Prophylaxis with Sirolimus and Tacrolimus ± Antithymocyte Globulin Reduces the Risk of Acute Graft-versus-Host Disease without an Overall Survival Benefit Following Allogeneic Stem Cell Transplantation
2010; Elsevier BV; Volume: 17; Issue: 6 Linguagem: Inglês
10.1016/j.bbmt.2010.09.017
ISSN1523-6536
AutoresLindsay Rosenbeck, Patrick J. Kiel, Iftekhar Kalsekar, Craig Vargo, John Baute, Cheryl K Sullivan, Lisa L. Wood, S. Abdelqader, Jennifer E. Schwartz, Shivani Srivastava, Rafat Abonour, Michael J. Robertson, Robert P. Nelson, Kenneth Cornetta, Christopher A. Fausel, Sherif Farag,
Tópico(s)Acute Myeloid Leukemia Research
ResumoMethotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival. Methotrexate (MTX) is a standard agent used in combination with calcineurin inhibitors for graft-versus-host disease (GVHD) prophylaxis in patients undergoing allogeneic hematopoietic cell (HCT) transplantation. We retrospectively compared the incidence of acute GVHD (aGVHD), transplant-related morbidity, and mortality in patients given sirolimus/tacrolimus ± antithymocyte globulin (ATG) versus MTX/tacrolimus or cyclosporine and allogeneic transplantation for hematologic malignancies. Between January 1, 2005, and April 30, 2009, 106 consecutive patients received peripheral blood HCT or bone marrow grafts after 1 of 6 myeloablative conditioning regimens. The incidence of grade II-IV aGVHD was 18.6% in patients who received sirolimus/tacrolimus compared to 48.9% who received MTX (P = .001). The incidence of grade III-IV aGVHD was 5% and 17% (P = .045), respectively. There was no difference in overall survival (OS) between the groups (P = .160). Chronic GVHD (cGVHD) occurred in 40.4% who received sirolimus and 41.9% receiving MTX (P = .89). The incidence of thrombotic microangiopathy or interstitial pneumonitis was not significantly different between groups. The reduction in the risk of severe aGVHD was offset by an increased (20% versus 4%, P = .015) incidence of and mortality from sinusoidal obstructive syndrome (SOS). Sirolimus/tacrolimus appears to reduce the incidence of aGVHD after conventional allotransplantion compared to MTX-calcineurin inhibitor prophylaxis; however, this did not improve survival. IntroductionGraft-versus-host disease (GVHD) remains 1 of the most important complications of hematopoietic cell transplantation (HCT). Currently, methotrexate (MTX) plus a calcineurin inhibitor serves as the standard for GVHD prophylaxis [1Storb R. Deeg H.J. Whitehead J. et al.Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease in marrow transplantation in for leukemia.N Engl J Med. 1986; 314: 729-735Crossref PubMed Scopus (1181) Google Scholar, 2Storb R. Deeg H.J. Pepe M. et al.Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow up of a controlled trial.Blood. 1989; 73: 1729-1734PubMed Google Scholar]. Using this combination, the incidence of grade II-IV GVHD ranges from 35% to 50% with matched, related donors (MRD), and approximately 40% to 70% after matched, unrelated donor (MUD) transplants [3Weisdorf D.J. Anasetti C. Antin J.H. et al.Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus match sibling donor transplantation.Blood. 2002; 99: 1971-1977Crossref PubMed Scopus (168) Google Scholar, 4Nash R.A. Antin J.H. Karanes C. et al.Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors.Blood. 2000; 96: 2062-2068PubMed Google Scholar, 5Ratanatharathorn V. Nash R.A. Przepiorka D. et al.Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.Blood. 1998; 92: 2303-2314PubMed Google Scholar].Sirolimus, the first inhibitor of the mammalian target of rapamycin (mTOR), binds to FK506 binding protein 12 (FKBP12) to inhibit several biochemical pathways that prevent progression of cells from S to G1 phase and interferes with signal transduction that mediates cytokine responses [6Sehgal S.N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.Clin Biochem. 