Sirolimus in Combination with Tacrolimus in Allogeneic Stem Cell Transplantation—Timing and Conditioning Regimen May Be Crucial
2008; Elsevier BV; Volume: 14; Issue: 8 Linguagem: Inglês
10.1016/j.bbmt.2008.05.004
ISSN1523-6536
AutoresDaniel Wolff, H Andree, Inken Hilgendorf, Jochen Casper, Mathias Freund, Christian Junghanß,
Tópico(s)Polyomavirus and related diseases
ResumoIn a recent issue of Biology of Blood and Bone Marrow Transplantation, Furlong and colleagues [1Furlong T. Kiem H.P. Appelbaum F.R. et al.Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors.Biol Blood Marrow Transplant. 2008; 14: 531-537Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] reported on the results of 2 prospective trials evaluating the combination of Sirolimus (SIR) with either Cyclosporine (CsA) or Tacrolimus (TAC) and additional methotrexate (MTX) for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation from unrelated donors (URD). In contrast to previous publications by Antin and colleagues [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar, 3Cutler C. Antin J.H. Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation.Bone Marrow Transplant. 2004; 34: 471-476Crossref PubMed Scopus (57) Google Scholar], both studies presented by Furlong et al. observed a high rate of toxicity and no reduction in aGVHD, which led to premature termination of both studies because of lack of efficacy. In this context 3 additional aspects need to be discussed.First, in the Furlong study, the immunosuppression combining CsA with SIR started on day −1, whereas in the phase II studies published by Antin et al. [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar] immunosuppression started on day −3. Because SIR has a potential inhibitory effect on function of dendritic cells, the delayed start of immunosuppression may have contributed to the higher rate of aGVHD [4Hackstein H. Taner T. Zahorchak A.F. et al.Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo.Blood. 2003; 101: 4457-4463Crossref PubMed Scopus (326) Google Scholar, 5Monti P. Mercalli A. Leone B.E. Valerio D.C. Allavena P. Piemonti L. Rapamycin impairs antigen uptake of human dendritic cells.Transplantation. 2003; 75: 137-145Crossref PubMed Scopus (151) Google Scholar, 6Woltman A.M. van der Kooij S.W. Coffer P.J. Offringa R. Daha M.R. van Kooten C. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression.Blood. 2003; 101: 1439-1445Crossref PubMed Scopus (131) Google Scholar]. Moreover, in vitro data and comparative clinical studies in renal transplantation showed a higher efficacy and potentially improved toxicity profile of the combination of TAC and SIR compared to CsA and SIR [7Ciancio G. Burke G.W. Gaynor J.J. et al.A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year.Transplantation. 2004; 77: 252-258Crossref PubMed Scopus (134) Google Scholar, 8Ciancio G. Burke G.W. Gaynor J.J. et al.A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year.Transplantation. 2004; 77: 244-251Crossref PubMed Scopus (114) Google Scholar, 9Koenen H.J. Michielsen E.C. Verstappen J. Fasse E. Joosten I. Superior T-cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T-lymphocyte induction, impaired memory responses, and persistent apoptosis.Transplantation. 2003; 75: 1581-1590Crossref PubMed Scopus (47) Google Scholar]. Another potential reason for a higher failure rate may have been the combination of a conditioning regimen containing busulfan (Bu) with an immunosuppression regimen containing TAC and SIR. In prior studies, Bu as well as cyclophosphamide (Cy) have been associated with increased toxicity to endothelial cells via decreased glutathione levels in hepatocytes and subsequent VOD, which potentially overlaps with decreased glutathione synthesis caused by SIR as shown in a rat model [10Bramow S. Ott P. Thomsen N.F. Bangert K. Tygstrup N. Dalhoff K. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin).Pharmacol Toxicol. 2001; 89: 133-139Crossref PubMed Google Scholar, 11DeLeve L.D. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation.Hepatology. 1996; 24: 830-837Crossref PubMed Google Scholar, 12DeLeve L.D. Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes.Pharmacology. 2000; 60: 143-154Crossref PubMed Scopus (88) Google Scholar]. This is supported by a report of Platzbecker et al. [13Platzbecker U. Pabst C. Kiani A. et al.Graft versus host disease prophylaxis with everolimus and tacrolimus in patients with myelodysplastic syndromes and acute myeloid leukaemia receiving allogeneic peripheral blood stem cell transplantation.Blood. 