Biol Blood Marrow Transplant 19 (2013) 1514e1529

Brief Articles ASBMT Absence of Post-Transplantation Lymphoproliferative American Society for Blood Disorder after Allogeneic Blood or Marrow Transplantation and Marrow Transplantation Using Post-Transplantation Cyclophosphamide as -versus-Host Disease Prophylaxis

Jennifer A. Kanakry 1,YvetteL.Kasamon2, Javier Bolaños-Meade 2, Ivan M. Borrello 2, Robert A. Brodsky 1, Ephraim J. Fuchs 2,NilanjanGhosh2, Douglas E. Gladstone 2, Christopher D. Gocke 3, Carol Ann Huff 2, Christopher G. Kanakry 2, Leo Luznik 2, William Matsui 2,HuzefaJ.Mogri4, Lode J. Swinnen 2, Heather J. Symons 5, Richard J. Jones 2, Richard F. Ambinder 2,*

1 Division of Hematology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 2 Department of Hematologic Malignancies, School of Medicine, Johns Hopkins University, Baltimore, Maryland 3 Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 4 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland 5 Department of Pediatric Oncology, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Article history: abstract Received 18 June 2013 Immunosuppressive regimens that effectively prevent graft-versus-host disease (GVHD) after allogeneic Accepted 9 July 2013 blood or marrow transplantation (allo-BMT) have been associated with an increased incidence of post- transplantation lymphoproliferative disorder (PTLD) in the first year after transplantation. We evaluated Key Words: the incidence of PTLD associated with the use of high-dose post-transplantation cyclophosphamide (PTCy) as Post-transplantation GVHD prophylaxis. Between 2000 and 2011, a total of 785 adult allo-BMT recipients were given PTCy as GVHD lymphoproliferative disorder prophylaxis at the Johns Hopkins Hospital, including 313 patients who received PTCy as sole GVHD Allogeneic blood or marrow prophylaxis. HLA-haploidentical or unrelated donor graft transplantation was performed in 526 patients transplantation (67%). No cases of PTLD occurred during the first year after allo-BMT in this series. PTLD is a rare occurrence Post-transplantation cyclophosphamide after allo-BMT using PTCy, even in high-risk alternative donor transplantations. Graft-versus-host disease Ó 2013 American Society for Blood and Marrow Transplantation. prophylaxis

INTRODUCTION HLA-haploidentical donors, and umbilical cord blood (UCB), The approach to graft-versus-host disease (GVHD) has been associated with increased risk for PTLD. This prophylaxis, including methods of graft manipulation and heightened risk seems related mainly to the intensified pharmacologic immunosuppression, affects immune recon- GVHD prophylaxis strategies often used with alternative stitution after allogeneic blood or marrow transplantation donor grafts. The incidence of PTLD in patients receiving URD (allo-BMT) and modulates the risk for post-transplantation or haploidentical grafts accompanied by ATG and/or selective lymphoproliferative disorder (PTLD). The risk of PTLD peaks T cell depletion is 4% to 8% [1]. The incidence of PTLD after in the early months after allo-BMT, and the vast majority UCB allo-BMT is 2% to 7%, but rates up to 17% have been re- of cases occur within the first year after transplantation ported with UCB allo-BMT using ATG [2-5]. [1]. PTLD lesions that arise after allo-BMT typically harbor The use of post-transplantation cyclophosphamide Epstein-Barr virus (EBV). (PTCy) as GVHD prophylaxis after allo-BMT is associated with A multi-institutional analysis of PTLD incidence among comparatively low rates of severe acute and chronic GVHD, 26,901 allo-BMTs performed at 271 institutions worldwide even with the use of URD and haploidentical grafts [6]. found that selective T cell depletion of grafts and, to a lesser However, given that approaches that are highly effective in extent, other approaches to lymphocyte depletion were preventing GVHD may be associated with higher rates of associated with increased risk for PTLD [1]. Patients who PTLD, we evaluated the incidence of PTLD associated with receive antithymocyte globulin (ATG) as GVHD prophylaxis PTCy at the Johns Hopkins Hospital (JHH). also are considered at higher risk for PTLD [1,2]. The use of alternative donors, including unrelated donors (URDs), MATERIALS AND METHODS Once JHH Institutional Review Board approval was obtained, the JHH Financial disclosure: See Acknowledgments on page 1516. Transplant Research databases were queried for patients age 18 years who * Correspondence and reprint requests: Richard F. Ambinder, Department received PTCy as GVHD prophylaxis at JHH between January 1, 2000, and of Hematologic Malignancies, Johns Hopkins University, 1650 Orleans St., December 31, 2011. Clinical notes, pathology reports, and radiology reports CRB 1, Rm 389, Baltimore, MD 21287. up through the first year after allo-BMT were reviewed. E-mail address: [email protected] (R.F. Ambinder). For myeloablative conditioning, patients received a regimen of busulfan 1083-8791/$ e see front matter Ó 2013 American Society for Blood and (Bu) and cyclophosphamide (Cy) as described previously [7]. Reduced- Marrow Transplantation. intensity conditioning (RIC) regimens were fludarabine (Flu)-based, with http://dx.doi.org/10.1016/j.bbmt.2013.07.013 the majority (n ¼ 354) consisting of Flu/Cy/ (TBI) [8]. J.A. Kanakry et al. / Biol Blood Marrow Transplant 19 (2013) 1514e1529 1515