1998; 31: 335-340Crossref PubMed Scopus (619) Google Scholar]. The unique mechanisms of sirolimus permit the inhibition of T cell proliferation rather than interleukin-2 production [6Sehgal S.N. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression.Clin Biochem. 1998; 31: 335-340Crossref PubMed Scopus (619) Google Scholar, 7Powell J.D. Lerner C.G. Schwartz R.H. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation.J Immunol. 1999; 162: 2775-2784PubMed Google Scholar]. Sirolimus also assists in expanding T-regulatory cells influencing alloreactivity, whereas calcineurin inhibitors are thought to negatively affect these cells [8Wekerle T. T-regulatory cells—what relationship with immunosuppressive agents?.Transplant Proc. 2008; 40: S13-S16Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar].Powell et al. [9Powell J.D. Fitzhugh C. Kang E.M. Hsieh M. Schwartz R.H. Tisdale J.F. Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.Transplantation. 2005; 80: 1541-1545Crossref PubMed Scopus (30) Google Scholar] demonstrated that sirolimus induced immunologic tolerance in cell cultures and after low-dose radiation in murine models, which suggested that sirolimus facilitates donor chimerism after transplantation for nonmalignant disorders. Sirolimus permitted the achievement of mixed-donor chimerism and reversed the sickle cell phenotype following nonmyeloablative allogeneic transplantation in 10 adult patients [10Hsieh M.M. Kang E.M. Fitzhugh C.D. et al.Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.N Engl J Med. 2009; 361: 2309-2317Crossref PubMed Scopus (312) Google Scholar]. These data suggest that sirolimus has the potential to induce immunologic tolerance that may account for the decrease in the incidence of acute GVHD (aGVHD) following allogeneic HCT when used in combination with tacrolimus [9Powell J.D. Fitzhugh C. Kang E.M. Hsieh M. Schwartz R.H. Tisdale J.F. Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.Transplantation. 2005; 80: 1541-1545Crossref PubMed Scopus (30) Google Scholar, 10Hsieh M.M. Kang E.M. Fitzhugh C.D. et al.Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.N Engl J Med. 2009; 361: 2309-2317Crossref PubMed Scopus (312) Google Scholar, 11Wu T. Sozen H. Luo N. et al.Rapamycin and T cell costimulatory blockade as post-transplant treatment promote fully MHC-mismatched allogeneic bone marrow engraftment under irradiation-free conditioning therapy.Bone Marrow Transplant. 2002; 29: 949-956Crossref PubMed Scopus (20) Google Scholar]. Additionally, sirolimus improves solid-organ allograft survival while preserving renal function [12Flechner S.M. Reviewing the evidence for de novo immunosuppression with sirolimus.Transplant Proc. 2008; 40: S25-S28Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar].Cutler et al. [13Cutler C. Ho V. Koreth J. et al.Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation.Blood. 2007; 109: 3108-3114PubMed Google Scholar] successfully utilized sirolimus and tacrolimus without MTX in a phase II trial of 83 patients undergoing HCT. The incidence of aGVHD was 20.5%, and the 30- and 100-day mortality rates were 0% and 4.8%, respectively. No difference was observed between MRD and MUD transplants with respect to the incidence of GVHD, transplant-related toxicity, and relapse-free (RFS) or overall survival (OS).Reports of sirolimus used with reduced-intensity conditioning (RIC) regimens suggest the agent to be effective in preventing GVHD with an acceptable safety profile [14Cutler 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, 15Armand P. Gannamaneni S. Kim H. et al.Improved survival in lymphoma patients recieving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning.J Clin Oncol. 