KEY WORDS: Allogeneic, Hematopoietic cell transplantation, Graft-versus-host disease, Immunosuppressants, Cyclosporine, Tacrolimus

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1 A Retrospective Comparison of Tacrolimus versus Cyclosporine with Methotrexate for Immunosuppression after Allogeneic Hematopoietic Cell Transplantation with Mobilized Blood Cells Yoshihiro Inamoto, 1 Mary E. D. Flowers, 1,2 Frederick R. Appelbaum, 1,2 Paul A. Carpenter, 1,3 H. Joachim Deeg, 1,2 Terry Furlong, 1,2 Hans-Peter Kiem, 1,2 Marco Mielcarek, 1,2 Richard A. Nash, 1,2 Rainer F. Storb, 1,2 Robert P. Witherspoon, 1,2 Barry E. Storer, 1,4 Paul J. Martin 1,2 This retrospective study was performed to compare results with tacrolimus versus cyclosporine in combination with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation (HCT) with granulocyte colony-stimulating factor mobilized blood cells. The cohort included 456 consecutive patients who received first allogeneic T cell-replete HCTwith mobilized blood cells from related or unrelated donors after high-intensity conditioning for treatment of hematologic malignancies. Study endpoints included grades II-IV acute graft-versus-host disease (agvhd), grades III-IV agvhd, chronic GVHD (cgvhd), end of treatment for cgvhd, overall mortality, disease-free survival (DFS), recurrent malignancy, and nonrelapse mortality (NRM). Adjusted multivariate Cox regression analysis showed no statistically significant differences between tacrolimus and cyclosporine for any of the endpoints tested. Although the size of the cohort is not sufficient to exclude clinically meaningful differences in outcomes, these results support the continued use of cyclosporine at centers that have not adopted tacrolimus as the standard of care after HCTwith mobilized blood cells after high-intensity conditioning regimens. A larger registry study should be performed to provide more definitive information comparing outcomes with the 2 calcineurin inhibitors. Biol Blood Marrow Transplant 17: (2011) Ó 2011 American Society for Blood and Marrow Transplantation KEY WORDS: Allogeneic, Hematopoietic cell transplantation, Graft-versus-host disease, Immunosuppressants, Cyclosporine, Tacrolimus INTRODUCTION From the 1 Division of Clinical Research, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, Seattle, Washington; 2 Department of Medicine, University of Washington School of Medicine, Seattle, Washington; 3 Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington; and 4 Department of Biostatistics, University of Washington School of Medicine, Seattle, Washington. Financial disclosure: See Acknowledgments on page Correspondence and reprint requests: Paul J. Martin, MD, Fred Hutchinson Cancer Research Center, P.O. Box 19024, Seattle, WA ( pmartin@fhcrc.org). Received December 15, 2010; accepted January 13, 2011 Ó 2011 American Society for Blood and Marrow Transplantation /$36.00 doi: /j.bbmt Graft-versus-host disease (GVHD) is a frequent immunologic complication after allogeneic hematopoietic cell transplantation (HCT). Cyclosporine or tacrolimus in combination with other agents represent widely accepted standards of care as immunosuppressive regimens after HCT. Results of open-label randomized prospective phase III studies have indicated that the risk of grades II-IV acute GVHD (agvhd) after bone marrow transplantation with related or unrelated donors was lower with the use of tacrolimus than with cyclosporine, in combination with methotrexate [1-3]. Overall survival (OS) appeared similar between the groups [1,3], although an imbalanced distribution of risk factors confounded the interpretation of results in 1 of the studies [2,4]. The source of cells used for HCT has changed since the 1990s, when the trials comparing tacrolimus and cyclosporine were done. Granulocyte colony-stimulating factor (G-CSF) mobilized blood cells are now used more frequently than bone marrow cells for HCT in adults with high-intensity conditioning [5,6]. The different composition of grafts between bone marrow and mobilized blood cells might influence the relative efficacy of the 2 calcineurin inhibitors. Outcomes with the 2 calcineurin inhibitors after HCT with G-CSF mobilized blood cells after high-intensity conditioning 1088

2 Biol Blood Marrow Transplant 17: , 2011 Comparison of Tacrolimus versus Cyclosporine after HCT 1089 have not been compared previously. In addition, recent practices, such as the lower targeted concentration of tacrolimus and the use of ursodeoxycholic acid to prevent hepatic complications, could affect the relative efficacy of the 2 calcineurin inhibitors. METHODS Patients The study cohort included 456 consecutive patients who received first allogeneic T cell-replete HCT with G-CSF mobilized blood cells from related or unrelated donors after high-intensity conditioning for treatment of hematologic malignancies between July 1, 2003, and December 31, 2009, at our center. High-intensity (ie, myeloablative ) conditioning regimens included fractionated total-body irradiation (TBI) at $12.0 Gy or busulfan at 4 mg/kg/day or 130 mg/m 2 /day for 4 consecutive days. Only patients who received either tacrolimus or cyclosporine in combination with