Table 1 prophylaxis in 313 of these allo-BMTs (40%), 295 of which Patient and Transplant Characteristics (n ¼ 785) involved myeloablative conditioning and HLA-matched Characteristic Value grafts. Haploidentical or URD grafts were used in 526 (67%) Age, yr, median (range) 52 (18-75) of the allo-BMTs overall. Male, n (%) 448 (57) Almost all patients (n ¼ 762; 97%) had sufficient follow-up Diagnosis, n (%) to assess for PTLD in the year after allo-BMT, with 505 patients AML or myelodysplastic syndrome 308 (39) followed for at least 1 year by JHH physicians, 203 surviving Mature B cell neoplasm 236 (30) Acute lymphoblastic 69 (9) less than 1 year but followed until death or hospice enroll- Myeloproliferative neoplasm, including CML 52 (7) ment, and 54 resuming care with an outside oncologist before Hodgkin’s lymphoma 48 (6) 1 year posteallo-BMT but corresponding with JHH when Mature T cell or natural killer cell neoplasm 36 (5) clinical issues arose. The cumulative incidence of death at Hemoglobinopathy or thalassemia 17 (2) 1 year was 34% (95% confidence interval [CI], 29% to 38%) for Aplastic anemia or paroxysmal nocturnal 9 (1) hemoglobinuria recipients of haploidentical allo-BMT, 30% (95% CI, 22% to 38%) Bilineage leukemia 7 (1) for recipients of URD allo-BMT, and 29% (95% CI, 23% to 34%) Histiocytic or dendritic cell neoplasm 2 for recipients of matched related donor allo-BMT (Figure 1). Lymphomatoid granulomatosis 1 No cases of PTLD were identified among the 762 patients with Conditioning regimen, n (%) fi Reduced-intensity 456 (58) adequate follow-up. Twenty-three patients had insuf cient Myeloablative 329 (42) follow-up to assess for PTLD through 1 year posteallo-BMT, ATG-containing conditioning regimen, n (%) 14 (2) but no cases of PTLD were identified during the available Donor, n (%) follow-up in these patients (median, 3.7 months; range,1.6 to HLA-haploidentical* 396 (50) 11.9 months). HLA-matched related 259 (33) fi HLA-matched or 1 antigen-mismatched unrelated 130 (17) DLI, adoptive EBV-speci c cellular immunotherapy, and Allograft source, n (%) rituximab therapy have proven effective in treating PTLD. In Marrow, T cell replete 748 (95) our cohort, 57 patients received DLI within the year after Peripheral blood, T cell replete 37 (5) allo-BMT, but in no case was DLI given for suspected or GVHD prophylaxis, n (%) fi fi PTCy alone 313 (40) con rmed PTLD. Adoptive immunotherapy with EBV-speci c PTCy on days þ3 and þ4 302 cytotoxic T lymphocytes was not used in this cohort. Sixty- PTCy on day þ311three patients received rituximab during the year after y PTCy on days þ3 and þ4/MMF/tacrolimus 382 (49) þ z allo-BMT, including 43 patients with CD20 lymphoma who PTCy on days þ3 and þ4/MMF 55 (7) x received 8 weekly doses of rituximab on engraftment after PTCy on day þ3/MMF/tacrolimus 20 (2) k PTCy on days þ3 and þ4/MMF/sirolimus 15 (2) RIC allo-BMT (41 haploidentical and 2 HLA-matched related Rituximab 12 months after allo-BMT, n (%) 63 (8) donor grafts) as part of a clinical protocol, 19 patients who HLA-haploidentical 55/396 (14) received rituximab as part of treatment for relapsed HLA-matched related 8/259 (3) B-lineage malignancy, and 1 patient who received 1 dose of HLA-matched or 1 antigen-mismatched unrelated 0/130 DLI 12 months after allo-BMT, n (%) 57 (7) preemptive rituximab for a modest, asymptomatic elevation HLA-haploidentical 13/396 (3) of EBV DNA copy number in the blood at 4 months after allo- HLA-matched related 41/259 (16) BMT at an outside institution, in keeping with that institu- HLA-matched or 1 antigen-mismatched unrelated 3/130 (2) tion’s protocol for posteallo-BMT EBV monitoring. That CML indicates chronic myelogenous leukemia; MMF, mycophenolate patient’s elevated EBV DNA copy number was not associated mofetil. * Total of 395 related donors and 1 unrelated donor. y MMF 15 mg/kg 3 times daily up to 1000 mg/dose on days 5-35 and tacrolimus (goal trough, 5-15 ng/mL) on days 5-180. Twenty patients received MMF 15 mg/kg twice daily on days 4-33. z MMF 15 mg/kg twice daily on days 4-33. x MMF 15 mg/kg twice daily on days 4-35 and tacrolimus (goal trough, 5-15 ng/mL) on days 4-50 (n ¼ 10) or days 4-180 (n ¼ 10). k MMF 15 mg/kg 3 times daily up to 1000 mg/dose on days 5-35 and sirolimus daily (goal trough, 5-15 ng/mL) on days 5-365.

