Letters to the Editor

* 2014 Lippincott Williams & Wilkins

islet cells during the pancreatic dissociation process. The risk to type I diabetes islet transplant recipients of acquiring vCJD, as determined by the original risk assessment (4, 10), remains negligible. Michael G. Tyshenko1 Lisa Bertram2,3 Li Li2,3 Susie ElSaadany4 John Samis5 Daniel Krewski1,6 Neil R. Cashman2,3 1

McLaughlin Centre for Population Health Risk Assessment, University of Ottawa Ottawa, Ontario, Canada 2 Brain Research Centre University of British Columbia Vancouver British Columbia, Canada 3 PrioNet Canada, Vancouver, British Columbia, Canada 4 Professional Guidelines and Public Health Practice Division, Centre for Infectious Disease Prevention and Control Public Health Agency of Canada Ottawa Ontario, Canada 5 Faculty of Health Sciences, University of Ontario Institute of Technology Oshawa Ontario, Canada 6 Department of Epidemiology and Community Medicine Faculty of Medicine, University of Ottawa Ottawa, Ontario, Canada The authors thank PrioNet Canada for funding support to complete this work. The authors declare no conflicts of interest. Address correspondence to: Michael G. Tyshenko, Ph.D., M.P.A., McLaughlin Centre for Population Health Risk Assessment, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5. E-mail: [email protected]

M.G.T. performed the islet cell isolation, participated in the performance of the research (mouse bioassay), writing of the article, and revising the article. L.L. participated in the performance of the research (Western blot) and reviewing the article. L.B. participated in the performance of the research (responsible for mouse intracardiac injections, dissections, and mouse bioassay) and participated in reviewing the article. S.E. participated in research design and revising the article. J.S. participated in research design and revising the article. D.K. participated in research design and revising the article. N.C. participated in research design and revising the article. Received 10 March 2014. Accepted 14 March 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9712-e73 DOI: 10.1097/TP.0000000000000176

ACKNOWLEDGMENTS Dr. Neil Cashman provided laboratory space, technical support and use of level 2 enhanced facilities for the islet cell isolation experiments. PrioNet Canada’s Bioassay and Pathogenesis Platform was invaluable for completion of the mouse bioassay.


2. 3. 4.

Shapiro AM, Ricordi C, Hering BJ, et al. Modeling rare and emerging diseases for decision making and policy implementation: extreme values and data management. Bioprocess Int 2004; 2: 30. Paget M, Murray H, Bailey CJ, et al. Human islet isolation: semi-automated and manual methods. Diab Vasc Dis Res 2007; 4: 7. Heim D, Kihm U. Risk management of transmissible spongiform encephalopathies in Europe. Rev Sci Tech 2003; 22: 179. ElSaadany S, Tyshenko MG, Oraby T, et al. The risk to human islet cell transplant recipients of acquiring variant CreutzfeldtJakob disease: a provisional quantitative risk assessment. Transplantation 2011; 92: e2.

5. 6.









Will RG. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br Med Bull 2003; 66: 255. Llewelyn CA, Hewitt PE, Knight RS, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417. Amselgruber WM, Bu¨ttner M, Schlegel T, et al. The normal cellular prion protein (PrPc) is strongly expressed in bovine endocrine pancreas. Histochem Cell Biol 2006; 125: 441. Strom A, Wang GS, Reimer R, et al. Pronounced cytosolic aggregation of cellular prion protein in pancreatic beta-cells in response to hyperglycemia. Lab Invest 2007; 87: 139. Guest WC, Plotkin SS, Cashman NR. Toward a mechanism of prion misfolding and structural models of PrP(Sc): current knowledge and future directions. J Toxicol Environ Health A 2011; 74: 154. Public Health Agency of Canada. 2008. Preliminary quantitative risk assessment of developing variant Creutzfeldt-Jakob disease (vCJD) from human islet cell transplantation. Available at: http://www.med.uottawa. ca/sites/tsalem/documents/Islet%20Risk% 20Assessment%20-%20Feb%2018,2008% 20-%20final.pdf. Accessed May 22, 2013. Roche Applied Science. 2013. Liberase R1 for rodent islet isolation, for dissociation of 40 rodent pancreata. December 2006. Available at: https://cssportal.roche.com/ LFR_PublicDocs/ras/11815032001_en_04.pdf. Accessed May 4, 2013. Roche Applied Science. 2013. Protocol for Rodent Pancreas Dissociation. Available at: http://www.roche-applied-science.com/ webapp/wcs/stores/servlet/PrintView?langId= -1&storeId=15016&articleId=68036. Accessed May 4, 2013. Roche Applied Science. 2013. Liberase Research Grade Insights-Liberase Enzyme Technology. Available at: http://www.roche-appliedscience.com/webapp/wcs/stores/servlet/PrintView? langId=-1&storeId=15016&articleId=68036. Accessed May 4, 2013.

