Tacrolimus instead of cyclosporine used for prophylaxis against graft-versus-host disease improves outcome after hematopoietic stem cell transplantation from unrelated donors, but not from HLA-identical sibling donors: a nationwide survey conducted in Japan

Abstract

Summary:Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSPbased and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, Po0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P ¼ 0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P ¼ 0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.

Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation

“…One possible explanation for this change is a decreased incidence of grade III-IV acute GVHD, particularly involving the gut and liver. Advances in HLA typing technology 15 and GVHD prophylaxis, 16 as well as early detection of and intervention in GVHD, 17 Abbreviations: AML = acute myeloid leukemia; ALL = acute lymphoblastic leukemia; ATL = adult T-cell leukemia/lymphoma; CML = chronic myeloid leukemia; HCT-CI = hematopoietic cell transplant comorbidity index; MDS = myelodysplastic syndrome; ML = malignant lymphoma; MPD = myeloproliferative disease; NRM = non-relapse mortality; PS = performance status; 95% CI= 95% confidence interval. Odds ratio (95% CI) a P-value Odds ratio (95% CI) a P-value Non-relapse mortality after stem cell transplantation Y Tanaka et al lower risk of bacterial infection due to bacterial translocation from the intestinal tract.…”

Target blood concentrations of CYA and tacrolimus in randomized controlled trials for the prevention of acute GVHD after hematopoietic SCT

“…10 In addition, an increase in the target blood concentration from 300 to 500 ng/ml in continuously infused-CYA significantly decreased the incidence of acute GVHD. 11 This difference was more prominent in transplantation from an unrelated donor, similar to the fact that the difference in the incidence of acute GVHD between patients who received CYA and those who received TAC was observed only in unrelated donor transplantation 5,11 (Table 2). Therefore, continuous infusion of CYA with a target concentration at 500 ng/ml may be as effective as TAC with a target concentration used in our daily practice.…”

“…[1][2][3][4] A large retrospective study in Japan also revealed that the incidence of grades II-IV acute GVHD was significantly lower in patients who received TAC than in those who received CYA in matched unrelated donor transplantation, whereas no such difference was observed in matched sibling donor transplantation. 5 Although it is difficult to directly compare the incidence of GVHD among these studies because of the difference in the study population, these findings suggest that although TAC is more effective than CYA for preventing acute GVHD, this benefit does not confer a survival benefit, probably because of increased toxicities.…”

Recent decrease in non-relapse mortality due to GVHD and infection after allogeneic hematopoietic cell transplantation in non-remission acute leukemia

“…There have been substantial improvements in HLA typing over the period of 1997-2008, with more accuracy in defining HLA haplotypes at highresolution. 26,27 In addition to high-resolution donor-recipient HLA matching, the more frequent use of tacrolimus, [28][29][30] the prompt initiation of treatment after a more thorough examination to diagnose GVHD, 31 and supportive care and nutritional management 32 may have contributed to the reduced risk of GVHD-related mortality as did in allo-HCT in remission. Alternatively, the unique HLA epidemiological genetics of Japanese patients may have affected the results.…”