2008; 26: 5756-5774Crossref Scopus (91) Google Scholar, 16Ho V. Aldridge J. Kim H. et al.Comparison of tacrolimus and sirolimus (Tac/Sir) versus tacrolimus, sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.Biol Blood Marrow Transplant. 2009; 15: 844-850Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar]. The utilization of mTOR inhibitors for antineoplastic effects has led to exploration of their use for the treatment of lymphoma [15Armand P. Gannamaneni S. Kim H. et al.Improved survival in lymphoma patients recieving sirolimus for graft-versus-host disease prophylaxis after allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning.J Clin Oncol. 2008; 26: 5756-5774Crossref Scopus (91) Google Scholar]. Patients with lymphoma who received sirolimus for GVHD prophylaxis experience a lower incidence of disease progression and improved survival compared with patients who did not receive sirolimus. The 100-day cumulative incidence of grade II-IV aGVHD was 14% in the sirolimus group compared to 22% in the group not receiving sirolimus.Numerous complications following HCT include drug and nondrug toxicities. Thrombotic microangiopathy (TMA) and interstitial pneumonitis (IP) are severe adverse events following allogeneic stem cell transplant and can be attributed to the transplant itself, but also to calcineurin and mTOR inhibitors [17Cutler 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, 18Pham P.T. Pham P.C. Danovitch G.M. et al.Sirolimus-associated pulmonary toxicity.Transplantation. 2004; 77: 1215-1220Crossref PubMed Scopus (261) Google Scholar, 19Garrean S. Massad M.G. Tshibaka M. Hanhan Z. Caines A.E. Benedetti E. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients.Clin Transplant. 2005; 19: 698-703Crossref PubMed Scopus (87) Google Scholar]. Sinusoidal obstructive syndrome (SOS) is a serious liver complication following myeloablative therapy after HCT, which has an occurrence rate of 5% to 15% [20McDonald G.B. Sharma P. Matthews D.E. Shulman H.M. Thomas E.D. Venocclusive disease of the liver after bone marrow transplantation: diagnosis, incidence, and predisposing factors.Hepatology. 1984; 4: 116-122Crossref PubMed Scopus (738) Google Scholar]. Data suggest an increased risk of SOS with sirolimus when used in GVHD prophylaxis [21Cutler C. Stevenson K. Kim H.T. et al.Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation.Blood. 2008; 112: 4425-4431Crossref PubMed Scopus (116) Google Scholar]. In this study, we report our experience using sirolimus and tacrolimus for prophylaxis of GVHD since adopting this regimen in January 2007, and compare the incidence of aGVHD following this regimen relative to MTX/calcineurin-based immunosuppression.Patients and MethodsStudy Design and Patient EligibilityThis study was a retrospective analysis conducted at Indiana University Simon Cancer Center (IUSCC), Indianapolis, Indiana. Data were collected from 106 consecutive patients between January 1, 2005 and April 30, 2009. The Indiana University-Purdue University institutional review board approved this observational study. Patients at our institution prior to January 1, 2007 primarily received MTX with either cyclosporine or tacrolimus for GVHD prophylaxis. After January 1, 2007, consecutive patients treated on standard-of-care regimens were given sirolimus/tacrolimus for GVHD prophylaxis, with antithymocyte globulin (ATG) also administered to recipients of mismatched, related donor or MUD transplants. However, some patients were specifically enrolled on research protocols where MTX-based regimens were mandated; and the decision to enroll was independent of knowledge of GVHD prophylactic regimen. The primary endpoints of the study were to compare the incidence of aGVHD in the first 100 days following transplantation. Secondary endpoints included the incidence of chronic GVHD (cGVHD), SOS, TMA, IP, and mortality.Patients were