Late Donor Bone Marrow Failure After Allogeneic Hematopoietic Stem Cell Transplantation ate secondary pancytopenia is relatively frequent after hematopoietic allogeneic stem cell transplantation. Most common causes are relapse of the primary malignancy and late rejections. Risk factors for acute or late rejections are known and include the primary disease, the human leukocyte antigen mismatch between recipient and donor, a T-cell depleted graft, a poor graft with low cellularity, a reduced intensity conditioning regimen, and posttransplantation events, such as viral infections or toxic exposure (1Y8).


In this case series, we report on four patients with late-onset secondary pancytopenia apparently of donor origin without relapse of the primary disease and without active graft-versus-host disease (GVHD) at the time of aplastic anemia (AA) (patient and transplant characteristics are summarized in Table 1). Patient 3 had no aplasia, whereas the three other patients showed neutrophil recovery within a month, patients 1 and 4 demonstrated platelet recovery within 3 months. Molecular chimerism studies revealed a 100% donor profile in all

patients within 100 days. Patient 2 demonstrated a partial hematological recovery with persistent pancytopenia and red blood cell and platelet transfusion dependency during the following 12 months without evidence of cytological or molecular relapse of her primary disease. Because this patient developed a severe chronic GVHD, initial cytopenia was assumed to be related to GVHD. Her blood cell count at the 12th month was as follows: hemoglobin, 9.8 g/dL; platelet, 37 G/L; leukocyte, 4.3 G/L with neutrophils at 3.3 G/L and remained stable for

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

MAC, myeloablative conditioning regimen; GVHD, graft-versus-host disease; Ig, immunoglobulin; RIC, reduced intensity conditioning regimen; ID, identity, *age at time of transplantation; F, female; M, male; ATG, anti-thymoglobulin; CSA, cyclosporine; MTX, methotrexate; MMF, mycophenolate mofetil; NA, not applicable because the patient had no aplasia after the conditioning regimen, Matched unrelated: HLA identical on HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (high resolution).



the next 21 months without cell support. None of these patients were treated in the early stage for a cytomegalovirus infection and three of them experienced a grade II acute GVHD treated with high-dose corticosteroids. Except for the patient 2 who was already pancytopenic, all experienced acute late-onset secondary pancytopenia that was not associated to any particular clinical symptoms nor GVHD exacerbation or new medication introduction. Events preceding late secondary pancytopenia worthy of mention were: (1) cyclosporine discontinuation in three patients (Table 1), Pentavac vaccination 1 month previously for patient 3, autoimmune thrombocytopenia 6 and 13 months before bone marrow failure in patients 3 and 4 (resolving by corticosteroids or immunoglobulin) and an early Epstein-Barr virus primo-infection with pneumonia without lymphoproliferative disease 2 months after transplantation treated by rituximab injection in patient 1 (9). Within a month, the pancytopenia worsened and bone marrow biopsies revealed a low cellularity, less than 30%, without any unusual cells or fibrosis. All patients demonstrated criteria for severe AA. Genetic markers have shown that marrow cells, peripheral blood cells, and T lymphocytes were 100% of donor origin (based on a cytogenetic sex mismatch between donor-recipient in patient 4). All microbiological investigations were negative except for parvovirus B19 positivity (8000 copies/mL in blood) in patient 3 which justified a treatment by intravenous polyvalent immunoglobulins (0.5 mg/kg), which did not prove to be effective. Autologous antinuclear antibodies with a nucleolar specificity were positive at 1/1600 for patients 2 and 3. Patients 1, 2, and 3 were treated for their late bone marrow failure by cyclosporine and corticosteroids. Patients 2 and 3 responded within a month with a return to the basal blood cell counts (mild cytopenia for patient 2 and normal cell count for patient 3). Furthermore, the blood cell count for patient 2 has progressively improved and reached normal ranges 4 years later while receiving low dose corticosteroids for chronic GVHD. Patient 1 finally received CD34 positive hematopoietic cell transplantation without prior conditioning, from the same donor and promptly normalized her blood cell count. Meanwhile,