methotrexate (MTX) for GVHD prophylaxis were included. Patients who received antithymocyte globulin (ATG) to prevent GVHD were excluded. Patients signed consent forms allowing medical records to be used for research, and the institutional review board approved the study. Posttransplant Management All patients received ursodeoxycholic acid from 2 weeks before conditioning until 90 days after HCT to prevent hepatic complications, and all patients received immunosuppression with either tacrolimus or cyclosporine in combination with methotrexate after HCT. Methotrexate was administered at 15 mg/m 2 on day 1 and at 10 mg/m 2 on days 3, 6, and 11 after HCT. Between 2003 and 2005, both tacrolimus and cyclosporine were used in parallel depending on the particular protocol. Thereafter, tacrolimus was the standard adopted for most protocols at our center. Cyclosporine dosing was adjusted to maintain whole blood trough concentrations at 150 to 450 ng/ml, as measured by immunoassay. Tacrolimus dosing was adjusted to maintain concentrations at 5 to 15 ng/ml, as measured by a liquid chromatography-tandem mass spectrometry assay for the parent compound. Study Endpoints Study endpoints included grades II-IV agvhd, grades III-IV agvhd, chronic GVHD (cgvhd), end of systemic treatment for cgvhd (ie, duration of treatment for patients with cgvhd), overall mortality, disease-free survival (DFS), recurrent malignancy, and nonrelapse mortality (NRM). Acute GVHD was graded according to previously described criteria [7], and cgvhd was diagnosed according to NIH criteria [8]. Grade II GVHD was subdivided according to the extent of liver and skin involvement [9]. Most patients with grade IIa GVHD had upper gastrointestinal symptoms, with or without stage 1 or stage 2 skin involvement (ie, \50% body surface affected by rash) and no liver involvement. Grade IIb GVHD included patients with stage 3 skin disease ($50% body surface affected by rash) or stage 1 liver involvement. Statistical Analysis Kaplan-Meier estimates were used for OS and DFS, and cumulative incidence estimates were used for other endpoints [10]. Multivariate Cox regression models were used to evaluate hazard ratios for results of tacrolimus compared with cyclosporine. The models were adjusted for patient age, donor type, recipient and donor gender combination, disease type, disease risk category, use of TBI in the conditioning regimen, and year of HCT. The analysis was performed during July RESULTS Patient Characteristics The median age of patients was 47 years (range: 1-66 years). Of the 456 patients, 232 (51%) had HLA-identical related donors, 187 (41%) had HLA-matched unrelated donors, and 37 (8%) had HLA-mismatched related or unrelated donors. The distributions of diagnoses at transplant, HLA-matching and donor type, and year of transplantation showed statistically significant differences according to type of immunosuppression (Table 1). Transplant Outcomes The median duration of follow-up among survivors was 45 months (range: 3-85 months) after HCT. Cumulative incidence rates of grades II-IV, IIb-IV, and III-IV agvhd at 120 days were 71%, 55%, and 11%, respectively, and the cumulative incidence of cgvhd at 3 years after HCT was 44%. The cumulative incidence of discontinued systemic treatment for cgvhd at 2 years after the onset of treatment for cgvhd was 16%. The remaining patients with cgvhd either continued treatment for more than 2 years or died or had recurrent malignancy during continued treatment within 2 years after the onset of the disease. OS and DFS rates at 3 years after HCT were 62% and 55%, respectively. The cumulative incidence rates of recurrent malignancy and NRM at 3 years after HCT were 28% and 18%, respectively. Multivariate Analysis of Outcomes for Tacrolimus Compared with Cyclosporine Adjusted multivariate Cox regression analysis showed no statistically significant differences between

3 1090 Y. Inamoto et al. Biol Blood Marrow Transplant 17: , 2011 Table 1. Patient Characteristics According to Type of Immunosuppression Characteristic Tacrolimus (n 5 292) Cyclosporine (n 5 164) P value Patient age (years), median (range) 47 (1-66) 46 (9-64).60 Diagnosis at transplant, no. (%) <.0001 Acute myeloid leukemia 125 (43) 59 (36) Acute lymphoblastic leukemia 51 (17) 21 (13) Chronic myeloid leukemia 16 (5) 31 (19) Myelodysplastic syndromes or myeloproliferative neoplasms 86 (29) 40 (24) Other (CLL, HD, NHL, MM) 14 (5) 13 (8) Disease risk category at transplant,* no. (%).31 Low risk 168 (58) 86 (52) Intermediate risk 14 (5) 13 (8) High risk 110 (38) 65 (40) Donor/patient gender, no. (%).49 Female/male 78 (27) 39 (24) Other 214 (73) 125 (76) High intensity conditioning regimens, no. (%).98 with total-body irradiation ($1200 cgy) 100 (34) 56 (34) without total-body irradiation 192 (66) 108 (66) HLA-matching and donor type, no. (%) <.0001 HLA-identical related 147 (50) 85 (52) HLA-matched unrelated 135 (46) 52 (32) HLA-mismatched 10 (3) 27 (16) Year of transplantation, no. (%) < (1) 132 (80) (40) 26 (16) (59) 6 (4) CLL indicates chronic lymphocytic leukemia; HD, Hodgkin lymphoma; NHL, non-hodgkin lymphoma; MM, multiple myeloma; HLA, human leukocyte antigen. *The low-risk category