included in the analysis if they were aged 18 years of age or older, received a myeloablative preparative regimen for transplantation for hematologic malignancy, and had received either MTX plus either cyclosporine or tacrolimus, or sirolimus/tacrolimus. All patients and recipients were matched at least at HLA-A, -B, and -DRB1 (high-resolution typing); those mismatched were mismatched at HLA-C and/or -DQB1. Patients were excluded if they received reduced-intensity regimens, haploidentical, syngeneic, or umbilical cord donor cells, or had more than 2 prior transplants. Transplantation risk was defined as “low” for patients with acute leukemia in first or subsequent remission, or chronic myeloid leukemia in chronic phase. All others were considered “high” risk.GVHD ProphylaxisPatients received MTX, 15 mg/m2 on day +1 followed by MTX, 10 mg/m2 on days +3, +6, and +11. In combination with MTX, cyclosporine was administered, 1.5 mg/kg intravenously (i.v.) every 12 hours beginning on day −1 with targeted serum concentrations of 200 to 300 ng/mL. Tacrolimus 0.02 mg/kg/day, i.v. by continuous infusion was started on day −3, targeting serum concentrations of 5 to 10 ng/mL. Sirolimus was begun on day −3, with a loading dose of 12 mg orally followed by 4 mg once daily (starting on day −2) to maintain a serum level of 5 to 15 ng/mL by microparticle enzyme immunoassay. Tacrolimus was administered to both groups similarly. Drug levels were monitored at least 3 times per week during hospitalization; cyclosporine and tacrolimus were changed to oral formulations prior to discharge. In the absence of GVHD, tapering of immunosuppression began on day +100 as tolerated, with a goal of stopping by day +180. Patients who received unrelated or mismatched donor cells, primarily after January 1, 2007, were also given rabbit ATG, 2.5 mg/kg i.v. on days −3, −2, and −1. Filgrastim, 5 μg/kg, subcutaneously (s.c.), was given daily starting on day 0 until the absolute neutrophil count (ANC) was >2000/μL for 2 days or 10,000/μL for 1 day. All patients received acyclovir, fluconazole, and ciprofloxacin for antimicrobial prophylaxis. After engraftment, sulfamethoxazole/trimethoprim or pentamidine was initiated for Pneumoncystis jiroveci prophylaxis. Cytomegalovirus (CMV) viral load was monitored weekly and a preemptive therapy utilized for reactivation [22Boeckh M. Myerson D. Bowden R.A. Early detection and treatment of cytomegalovirus infections in marrow transplant patients: methodological aspects and implications for therapeutic interventions.Bone Marrow Transplant. 1994; 14: S66-S70PubMed Google Scholar]. Acute GVHD and cGVHD were graded according to previously published criteria [23Przepiorka D. Weisdorf D. Martin P. et al.1994 Consensus conference on acute GVHD grading.Bone Marrow Transplant. 1995; 15: 825-882PubMed Google Scholar, 24Shulman H.M. Sullivan K.M. Weiden P.L. et al.Chronic graft-versus-host syndrome in man: a long term clinicopathologic study of 20 Seattle patients.Am J Med. 1980; 69: 204-217Abstract Full Text PDF PubMed Scopus (2137) Google Scholar], and biopsy was required for confirmation of diagnosis.Statistical AnalysisAnalysis was performed based on an intent-to-treat basis. Baseline demographic and clinical characteristics between the 2 study groups were compared using the chi-square or Fisher exact test for categoric variables and the Student t test or Mann-Whitney U test as appropriate. Data for the analysis were sealed on October 31, 2009, allowing a minimum of 6 months follow-up for all patients. The time to aGVHD and to OS between the 2 groups was estimated using Kaplan-Meier analysis [25Kaplan E. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 457-481Crossref Scopus (47675) Google Scholar] and compared using the log-rank test [26Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration.Cancer Chemother Rep. 1966; 50: 163-170PubMed Google Scholar]. Multivariate analysis was performed to examine the impact of the GVHD prophylactic regimen on risk of aGVHD and survival. A stepwise (forward conditional) Cox-proportional hazards model [27Cox D.R. Regression models and life-tables.J R Stat Soc B. 1972; 34: 187-220Google Scholar] was used. The model included the following variables: type of prophylactic regimen, transplant date (prior or after January 1, 2007) and disease risk. The remaining control variables such as age, sex, HLA mismatch, type of donor (related or unrelated), sex mismatch, underlying malignancy, stem cell source (bone marrow versus peripheral blood), conditioning regimen, donor and recipient CMV status, and ATG use were entered in the model in a stepwise fashion. All the survival models were tested for the proportionality hazards assumption. Univariate and multivariate logistic regression (forward conditional models similar to the Cox proportional hazards models) were used to assess the impact of the prophylactic regimen on the incidence of SOS, TMA, and IP. All statistical analyses were performed using SPSS 17.0 (SPSS, Inc., Chicago, IL) and STATA 9.0 (STATA Corp., College Station, TX). Statistical significance was set at 0.05 (2 sided).ResultsPatient and Transplant CharacteristicsTable 1 summarizes the baseline characteristics of the 2 groups. Fifty-nine patients received sirolimus/tacrolimus and 47 received MTX-based immunosuppression. Of patients receiving MTX, 33 (70%) received cyclosporine and 14 (30%), tacrolimus. The median (range) ages for the sirolimus and MTX groups were 44 (21-59) and 39 (20-57) years, respectively (P = .069). Thirty-four (57%) in the sirolimus group and 19 (40%) patients in the MTX group received stem cells from unrelated donors (P = .078). Eleven patients in the tacrolimus/sirolimus group had unrelated donors and mismatched at 1 locus (9 of 10). Two patients were mismatched at 2 loci (8 of 10), 1 with an unrelated donor and 1 a related donor. Of the patients with unrelated donors in the MTX group, 7 were mismatched 9 of 10, and 1 was an 8 of 10 mismatch. One patient was a 5 of 6 HLA mismatch with a related donor. Other baseline characteristics were similar between the groups (Table 1) with the exception that the sirolimus group had a higher proportion of patients with acute leukemia (P = .007) and a greater fraction received ATG (P < .001). The percentage of patients having high-risk AML was similar between the 2 groups (P = .873). Conditioning regimens were classified as either radiation-based (total-body irradiation [TBI]/cyclophosphamide [Cy] and TBI/etoposide) or chemotherapy-based (busulfan [Bu]/Cy, Bu/clofarabine, Bu/fludarabine, or thiotepa/Cy). Mean tacrolimus and sirolimus levels calculated from day 0 to day +35 were 8.8 ng/mL and 9.6 ng/mL, respectively.Table 1Baseline CharacteristicsSirolimus/TacrolimusMTX-BasedP Valuen = 59n = 47Median age, years (range)44 (21-59)39 (20-57)0.069Male sex, n (%)28 (48)25 (55)0.441Matched, unrelated donors, n (%)34 (58)19 (40)0.078HLA mismatched, n (%)13 (22)9 (19)0.716Sex mismatch, n (%)29 (49)23 (49)0.982Disease Acute leukemia, n (%)50 (85)30 (64)0.007ALL11 (19)9 (19)MDS5 (8)3 (6)AML34 (58)18 (38) Other, n (%)9 (15)17 (36)CML/CMML4 (7)7 (15)NHL4 (7)9 (19)Myelofibrosis1 (2)1 (2)High-risk leukemia11 (18.6)6 (12.8)0.413Stem cell source0.261 Peripheral blood, n (%)47 (80)33 (70) Bone marrow, n (%)12 (20)14 (30)CMV status Recipient seropositive, n (%)35 (59)27 (57)0.846 Donor seropositive, n (%)26 (44)18 (38)0.549Conditioning regimen Radiation-based32 (54)21(45)0.328TBI/Cy21 (36)16 (34)TBI/Etoposide11 (19)5 (11) Chemotherapy-based27 (46)26 (55)Busulfan/Cy024 (51)Busulfan/clofarabine14 (24)0Busulfan/fludarabine8 (14)2 (4)Thiotepa/Cy5 (9)0Received ATG, n (%)28 (48)1 (2)<0.001HLA