Autoantibody-Mediated Agranulocytosis in Association with Chronic GVHD

LETTER TO THE EDITOR Autoantibody-mediated agranulocytosis in association with chronic GVHD

Bone Marrow Transplantation (2008) 42, 359–360; 1 mg/kg/day, which led to rapid resolution of the throm- doi:10.1038/bmt.2008.173; published online 23 June 2008 bocytopenia. At this time, PB and BM showed complete donor chimerism and bcr-abl transcripts were not detectable. Although prednisolone was continued, CYA was Chronic GVHD (cGVHD) is the major cause of late non- tapered 9 months after BMT resulting in progressive sicca relapse morbidity and mortality after allogeneic SCT, symptoms of the eyes (NIH grade 1) and a mild cutaneous occurring in up to 70% of long-term survivors. Chronic rash (NIH grade 1) that resolved after restarting CYA. GVHD commonly affects skin, gut, liverand lung but may During subsequent tapering of steroids to a every other day resemble autoimmune disorders such as polymyositis, (QOD) schedule 15 months afterBMT, the patient myasthenia gravis, autoantibody-mediated hemolysis and developed severe neutropenia and was admitted to hospital scleroderma.1 However, the pathogenesis of cGVHD is owing to neutropenic fever on day 431 post transplant. The incompletely understood and it remains unclear how absolute leukocyte count was 1.5 Â 109 cells/l; both autoimmune responses develop. Traditionally, cGVHD is lymphocyte and granulocyte counts were diminished to thought to be mediated by donor-derived, alloreactive 0.62 Â 109 and 0.38 Â 109 cells/l, respectively. Antibodies T cells, but there is mounting evidence of an additional against granulocytes were detected by the granulocyte implication of B cells. The pathologic role of B cells might immunofluorescence test. In brief, granulocytes from be mediated through dysregulated autoimmune antibody healthy blood donors are isolated by density gradient synthesis and allogeneic antibody induction.2 The forma- centrifugation, fixed in paraformaldehyde and incubated tion of allogeneic antibodies to Y chromosome-associated with the serum to be studied. After washing the granulo- antigens (H-Y antigens) aftersex-mismatch transplanta- cytes, cell-bound antibodies are detected with FITC-labeled tion and reports about effective treatment of cGVHD rabbit anti-human IgG. The granulocyte immunofluores- with a monoclonal CD20 antibody strengthen this cence test may yield positive results due to HLA class I hypothesis.2,3 These H-Y antibodies were thought to be a antibodies, as the corresponding antigens are expressed on product of naive engrafted donor B cells proliferating neutrophils. HLA I antibodies were excluded in this in response to disparate host antigens.2 Moreover, patient. The rather insensitive granulocyte agglutination autoantibodies are frequently detected in association test gave a negative result. As HLA class I antibodies could with cGVHD.4 Here, we present a patient who be ruled out and no human neutrophil antigen specificity developed antibody-mediated agranulocytosis in associa- was identified, these antibodies were most likely autoreac- tion with cGVHD. tive. At that time, a discrete mixed chimerism (1% recipient A 26-year-old man received a BMT from an HLA– origin) was detectable in BM. Besides a slight viral EBV matched, AB0-compatible unrelated male donor for CML load of 2 Â 103 EBV DNA PCR genomes, no othercauses in chronic phase not responding molecularly to imatinib, for agranulocytosis were detectable including negative after conditioning with treosulfan, fludarabine and antith- testing for cytomegalovirus, Parvovirus B19 and human ymocyte globulin. GVHD prophylaxis consisted of CYA herpes virus 6. In addition, the patient developed mild- and MTX. He developed acute cutaneous GVHD (grade 1) to-moderate hemolysis, with a hematocrit of 24% due on day 11 post BMT, which resolved without additional to antierythrocyte antibodies (allo-antibodies anti-LW(a) immunosuppressive treatment. On day 33, complete donor and anti-LW(b)) in association with moderate eosinophilia. chimerism was detected in peripheral blood (PB) and BM As agranulocytosis and hemolysis were interpreted as a by short tandem repeat analysis. On day 89, he presented manifestation of cGVHD, rituximab was administered at with complete donor chimerism in PB but discrete mixed a dose of 375 mg/m2 perweek fromday 436 forfour chimerism (1–3%) in BM. Subsequently, he developed on consecutive weeks, and prednisolone at 1 mg/kg/day and day 136 after BMT eosinophilia, progressive nausea and CYA were continued but neutropenia and significant emesis associated with weight loss, which were interpreted eosinophilia persisted. From day 454, G-CSF at a dose of as clinical signs of cGVHD, although cGVHD could not be 34 million IU lenogastrim per day was administered s.c. verified histologically by biopsy samples of gastric and without effect on the neutropenia. Therefore, high-dose duodenal epithelium. Treatment with enteral budenosid methylprednisolone (10 mg/kg) for four consecutive days resulted in resolution of the gastrointestinal problems, but was started at day 490, resulting in disappearance of the on day 153, the patient developed autoimmune thrombo- eosinophilia and rapid hematological regeneration with a cytopenic purpura due to IgG autoantibodies against neutrophil count of 6.37 Â 109 cells/l 3 days afterthe steroid platelet