Other RIC regimens included Flu/TBI (n ¼ 72), Bu/Flu (n ¼ 14), ATG/Flu/Cy/TBI (n ¼ 14) [9], and alemtuzumab/Flu/TBI (n ¼ 2). All grafts were T cell replete. When used as sole GVHD prophylaxis, PTCy 50 mg/kg/day was given i.v. on days þ3 and þ4 after allo-BMT [7] in all but 11 patients, who received PTCy on day þ3 only. Most recipients of haploidentical grafts and/or RIC received additional immunosuppression after PTCy on days þ3 and þ4 after allo-BMT, with the majority receiving mycophenolate mofetil and tacroli- mus. GVHD prophylaxis regimens are shown in Table 1. PTLD was defined using the 2008 World Health Organization classifi- cation scheme [10]. Data on the use of posteallo-BMT therapies that could modulate PTLD risk, including donor lymphocyte infusion (DLI) and ritux- imab therapy, were compiled. Death was considered a competing risk for PTLD. R version 2.15.2 (R Core Development Team, Vienna, Austria) was used to estimate the cumulative incidence of death.

RESULTS Figure 1. Cumulative incidence of death by allograft type. At 1 year, the cumulative incidence of death was similar for recipients of HLA-haploidentical, Between 2000 and 2011, a total of 785 allo-BMTs were unrelated, and HLA-matched related donor allografts at 34% (95% CI, 29% to performed at JHH, with PTCy administered as GVHD 38%), 30% (95% CI, 22 to 38%), and 29% (95% CI, 23% to 34%), respectively. The prophylaxis (Table 1). PTCy was used as the sole GVHD cumulative incidence of PTLD is not shown, given the absence of events. 1516 J.A. Kanakry et al. / Biol Blood Marrow Transplant 19 (2013) 1514e1529

with fever, lymphadenopathy, organ dysfunction, or any Regardless of the cause, PTCy is associated with very low to other clinical findings of concern for PTLD. EBV DNA moni- absent rates of PTLD after allo-BMT, even with the use of toring was continued, and viral DNA was intermittently unrelated or HLA-mismatched donors. detected, but the patient remained without signs or symp- toms of EBV-associated disease and was healthy at nearly 3 years after allo-BMT. ACKNOWLEDGMENTS Financial disclosure: This work was supported by the National Cancer Institute (grants P01CA15396, P50CA96888, DISCUSSION The absence of PTLD after allo-BMT using PTCy is note- P30CA006973, and T32HL7525). The authors have no conflicts of interest to report. worthy, particularly given that no routine EBV monitoring was performed. Many transplantation centers perform EBV monitoring and administer rituximab preemptively in an REFERENCES attempt to decrease the risk for PTLD after allo-BMT, 1. 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Sex and Body Mass Index but Not CXCL12 801 G/A Polymorphism Determine the Efficacy of Hematopoietic Cell Mobilization: A Study in Healthy Volunteer Donors