CSA MMF 12.26108/kg Grade II acute 4.46106/kg and moderate chronic GVHD (eyes, mouth, liver), remission Bone CSA MTX 2.18108/kg Grade II acute marrow 3.08106/kg and severe chronic GVHD (sclerodermia), stable 17 M Acute MAC: TBI 10 Gy lymphoblastic Melphalan leukemia Fludarabine 4

HLA matched sibling


RIC: TBI 2Gy Fludarabine 51 M Myeloma 3

Matched unrelated

8108/kg Grade II acute 5.43106/kg and severe chronic GVHD (skin and fasciitis), remission CSA MMF PBSC Matched unrelated Chronic myeloid leukemia

RIC: Busulfan Fludarabine 59 F

Sickle cell anemia


MAC: Busulfan HLA matched cyclophosphamide sibling ATG

Bone CSA MTX marrow

5.12108/kg 12.4106/kg


Discontinuation CD3/CD4+: 673/KL 9 months before CD3+/CD8+: 1897/mL IgG: 5.1 g/L Anti-nuclear negative Progressive CD3/CD4+: 219/KL discontinuation CD3/CD8+: 52/mL 1 of CSA during IgG: 5.18 g/L AA diagnosis Anti-nuclear 1/1600 Native DNA + IgM 577 Anti-tissue negative Rheumatoid factor negative Discontinuation CD3/CD4+: 639/KL 5 months before CD3/CD8: 1055/mL IgG: 16.10 g/L Anti-nuclear 1/1600 Native DNA negative Anti-tissue negative CSA Lymphopenia: 0.5G/L Immunoglobulin: 8 g/L Anti-nuclear negative Native DNA negative Anti-tissue : smooth muscle 1/50


& Volume 97, Number 12, June 27, 2014



Source of stem cell Conditioning regimen Primary disease Age* ID gender



GVHD history status at time of AA

Immunological investigations at time of bone marrow failure Nucleated cells infused and GVHD CD34+ cells prophylaxis infused

TABLE 1. Transplantation characteristics and hematological recovery



Time to severe Immunosuppressive aplastic anemia therapy at time of bone marrow failure (months)


Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Letters to the Editor

* 2014 Lippincott Williams & Wilkins

patient 4 received a second bone marrow transplantation from the same donor after fludarabine and anti-thymoglobulin conditioning. Patient 4 has demonstrated a durable hematological recovery. Thirteen years after his second transplantation, he is now free of immunosuppressive therapy but is still treated with monthly polyvalent intravenous immunoglobulins for a persistent hypogammaglobulinemia. All these four patients with a severe AA of donor origin have required an immunosuppressive treatment or a second transplantation and had no evident or classical causes for pancytopenia (e.g., no apparent active GVHD, no new toxic drugs). These patients showed similar biological presentations to patients with AA, and some of them had autoantibodies. Interestingly, reinjections of cells from the same donor have enabled a perfect hematological recovery even for the patient who received neither pretransplant conditioning nor GVHD prophylaxis. Immune-mediated cytopenia have previously been reported after allogeneic hematopoietic stem cell transplantation and were not systematically associated with GVHD. The mechanism remains poorly understood, and the response to steroid is variable (10Y12). An immune-mediated destruction of hematopoietic stem cells and of the bone marrow niche (13) is also postulated in AA of donor origin and may possibly be triggered by antigenic stimulation, such as a virus, vaccination, or GVHD. Currently, when we suspect an AA of donor origin, an immunosuppressive treatment is preferred before requesting a new donation. This entity seems to be underestimated and probably deserves a better nosology.

