzumab, MMF, and daclizumab.

Aspergillosis in patients treated with monoclonal antibodies

“…22 In addition, TNF-a is central in the pathophysiology of GVHD following haematopoietic stem cell transplantation (HSCT). 15 Based on TNF-a role in acute and chronic inflammation, anti-TNF-a agents have been used in the treatment of conditions such as Crohn's disease, 69 ulcerative colitis, 90 rheumatoid arthritis, 17,28,64 psoriatic arthritis, 12,68 ankylosing spondylitis, 7,8,18,33 juvenile rheumatoid arthritis, 74 Behcet disease, 55 sarcoidosis, 83 Wegener's granulomatosis 48 and GVHD. 15,35,36 Several biologic agents targeting TNF-a have been developed during the past decade.…”

“…64 One case of A. versicolor infection was reported in a pancreas transplant recipient with pure cell aplasia following immunosuppressive therapy with daclizumab, mycophenolate mofetil and alemtuzumab. 18 In a retrospective analysis of lung transplant patients, 40 induction of immunosuppression with daclizumab in comparison with polyclonal preparations (anti-thymocyte globulin or anti-lymphocyte globulin) was associated with a higher recovery rate of Aspergillus species from clinical samples (including colonisation and invasive disease; OR 2.05, 95% CI 1.14-3.75). However, more patients on the daclizumab group were also receiving therapy with corticosteroids.…”