indicates human leukocyte antigen; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia; NHL, non-Hodgkin lymphoma; CMV, cytomegalovirus; TBI, total-body irradiation; Cy, cyclophosphamide; ATG, antithymocyte globulin. Open table in a new tab Acute GVHDThe incidence of grade II-IV aGVHD before day +100 was 18.6% (11 of 59) in patients receiving sirolimus/tacrolimus, compared to 48.9% (23 of 47) receiving MTX (P = .001). The incidence of grade III-IV aGVHD was 5.1% (3 of 59) and 17% (8 of 47) for the sirolimus and MTX groups, respectively (P = .045). As show in Figure 1, the risk of developing aGVHD was significantly lower in patients who received sirolimus and tacrolimus (P = .002). Among patients who developed aGVHD by day +100, the mean time to develop aGVHD was 90 days, compared to 70 days for those who received a MTX-based regimen (P = .002). The results of multivariate analysis are shown in Table 2. After controlling for other baseline demographic, clinical, and treatment characteristics, the hazard for aGVHD in patients using MTX-based prophylaxis was 5.8 times higher than those given the sirolimus/tacrolimus regimen (P = .002). The only other significant variable affecting risk of aGVHD was recipient CMV status hazard ratio (HR) 2.84 (95% confidence interval [CI], 1.28-6.29). Having an unrelated donor and HLA mismatch also did not appear to affect incidence or severity of GVHD. Two of 12 with mismatched, unrelated donors receiving tacrolimus/sirolimus/ATG developed GVHD. In the MTX group, 4 of the 8 with mismatched, unrelated donors developed GVHD, 1 being grade 4.Table 2Cox-proportional Hazard Model for the Impact of Type of Prophylactic Regimen on Acute GVHD and SurvivalAcute GVHDOverall SurvivalHazard Ratios(95% Confidence Interval)P ValueHazard Ratios(95% Confidence Interval)P ValueMethotrexate as a prophylactic agent (reference: Sirolimus)5.84 (1.96-17.4)0.0020.69 (0.23-2.14)0.525Transplant (day 0) prior to Jan 20070.5 (0.2-1.25)0.141.4 (0.48-4.13)0.54High-risk leukemia1.01 (0.36-2.8)0.991.4 (0.64-2.95)0.42GVHD indicates graft-versus-host disease; MUD, matched, unrelated donor; CMV, cytomegalovirus.The stepwise forward conditional models were additionally controlled for the following variables: age, sex, HLA mismatch, type of donor (related or unrelated), sex mismatch, underlying malignancy, stem cell source (bone marrow versus peripheral blood), conditioning regimen, donor and recipient CMV status, and ATG use. Open table in a new tab SurvivalSurvival at days +30 and +100 were similar between the sirolimus/tacrolimus group and MTX group. At day +30, 96.6% (57/59) of patients receiving sirolimus and 97.9% (46 of 47) receiving MTX were alive (P = .697). By day +100, 79.9% (47 of 59) and 91.4% (43 of 47) of patients were living in each group, respectively (P = .091). There was no difference in OS between the prophylactic regimens (log-rank, P = .160) (Figure 2A). As shown in Table 2 for multivariable analysis, no significant association was observed between the GVHD prophylactic regimen and OS after adjusting for other variables. Patient age, HR 1.03 (95% CI, 1-1.06), and having an unrelated donor, HR 2.4 (95% CI, 1.34-4.33), were the only significant variables that affected survival. Similarly, as shown in Figure 2B, no difference was observed between the 2 groups with respect to RFS (P = .13).Figure 2(A) OS. (B) RFS.