Juliane Lenk 1, Martin Bornhauser 1,2,*, Michael Kramer 1, Kristina Hölig 1, Kirsten Poppe-Thiede 3, Helmuth Schmidt 4, Markus Wiesneth 5, Kerstin Schaefer-Eckart 6, Peter Schlenke 7, Michael Punzel 4, Sonja Martin 8, Frank Kroschinsky 1, Alexander H. Schmidt 9, Gerhard Ehninger 1, Christian Thiede 1

1 Medizinische Klinik und Poliklinik I, University Hospital, Dresden, Germany 2 Center for Regenerative Therapies, Dresden, Germany 3 Cellex, Zentrum für Zellgewinnung, Dresden, Germany 4 Cellex, Zentrum für Zellgewinnung, Köln, Germany 5 Institut für Klinische Transfusionsmedizin und Immungenetik, University Hospital, Ulm, Germany 6 Medizinische Klinik 5, Klinikum Nürnberg, Germany 7 Institut für Transfusionsmedizin und Transplantationsimmunologie, University Hospital Münster, Germany 8 Hämatologie, Onkologie und Palliativmedizin, Robert Bosch Hospital Stuttgart, Germany 9 DKMS German Bone Marrow Donor Center, Tübingen, Germany

Article history: abstract Received 4 April 2013 Analyses of healthy donors of granulocyte colony-stimulating factor (G-CSF) mobilized hematopoietic stem and Accepted 16 July 2013 progenitor cells (HSPCs) and of patients undergoing autologous stem cell transplantation have suggested that individuals harboring the CXCL12-A allele mobilize a higher number of CD34 þ HSPCs after G-CSF adminis- Key Words: tration. We typed 463 healthy unrelated donors (376 men and 87 women) who had received daily subcuta- CD34þ mobilization neous injections at a mean dose of 7.36 1.71 mg/kg G-CSF for 5 days for CXCL12 801 G/A using a real-time PCR CXCL12 assay. Interestingly, the median concentration of mobilized CD34 þ cells on day 5 was almost identical in Hematopoietic cell donors with the A-allele (79/mL; range, 11 to 249/mL) and the G/G-group (82/mL; range, 15 to 268/mL). In addition, mobilization the allelic distribution was not different in donors (n ¼ 11) who mobilized less than 20/mLCD34þ cells. No Hematopoietic stem and þ þ progenitor cells difference in the overall yield of CD34 cells in the apheresis product and in the number of CD34 cells/kg Healthy volunteer donors recipient could be detected between both groups. In a multivariate regression model for the endpoint G-CSF CD34 þ cells/mL at day 5, only male sex (regression coefficient, 11.5; 95% confidence interval, 1.7 to 21.2, P ¼ .021) and body mass index as continuous variables (regression coefficient, 3.5; 95% confidence interval, 2.5 to 4.5, P ¼ .0001) but not age, smoking status, or CXCL12 allelic status represented independent variables. Our data derived from a large well-controlled cohort contradict previous analyses suggesting an association between CXCL12 allelic status and the yield of CD34 þ HSPC after G-CSF mobilization. Concentration of CD34 þ cells in the peripheral blood, the most objective parameter, could not be predicted by CXCL12 genotype. Ó 2013 American Society for Blood and Marrow Transplantation.

INTRODUCTION Peripheral blood stem cells (PBSCs) collected after mobi- lization with granulocyte colony-stimulating factor (G-CSF) Financial disclosure: See Acknowledgments on page 1521. are the most frequently applied source of hematopoietic stem * Correspondence and reprint requests: Martin Bornhauser, MD, Techni- sche Universität, Medizinische Klinik und Poliklinik I, Universitätsklinikum and progenitor cells (HSPCs) for allogeneic transplantation. Carl Gustav Carus, Fetscherstrasse 74, 01307 Dresden, Germany. This preference is mainly due to a faster engraftment of E-mail address: [email protected] neutrophils and platelets and to a less invasive procedure not (M. Bornhauser). requiring in-hospital stays or general anesthesia [1]. 1083-8791/$ e see front matter Ó 2013 American Society for Blood and Marrow Transplantation. In approximately 75% of donors, one single leukapheresis http://dx.doi.org/10.1016/j.bbmt.2013.07.018 is sufficient to collect the CD34 þ cell dose required, whereas