Mathieu Meunier1 Anne-Claire Manez2 Alie´nor Xhaard2 Re´gis Peffault de Latour2 Flore Sicre de Fontbrune2 Nathalie Dhedin2 Ge´rard Socie´2 Marie Robin2 1 Service de greffe de moelle, Chu de Grenoble, Grenoble, France. 2 Service d’he´matologie-greffe, Hoˆpital Saint-Louis, Assistance Publique, hoˆpitaux de Paris, Universite´ Paris, Paris, France

The authors declare no funding or conflicts of interest. Address correspondence to: Marie Robin, M.D., Ph.D., 1 avenue Claude Vellefaux, 75010 Paris. E-mail: [email protected] M.R. and G.S. designed the study. M.M. and M.R. wrote the article. A.X., R.P.L., F.S.F., N.D., M.R., and G.S. took care of the patients. Received 7 February 2014. Revision requested 24 February 2014. Accepted 17 March 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9712-e75 DOI: 10.1097/TP.0000000000000177

3. 4.







ACKNOWLEDGMENTS The authors thank Dr Alix O’Meara for her English review.




Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma. N Engl J Med 1989; 320: 197. Doney K, Leisenring W, Storb R, et al. Primary treatment of acquired aplastic anemia: outcomes with bone marrow transplantation and immunosuppressive therapy. Seattle Bone Marrow Transplant Team. Ann Intern Med 1997; 126: 107.




Lucarelli G, Giardini C, Baronciani D. Bone marrow transplantation in thalassemia. Semin Hematol 1995; 32: 297. Marmont AM, Horowitz MM, Gale RP, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120. Singhal S, Powles R, Treleaven J, et al. A low CD34+ cell dose results in higher mortality and poorer survival after blood or marrow stem cell transplantation from HLA-identical siblings: should 2  10(6) CD34+ cells/kg be considered the minimum threshold? Bone Marrow Transplant 2000; 26: 489. Torok-Storb B, Boeckh M, Hoy C, et al. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood 1997; 90: 2097. Carrigan DR, Knox KK. Bone marrow suppression by human herpesvirus-6: comparison of the A and B variants of the virus. Blood 1995; 86: 835. Broliden K. Parvovirus B19 infection in pediatric solid-organ and bone marrow transplantation. Pediatr Transplant 2001; 5: 320. Teira P, Agbalika F, Bergeron A, et al. Primary Epstein-Barr virus infection with pneumonia transmitted by allogeneic bone marrow after transplantation. Clin Infect Dis 2006; 43: 892. Tsirigotis PD, Resnick IB, Or R, et al. Posthematopoietic stem cell transplantation immune-mediated cytopenias. Immunotherapy 2009; 1: 39. Klumpp TR, Block CC, Caligiuri MA, et al. Immune-mediated cytopenia following bone marrow transplantation. Case reports and review of the literature. Medicine (Baltimore) 1992; 71: 73. Hartert A, Willenbacher W, Gunzelmann S, et al. Successful treatment of thrombocytopenia and hemolytic anemia with IvIG in a patient with lupus-like syndrome after mismatched related PBSCT. Bone Marrow Transplant 2001; 27: 337. Shono Y, Ueha S, Wang Y, et al. Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. Blood 2010; 115: 5401.

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Late donor bone marrow failure after allogeneic hematopoietic stem cell transplantation.

Late donor bone marrow failure after allogeneic hematopoietic stem cell transplantation. - PDF Download Free
85KB Sizes 3 Downloads 5 Views