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 3 shows the causes of death for patients in the 2 groups. Of 12 with SOS in the sirolimus group, 8 died. Viral infections also accounted for a larger number of deaths in the sirolimus group; these patients all received ATG (5 versus 1 patient). Mortality because of GVHD was similar in both groups. OS was not significantly impacted in those patients who received busulfan-based conditioning regimens, P = .229. Additionally, ATG did not appear to influence relapse rates as 29% (9 of 31) who relapsed who did not receive ATG compared to 31% (9 of 29) of those who did received ATG, relapsed.Table 3Cause of DeathSirolimus/Tacrolimusn = 41MTX-basedn = 25Relapse139SOS80GVHD32Infection88 Viral51 Mold33Multisystem organ failure12SOS indicates sinusoidal obstructive syndrome; GVHD, graft-versus-host disease. Open table in a new tab Chronic GVHD and Transplant-Related ToxicityOf patients who lived 100 days posttransplant, 19 of 47 had cGVHD in the sirolimus group compared to 18 of 43 in the MTX group (40.4% versus 41.9%, P = .89). There was no significant difference in the incidence of TMA (10.2% versus 4.3%, P = .296) or IP (11.9% versus 14.9%, P = .647).The incidence of SOS of the liver occurred in 20.3% (12 of 59) who received sirolimus compared to 4.2% (2 of 47) in those who received MTX, P = .015. Patients in the sirolimus group who developed SOS had a significantly higher mean trough sirolimus level during the first 35 days posttransplant compared to those who did not develop SOS (unpublished data). In brief, the mean (±SD) blood sirolimus concentration levels for patients who developed SOS was increased relative to those who did not develop SOS, 10.5 ng/mL (1.7 ng/mL) versus 8.7 ng/mL (1.8 ng/mL), P = .003. In patients who developed SOS, the mean (±SD) blood trough tacrolimus concentration levels were 9.2 ng/mL (1.9 ng/mL) compared to 8.4 ng/mL (1.1 ng/mL) for non-SOS patients, P = .085.Of the patients receiving concomitant sirolimus and busulfan (n = 22), 4 developed SOS: 3 were fatal. These 3 fatalities received Bu/fludarabine and the other Bu/clofarabine. Of the patients receiving sirolimus and TBI/Cy (n = 21), 7 developed SOS: 5 were fatal. One of the 11 patients receiving TBI/etoposide developed SOS that was nonfatal. Nonfatal SOS was diagnosed in 2 patients in the MTX group; both had received Bu/Cy. Overall, busulfan was part of the myeloablative conditioning regimen in 33% of patients who developed SOS and 38% of patients who did not develop SOS (P = 1).Results of the multivariate logistic regression were consistent with the univariate analysis and did not indicate a significant impact of type of prophylactic regimen on cGVHD and transplant-related toxicity (data not shown).DiscussionAlthough the goal of HCT is to eradicate the malignancy, transplant-related morbidity and mortality present barriers to the overall success of the procedure. Our analysis demonstrates a reduction in aGVHD for patients who received sirolimus/tacrolimus compared to MTX-based GVHD prophylaxis; patients who received MTX-based prophylaxis were almost 6 times more likely to develop aGVHD as those receiving sirolimus.A previous report observed rates of aGVHD among MRD and MUD allogeneic transplants of 20% [13Cutler C. Ho V. Koreth J. et al.Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation.Blood. 2007; 109: 3108-3114PubMed Google Scholar], similar to those observed in our study despite a more heterogeneous population analyzed. However, a recent pilot of tacrolimus/sirolimus GVHD prophylaxis by Rodriguez et al. [28Rodriguez R. Nakamura R. Palmer J.M. et al.A phase II pilot study of tacrolimus/sirolimus GVHD prophylaxis for sibling donor hematopoietic stem cell transplant using three conditioning regimens.Blood. 2009; 115: 1098-1105Crossref PubMed Scopus (82) Google Scholar], demonstrated a much higher incidence of grade II-IV aGVHD (43%) and grade III-IV (19%). The reasons for the apparently significant differences in incidence of aGVHD observed between the Dana Farber Cancer Institute (DFCI) and our study and those reported by Rodriquez is not immediately clear, but may be related to differences in population, intensity of immunosuppression,
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