Bone Marrow Transplantation (2011) 46, 870–875 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11 www.nature.com/bmt ORIGINAL ARTICLE Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage Hodgkin’s lymphoma in Sweden: high incidence of post transplant lymphoproliferative disorder J-E Johansson1, M Remberger2, VLj Lazarevic3, H Hallbo¨o¨k4, A Wahlin5, E Kimby6, G Juliusson3, H Omar6 and H Ha¨gglund6 1Department of Hematology and Coagulation, Sahlgrenska University Hospital, Go¨teborg, Sweden; 2Division of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden; 3Department of Hematology, Ska˚ne University Hospital, Lund University, Lund, Sweden; 4Department of Hematology, Uppsala University Hospital, Uppsala, Sweden; 5Department of Hematology, Cancer Centre, University Hospital, Umea˚, Sweden and 6Hematology Center, Karolinska University Hospital Huddinge, Stockholm, Sweden Allogeneic transplantation after reduced intensity con- compared with conventional dose salvage chemotherapy— ditioning (allo-RIC) is a treatment option for patients with can successfully treat patients with chemosensitive relapsed Hodgkin’s lymphoma (HL) relapsing after autologous Hodgkin’s lymphoma (HL),1,2 no prospective, randomised transplantation. In all, 23 adult patients with HL under- studies have examined how to manage patients with relapse went allo-RIC in Sweden between 2000 and 2007. The or progression after autologous transplant. Several retro- median number of previous treatment lines was five and 20 spective reports have evaluated allogeneic transplantation patients (87%) were previously autografted. TRM at 100 after full intensity conditioning3–6 and several more recent days and at 1 year was 13 and 22% respectively. Acute studies have evaluated allogeneic transplantation after GVHD grades II–IV developed in 7 out of 23 patients reduced intensity conditioning (allo-RIC).7–15 In these (30%) and chronic GVHD in 10 out of 20 patients at risk trials, the selected patients were in an advanced disease (50%). The OS and EFS at three years was 59 and 27%, stage and heavily pre-treated and both TRM and the respectively. Four patients (17%) developed post trans- relapse rates were high. The present trial, the first national plant lymphoproliferative disease (PTLD) after a median compilation study, summarises experiences of allogeneic time of 55 days (range 38–95); two of these patients later transplantation after reduced intensity conditioning in died. The study confirmed that allo-RIC is feasible, adult HL patients in Sweden. but associated with a substantial relapse rate: only 20% of the patients were still alive 7 years after the transplant. A finding of high incidence of PTLD needs to be Patients and methods confirmed in a larger trial that includes patients with non-HL and CLL. The patients and their donors were identified using the Bone Marrow Transplantation (2011) 46, 870–875; Swedish transplant centres’ UPN-lists. Data were collected doi:10.1038/bmt.2010.238; published online 18 October 2010 locally at each participating centre from patient files, local Keywords: allogeneic; transplantation; Hodgkin’s lym- registries and the European Group for Blood and Marrow phoma; post transplant lymphoproliferative disorder; Transplantation (EBMT) database for all adult patients reduced intensity conditioning (X18 years) who had been treated with allogeneic transplantation after reduced intensity conditioning due to HL. In total, 23 patients from five centres were transplanted between January 2000 and December 2007. Data were available for all 23 transplanted patients. One Introduction patient was reported in a previously published EBMT study,16 but data on the remaining 22 patients had not been Although two randomised studies have demonstrated that used in earlier studies. The study protocol was approved by high-dose therapy with autologous stem cell rescue— the Regional Ethical Review Board in Goteborg and patients gave informed consent before transplant. The median number of treatment lines before the Correspondence: Dr J-E Johansson, Department of Hematology and allogeneic transplant was five (range 2–8), and 20 patients Coagulation, Sahlgrenska University Hospital, S-413 45 Go¨teborg, (87%) had previously undergone an autologous transplant. Sweden. E-mail: [email protected] The median time from diagnosis to the allograft was 53 Received 14 June 2010; revised and accepted 23 August 2010; published months (range 17–162 months). Three patients (13%) were online 18 October 2010 chemorefractory at the time of the allograft. The donors Allogeneic transplantation for Hodgkin’s lymphoma J-E Johansson et al 871 were HLA-identical related in three cases (13%), HLA-A, Conditioning regimen -B and –DR identical unrelated in 14 cases (61%) and The conditioning was considered reduced or