glycoproteins IIb/IIIa and Ib/IX, which was bolus. The patient was doing well with normal PB counts interpreted as an additional manifestation of cGVHD. up to day 539 afterBMT, in remissionof cGVHD, and Therefore, budenosid was replaced by prednisolone at receiving immunosuppression with CYA and prednisolone Letter to the Editor 360 at 1 mg/kg/day. Owing to fluctuating neutrophil counts, S Ruck1, I Hilgendorf1,BMu¨ ller-Hilke2, V Kiefel3, treatment with rituximab was repeated six times at a dose C Junghanss1, M Freund1, H Greinix4 and D Wolff1 of 375 mg/m2. Despite ongoing treatment with rituximab, 1Division of Hematology and Oncology, University of the patient relapsed again with neutropenic fever on day Rostock, Rostock, Germany; 561. As IgG serum levels were below 4 g/l on day 561, IgG 2Institute of Immunology, University of Rostock, Rostock, was administered i.v. with an absolute dose of 30 g. Germany; Interestingly, neutrophil recovery was noted 3 days after 3Division of Transfusion Medicine, University of Rostock, IgG infusion. A subsequent drop in neutrophil count on Rostock, Germany and day 597 again responded to i.v. IgG. The patient is now 4Department of Internal Medicine I, Medical University of doing well with normal PB counts on day 631 after BMT, Vienna, Vienna, Austria in remission of cGVHD. E-mail: [email protected] Although the pathogenesis of cGVHD is not yet completely understood, an implication of B cells and autoantibodies is hypothesized. Ourpatient developed References early autoimmune thrombocytopenic purpura, which is 5,6 1 Sanz J, Arriaga F, Montesinos P, Orti G, Lorenzo I, Cantero S known to be a manifestation of cGVHD. Platelet et al. Autoimmune hemolytic anemia following allogeneic antibodies are frequently detected in patients with hematopoietic stem cell transplantation in adult patients. Bone cGVHD-associated thrombocytopenia, which is thought Marrow Transplant 2007; 39: 555–561. to represent a B-cell dysregulation leading to clinical 2 CutlerC, Miklos D, Kim HT, TreisterN, Woo SB, Bienfang D disease. In addition, an autoimmune hemolytic anemia et al. Rituximab for steroid-refractory chronic graft-versus-host with othercytopenias post transplantas cGVHD manifes- disease. Blood 2006; 108: 756–762. tations has been described by Page et al.7 with a high 3 Miklos DB, Kim HT, Zorn E, Hochberg EP, Guo L, incidence in very young babies. The incidence in older Mattes-Ritz A et al. Antibody response to DBY minor children is significantly lower, but similarity of symptoms in histocompatibility antigen is induced afterallogeneic stem cell Blood ourpatient and these babies may confirmthe hypothesis of transplantation and in healthy female donors. 2004; 103: 353–359. neutropenia being a manifestation of cGVHD. Shortly 4 Fujii H, CuvelierG, She K, Aslanian S, Shimizu H, Kariminia afterdetection of mixed chimerism,the patient developed A et al. Biomarkers in newly diagnosed pediatric-extensive neutropenia due to antigranulocyte antibodies. In a mouse chronic graft-versus-host disease: a report from the Children’s model, Perruche et al.8 recently reported the occurrence of Oncology Group. Blood 2008; 111: 3276–3285. host-derived pathogenic autoantibodies to be higher in 5 Anasetti C, Rybka W, Sullivan KM, Banaji M, SlichterSJ. mixed chimeric mice that subsequently developed Graft-v-host disease is associated with autoimmune-like throm- cGVHD-like lesions. The chronology in our case also bocytopenia. Blood 1989; 73: 1054–1058. strengthens the hypothesis that neutropenia occurred as a 6 Kottaridis PD, Rees H, Smith G, Garner SF, Perry AR, Peniket manifestation of cGVHD. Previous studies showed AJ et al. A fatal case of autoimmune thrombocytopenia with an the efficacy of rituximab in cGVHD-related autoanti- IgM anti-GPIb/IX following one antigen mismatched unrelated donor bone marrow transplantation. Bone Marrow Transplant body-mediated manifestations including refractory 1999; 23: 739–741. 2,9 immune-mediated thrombocytopenia. Rituximab, how- 7 Page KM, Mendizabal A, Szabolsc P, Wood S, Prasad V, ever, did not lead to resolution of the neutropenia, which Kurtzberg J. Post transplant autoimmune hemolytic anemia was achieved subsequently by high-dose methylpredniso- and other cytopenias are increased in very young babies after lone. Although a late response to rituximab could not be unrelated donor umbilical cord blood transplantation. Blood excluded initially, it could be excluded later, when recurring 2007; 110: 319a. neutropenia occurred despite treatment with rituximab. 8 Perruche S, Kleinclauss F, Tiberghien P, Saas P. B Cell The association of neutrophil recovery after administration allogeneic responses after hematopoietic cell transplantation: of immunoglobulins supports the presence of an autoanti- is it time to address this issue? Transplantation 2005; 79 (3 body-mediated agranulocytosis. We hypothesize that the Suppl): S37–S39. 9 Ratanatharathorn V, Carson E, Reynolds C, Ayash LJ, Levine persistence of eosinophilia in association with neutropenia, J, Yanik G et al. Anti-CD20 chimeric monoclonal antibody despite the use of prednisolone and CYA, was caused by treatment of refractory immune-mediated thrombocytopenia in stimulatory Th-2 T cells that led to activation of B cells and a patient with chronic graft-versus-host disease. Ann Intern Med antibody production. 2000; 133: 275–279.

Bone Marrow Transplantation