2006; 108: 2886Crossref Google Scholar], who observed an increased rate of VOD after Busulfan-based conditioning regimen and posttransplantation immunosuppression with Everolimus and TAC. Furthermore, the increased endothelial toxicity of the combination of SIR and TAC is reflected by an increased rate of thrombotic microangiopathy, which may have led to dose reduction of the immunosuppression and a subsequent higher rate of GVHD [14Cutler C. Henry N.L. Magee C. et al.Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2005; 11: 551-557Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar].The influence of the conditioning regimen is supported by the results of a retrospective analysis of 8 patients receiving SIR in combination with TAC and MTX after allogeneic peripheral stem cell transplantation at our institution. All 8 patients had high risk features (acute myelogenous leukemia [AML] first partial remission [PR; n = 2], refractory AML [n = 2], secondary myelodysplastic syndromes [MDS] RAEB II [n = 1], CML second AP [n = 1], non-Hodgkin Lymphoma [NHL] second PR [n = 1], and refractory CLL [n = 1]). Donor types were HLA mismatched unrelated n = 4 (8 of 10 [n = 3], 9 of 10 [n = 1], matched unrelated (10 of 10 [n = 2]), and matched related (n = 2). The median age of patients was 59 years (52-65 years). The conditioning regimen consisted of Fludarabine 5 × 30 mg/m2 day –7 to day –3 and Treosulfan either 5 × 10 g/m2 day –7 to day –3 (n = 7) or 3 × 14 g/m2 day –7 to day –5 (n = 1). GVHD prophylaxis consisted of SIR starting on day –2, with a loading dose of 12 mg followed by 4 mg/day and dose adjustment according to plasma levels 5-15 ng/mL. TAC was administered intravenously as continuous infusion beginning on day –2 with an initial dose of 0.03 mg/kg bodyweight and subsequent dose adjustment for plasma levels 5-15 ng/mL. Additional MTX was given with a dose of 5 mg/m2 on days 1, 3, 6, and 11 after transplantation to recipients of unrelated donors. With a median follow-up of 220 days (158-356 days) no treatment-related mortality (TRM) was observed. aGVHD was observed in 2 patients after stop of immunosuppression (grade II [n = 1], grade III [n = 1]), with an onset on days 101 and 172. Moderate steroid-responsive chronic GVHD (cGVHD) occurred in 2 additional patients after the stop of immunosuppression. Two patients with refractory AML before transplantation died because of relapse of AML on days 114 and 180. A relevant side effect because of conditioning-related toxicity of Treosulfan was a transient elevation of liver enzymes. Mild microangiopathy associated solely with mild hemolysis was observed in 3 of 8 patients, which resolved after dose reduction of SIR. Although VOD of the liver was not observed, mild to moderate nephrotoxicity mainly in association with infectious complications was observed in 4 patients, which resolved after dose reduction of TAC.Although the low number of patients does not permit any statistical conclusion, the results are in line with the results published by Antin et al. [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar] in terms of efficacy and toxicity despite the inclusion of 3 patients with unrelated donors differing in 2 HLA alleles with the recipient. Moreover, the use of SIR after conditioning with Treosulfan was not associated with VOD. The discrepant results reported by Furlong and Antin and their colleagues demonstrate the urgent need for comparison of SIR-based immunosuppressive regimens with the current standard based on the combination of a calcineurin inhibitor and MTX in a randomized trial, which is currently recruiting under the sponsorship of the National Cancer Institute (BMT CTN 0402), but timing and conditioning regimen may be of additional relevance. In a recent issue of Biology of Blood and Bone Marrow Transplantation, Furlong and colleagues [1Furlong T. Kiem H.P. Appelbaum F.R. et al.Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors.Biol Blood Marrow Transplant. 2008; 14: 531-537Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar] reported on the results of 2 prospective trials evaluating the combination of Sirolimus (SIR) with either Cyclosporine (CsA) or Tacrolimus (TAC) and additional methotrexate (MTX) for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation from unrelated donors (URD). In contrast to previous publications by Antin and colleagues [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar, 3Cutler C. Antin J.H. Sirolimus for GVHD prophylaxis in allogeneic stem cell transplantation.Bone Marrow Transplant. 