non-myeloa- mismatched unrelated in six cases (26%). Patient blative according to the consensus criteria proposed by the characteristics are described in Table 1. Regimen-Related Toxicity Working Committee of the Center for International Blood and Marrow Transplant 12,17,18 Table 1 Patient characteristics of the 23 patients included Research, criteria that has been used in other studies. The conditioning regimens used are described in Table 1. Characteristic Measurement Age (Years) 36 (19–49) GVHD prophylaxis Men 13 (57) Women 10 (43) In two cases, CYA alone was used and in the remaining 21 cases CYA together with a short course of MTX was used. Donor Anti-thymocyte globuline was used for in vivo T-cell Matched related 3 (13) depletion before transplant if the donor was unrelated. Matched unrelated 14 (61) Mismatched unrelated 6 (26) Stem cell source CMV serology (recipient/donor) À/À 5 (22) In 17 cases (74%), PBSCs were used and in the remaining À/+ 5 (22) six cases (26%) BM was used. The median CD34 cell dose +/À 8 (35) count was 5.4  106/kg (range 2.1–12.4). +/+ 5 (22) EBV serology (recipient/donor) Statistics +/+ 12 (52) The analysis was performed in February 2010. The À/+ 2 (9) +/À 1 (4) probabilities of overall survival and relapse-free survival unknown/+ 4 (17) were estimated using the method developed by Kaplan– +/unknown 3 (13) Meier and compared with the log-rank test.19 The incidence unknown/unknown 1 (4) of GVHD, TRM and relapse were estimated non-para- metrically. Patients were censored at the time of death, Female donor—male recipient 4 (17) Time from diagnosis to allograft (months) 53 (17–162) relapse, or last follow-up. Relapse and non-relapse No. of previous treatment lines 5 (2–8) mortality are competing events. Their incidence rates were Previously autografted 20 (87) estimated using a non-parametric estimator of cumulative Time from autograft to allograft (months) 22 (9–63) incidence curves.20 Predictive analyses for GVHD, TRM Histological subtype and relapse were based on the proportional hazard model Nodular sclerosis 22 (96) for subdistribution of competing risk. Univariate and Lymphocyte rich 1 (4) multivariate analyses were then performed using Gray’s test and the proportional sub-distribution hazard regres- Status at allo transplantation sion model developed by Fine and Gray.21 All tests were CR or CRu 2 (9) PR 18 (78) two-sided. The type I error rate was fixed at 0.05 for factors Refractory 3 (13) potentially associated with time-to-event outcomes. Analyses were performed using the cmprsk package Conditioning (developed by Gray, June 2001), Splus 6.2 software (S-plus Flu/Mel 14 (61) Flu/Bu 4 (17) 6.2, Insightful, Seattle, WA, USA) and Statistica software Flu/Cy/TBI 3 (13) (Statistica, StatSoft, Tulsa, OK, USA). Flu/Cy 2 (9) Antilymphocyte antibodies used Yes 20 (87) Results No 3 (13) Engraftment and GVHD Stem cell source All 23 patients were engrafted. The median time to reach an BM 6 (26) 9 PBSC 17 (74) ANC of more than 0.5  10 /L and to achieve a platelet count of more than 20  109/L was 17 and 16 days, CD34 dose (  106/kg) 5.4 (2.1–12.4) respectively (Table 2). One patient’s platelet count was never below 20  109/L during the transplant course. Acute GVHD prophylaxis CyA/Mtx 21 (91) GVHD developed in 10 out of 23 patients (43%). Chronic CyA 2 (9) GVHD (cGVHD) developed in 10 out of 20 patients at risk (50%). In all, 7 out of the 10 patients (70%) who developed Abbreviations: Flu/Bu ¼ fludarabine 150 mg/m2, busulphan 8 mg/kg; cGVHD had no previous acute GVHD (de novo cGVHD). Flu/Cy ¼ fludarabine 150 mg/m2, CY 60 mg/kg; Flu/Cy/TBI ¼ fludarabine The extent of cGVHD was limited in two cases and 180 mg/m2, CY 60 mg/kg, TBI 3 Gy  2; Flu/Mel ¼ fludarabine 150 mg/m2, melphalan 140 mg/m2. extensive in eight cases. The 1-year and 3-year cumulative Data are no. of individuals (%) or median (range). Percentage may exceed incidence of cGVHD was 45% (Figure 1). Transplant 100 owing to rounding. outcome is summarised in Table 2. Bone Marrow Transplantation Allogeneic transplantation for Hodgkin’s lymphoma J-E Johansson et al 872 Table 2 Transplantation outcomes (n ¼ 23) 1.0 100 days: 13% 1 year: 22% Follow-up all patients (months) 25 (1–92) 0.8 Follow-up of survivors (months) 46 (3–92) Engraftment 0.6 Neutrophils (days to 40.5  109/L) 17 (11–28) Platelets (days to 420  109/L) 16 (11–35) TRM 0.4 Acute GVHD 0.2 Grades 0–I 16 (70) Grades II–IV 7 (30) 0.0 0 365 730 1095 Day of onset of acute GVHD 22 (16–59) Patients at risk of chronic GVHD 20 Days after HSCT Chronic GVHD Figure 2 Transplant-related mortality. None 13 (65) Limited 2 (10) Extensive 8 (40) Four patients (17%) developed post transplant lympho- proliferative disease (PTLD) after a median time of 55 days Day of onset of chronic GVHD 174 (100–362) (range 38–95), two of these patients died.