included chronic myeloid leukemia in chronic phase, acute leukemia in remission, and refractory anemia without excess blasts. The intermediate-risk category included CLL, HD, NHL, and MM. The high-risk category included all other diseases and stages. tacrolimus and cyclosporine for any of the endpoints tested (Table 2). Further analysis did not identify any subgroup according to age, diagnosis, disease risk, recipient and donor gender combination, conditioning regimen, or donor type in which the risk of grades II-IV GVHD was lower with tacrolimus than with cyclosporine (data not shown). DISCUSSION Our retrospective results, which demonstrate that tacrolimus offered no statistically significant advantage over cyclosporine for preventing grades II-IV agvhd, contrast with results from 3 previous randomized prospective studies, which all demonstrated that the risk of agvhd after bone marrow transplantation was lower with the use of tacrolimus compared with cyclosporine [1-3]. At least 2 explanations might account for the different results. First, the higher risks of agvhd and cgvhd after HCT with G-CSF mobilized blood cells compared with bone marrow might influence the relative efficacy of the 2 calcineurin inhibitors [11-14]. Second, the targeted whole blood concentration of tacrolimus used at our center was lower than the concentrations evaluated in the prospective trials (10-40, 10-30, and ng/ml, respectively) [1-3], but other studies have suggested that tacrolimus levels.20 ng/ml increased the risk of toxicity without decreasing the risk of GVHD [15,16]. Table 2. Multivariate Analysis of Outcomes for Tacrolimus Compared with Cyclosporine Endpoint No. of Events Hazard Ratio* (95% CI) P value Grades II-IV acute GVHD ( ).52 Grades IIb-IV acute GVHD ( ).41 Grades III-IV acute GVHD ( ).19 Chronic GVHD ( ).61 End of systemic treatment for chronic GVHD ( ).73 Overall mortality ( ).86 Disease-free survival ( ).67 Recurrent malignancy ( ).25 Nonrelapse mortality ( ).54 CI indicates confidence interval; GVHD, graft-versus-host disease. *The models were adjusted for patient age, donor type, recipient, and donor gender combination, disease type, disease risk category, use of total-body irradiation in the conditioning regimen, and year of transplantation. See Methods for definition of grade IIb GVHD.

4 Biol Blood Marrow Transplant 17: , 2011 Comparison of Tacrolimus versus Cyclosporine after HCT 1091 Our results showing no statistically significant differences with the 2 calcineurin inhibitors in OS, DFS, and recurrent malignancy after mobilized blood cell transplantation are consistent with results from previous studies of bone marrow transplantation [1,4]. A randomized, prospective Japanese study showed an increased incidence of recurrent malignancy with tacrolimus after bone marrow transplantation from related donors [3], but this effect was not observed in a large, retrospective Japanese study [17] or in a randomized, prospective U.S. study [2]. The retrospective Japanese study showed that the risk of NRM after bone marrow transplantation from unrelated donors was lower with tacrolimus than with cyclosporine [17].Inthatstudy,thelowerriskofNRM in the tacrolimus group was associated with a lower risk of agvhd and higher survival compared with the cyclosporine group. The Japanese results differ from those observed in our retrospective study, suggesting that the type of graft or the ethnicity of patients might influence the relative efficacy of calcineurin inhibitors. The routine use of prophylactic ursodeoxycholic acid started at our center in 2003 [18,19] and has decreased the incidence of agvhd and hepatic complications (data not shown). The choice of calcineurin inhibitor was changed to tacrolimus for virtually all transplant protocols with high-intensity conditioning at our center in early Although we do not believe that any other transplant practices have changed during the study period, we cannot completely exclude effects of unknown confounders even if the multivariate analysis is adjusted for year of transplantation. The incidence of grades II-IV agvhd at our center is higher than reported at other centers, reflecting a high sensitivity for diagnosing upper gastrointestinal GVHD [20]. Even so, we believe that our results showing no difference in the risk of grades II- IV agvhd are likely to be representative of experience at other centers, because we found no statistically significant advantage for tacrolimus in preventing more severe grades IIb-IV or III-IV GVHD. Our results support the continued use of cyclosporine at centers that have not adopted tacrolimus as the standard of care after HCT with mobilized blood cells after high-intensity conditioning regimens, but the size of our cohort is not sufficient to exclude clinically meaningful differences in outcomes with the 2 calcineurin inhibitors. A larger registry study should be performed to provide more definitive information comparing outcomes with the 2 calcineurin inhibitors. ACKNOWLEDGMENTS Y.I. is a recipient of Banyu Fellowship from Banyu Life Science Foundation International. The authors declare no competing financial interests. 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