2004; 34: 471-476Crossref PubMed Scopus (57) Google Scholar], both studies presented by Furlong et al. observed a high rate of toxicity and no reduction in aGVHD, which led to premature termination of both studies because of lack of efficacy. In this context 3 additional aspects need to be discussed. First, in the Furlong study, the immunosuppression combining CsA with SIR started on day −1, whereas in the phase II studies published by Antin et al. [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar] immunosuppression started on day −3. Because SIR has a potential inhibitory effect on function of dendritic cells, the delayed start of immunosuppression may have contributed to the higher rate of aGVHD [4Hackstein H. Taner T. Zahorchak A.F. et al.Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo.Blood. 2003; 101: 4457-4463Crossref PubMed Scopus (326) Google Scholar, 5Monti P. Mercalli A. Leone B.E. Valerio D.C. Allavena P. Piemonti L. Rapamycin impairs antigen uptake of human dendritic cells.Transplantation. 2003; 75: 137-145Crossref PubMed Scopus (151) Google Scholar, 6Woltman A.M. van der Kooij S.W. Coffer P.J. Offringa R. Daha M.R. van Kooten C. Rapamycin specifically interferes with GM-CSF signaling in human dendritic cells, leading to apoptosis via increased p27KIP1 expression.Blood. 2003; 101: 1439-1445Crossref PubMed Scopus (131) Google Scholar]. Moreover, in vitro data and comparative clinical studies in renal transplantation showed a higher efficacy and potentially improved toxicity profile of the combination of TAC and SIR compared to CsA and SIR [7Ciancio G. Burke G.W. Gaynor J.J. et al.A randomized long-term trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year.Transplantation. 2004; 77: 252-258Crossref PubMed Scopus (134) Google Scholar, 8Ciancio G. Burke G.W. Gaynor J.J. et al.A randomized long-term trial of tacrolimus and sirolimus versus tacrolimus and mycophenolate mofetil versus cyclosporine (NEORAL) and sirolimus in renal transplantation. I. Drug interactions and rejection at one year.Transplantation. 2004; 77: 244-251Crossref PubMed Scopus (114) Google Scholar, 9Koenen H.J. Michielsen E.C. Verstappen J. Fasse E. Joosten I. Superior T-cell suppression by rapamycin and FK506 over rapamycin and cyclosporine A because of abrogated cytotoxic T-lymphocyte induction, impaired memory responses, and persistent apoptosis.Transplantation. 2003; 75: 1581-1590Crossref PubMed Scopus (47) Google Scholar]. Another potential reason for a higher failure rate may have been the combination of a conditioning regimen containing busulfan (Bu) with an immunosuppression regimen containing TAC and SIR. In prior studies, Bu as well as cyclophosphamide (Cy) have been associated with increased toxicity to endothelial cells via decreased glutathione levels in hepatocytes and subsequent VOD, which potentially overlaps with decreased glutathione synthesis caused by SIR as shown in a rat model [10Bramow S. Ott P. Thomsen N.F. Bangert K. Tygstrup N. Dalhoff K. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin).Pharmacol Toxicol. 2001; 89: 133-139Crossref PubMed Google Scholar, 11DeLeve L.D. Cellular target of cyclophosphamide toxicity in the murine liver: role of glutathione and site of metabolic activation.Hepatology. 1996; 24: 830-837Crossref PubMed Google Scholar, 12DeLeve L.D. Wang X. Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes.Pharmacology. 2000; 60: 143-154Crossref PubMed Scopus (88) Google Scholar]. This is supported by a report of Platzbecker et al. [13Platzbecker U. Pabst C. Kiani A. et al.Graft versus host disease prophylaxis with everolimus and tacrolimus in patients with myelodysplastic syndromes and acute myeloid leukaemia receiving allogeneic peripheral blood stem cell transplantation.Blood. 2006; 108: 2886Crossref Google Scholar], who observed an increased rate of VOD after Busulfan-based conditioning regimen and posttransplantation immunosuppression with Everolimus and TAC. Furthermore, the increased endothelial toxicity of the combination of SIR and TAC is reflected by an increased rate of thrombotic microangiopathy, which may have led to dose reduction of the immunosuppression and a subsequent higher rate of GVHD [14Cutler C. Henry N.L. Magee C. et al.Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation.Biol Blood Marrow Transplant. 2005; 11: 551-557Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. The influence of the conditioning regimen is supported by the results of a retrospective analysis of 8 patients receiving SIR in combination with TAC and MTX after allogeneic peripheral stem cell transplantation at our institution. All 8 patients had high risk features (acute myelogenous leukemia [AML] first partial remission [PR; n = 2], refractory AML [n = 2], secondary myelodysplastic syndromes [MDS] RAEB II [n = 1], CML second AP [n = 1], non-Hodgkin Lymphoma [NHL] second PR [n = 1], and refractory CLL [n = 1]). Donor types were HLA mismatched unrelated n = 4 (8 of 10 [n = 3], 9 of 10 [n = 1], matched unrelated (10 of 10 [n = 2]), and matched related (n = 2). The median age of patients was 59 years (52-65 years). The conditioning regimen consisted of Fludarabine 5 × 30 mg/m2 day –7 to day –3 and Treosulfan either 5 × 10 g/m2 day –7 to day –3 (n = 7) or 3 × 14 g/m2 day –7 to day –5 (n = 1). GVHD prophylaxis consisted of SIR starting on day –2, with a loading dose of 12 mg followed by 4 mg/day and dose adjustment according to plasma levels 5-15 ng/mL. TAC was administered intravenously as continuous infusion beginning on day –2 with an initial dose of 0.03 mg/kg bodyweight and subsequent dose adjustment for plasma levels 5-15 ng/mL. Additional MTX was given with a dose of 5 mg/m2 on days 1, 3, 6, and 11 after transplantation to recipients of unrelated donors. With a median follow-up of 220 days (158-356 days) no treatment-related mortality (TRM) was observed. aGVHD was observed in 2 patients after stop of immunosuppression (grade II [n = 1], grade III [n = 1]), with an onset on days 101 and 172. Moderate steroid-responsive chronic GVHD (cGVHD) occurred in 2 additional patients after the stop of immunosuppression. Two patients with refractory AML before transplantation died because of relapse of AML on days 114 and 180. A relevant side effect because of conditioning-related toxicity of Treosulfan was a transient elevation of liver enzymes. Mild microangiopathy associated solely with mild hemolysis was observed in 3 of 8 patients, which resolved after dose reduction of SIR. Although VOD of the liver was not observed, mild to moderate nephrotoxicity mainly in association with infectious complications was observed in 4 patients, which resolved after dose reduction of TAC. Although the low number of patients does not permit any statistical conclusion, the results are in line with the results published by Antin et al. [2Antin J.H. Kim H.T. Cutler C. et al.Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation.Blood. 2003; 102: 1601-1605Crossref PubMed Scopus (142) Google Scholar] in terms of efficacy and toxicity despite the inclusion of 3 patients with unrelated donors differing in 2 HLA alleles with the recipient. Moreover, the use of SIR after conditioning with Treosulfan was not associated with VOD. The discrepant results reported by Furlong and Antin and their colleagues demonstrate the urgent need for comparison of SIR-based immunosuppressive regimens with the current standard based on the combination of a calcineurin inhibitor and MTX in a randomized trial, which is currently recruiting under the sponsorship of the National Cancer Institute (BMT CTN 0402), but timing and conditioning regimen may be of additional relevance. Sirolimus in Combination with Cyclosporine or Tacrolimus Plus Methotrexate for Prevention of Graft-versus-Host Disease following Hematopoietic Cell Transplantation from Unrelated DonorsBiology of Blood and Marrow TransplantationVol. 14Issue 5PreviewIn 2 consecutive prospective clinical trials, we evaluated the efficacy of sirolimus together with a calcineurin inhibitor (cyclosporine or tacrolimus) and low-dose methotrexate for prevention of graft-versus-host disease (GVHD) after unrelated hematopoietic cell transplantation (HCT). Nine patients received sirolimus with cyclosporine, and 17 received sirolimus with tacrolimus. The incidence of grade II-IV GVHD was 77%, with the median onset at day 7 after HCT. Because of toxicity, administration of sirolimus was discontinued earlier than planned in 11 patients, but after the onset of GVHD. Full-Text PDF Open Archive
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