The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

Pérez-Simón, Josè Antonio; Martino, Rodrigo; Parody, Rocío; Cabrero, Mónica; López-Corral, Lucía; Valcárcel, David; Martı́nez, Carmen; Solano, Carlos; Vázquez, Lourdes; Márquez-Malaver, Francisco J.; Sierra, Jordi; Caballero, Dolores

doi:10.3324/haematol.2012.065599

Cited by 35 publications

(49 citation statements)

References 39 publications

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“…By contrast, in the reduced-intensity conditioning regimen setting, TAC/MTX was also used until October 2008; subsequently, SIR plus TAC was used in the context of a phase II prospective multicenter trial (2007-006416-32 trial by GEL-TAMO/GETH) until October 2010, and as a standard procedure for patients receiving reduced-intensity conditioning allo-HSCT thereafter. 25 In the current study, we analyzed retrospectively all consecutive allogeneic HSCT recipients (aged over 18 years) who received a TACbased regimen for GVHD prophylaxis between April 2007 and July 2012 in our unit (n ¼ 102). Thirty-four received TAC/MTX and 68 TAC/SIR combinations.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

“…Twenty-eight out of 68 patients in the TAC/SIR group have been included in a phase II trial, and the results have already been published. 25 Supportive care…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

“…[17][18][19]21,22 In a recent phase II multicenter prospective trial conducted by our group, including some of the patients in this study, no differences were observed in the incidence of TA-TMA when TAC/SIR was compared with patients included in a prior prospective trial using CYA-mycophenolate (the overall incidences of TA-TMA were 10% and 6%, respectively). 25 In addition, very few studies 23,24 have evaluated the risk of TA-TMA among patients receiving the TAC/SIR combination in comparison with other TAC-based regimens. To shed further light on this matter, we performed a retrospective analysis in 102 allogeneic HSCT recipients who consecutively received TAC/SIR (n ¼ 68) or TAC/MTX ± ATG (n ¼ 34) for GVHD prophylaxis.…”

Section: Baseline Characteristics Of Patientsmentioning

confidence: 99%

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Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

Labrador

López-Corral

López‐Godino

et al. 2014

Bone Marrow Transplant

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Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n ¼ 68) or plus MTX (TAC/MTX) ± ATG (n ¼ 34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX ± ATG (7.4% vs 8.8%, P ¼ 0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC 425 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (Po0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.

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Section: Patients and Methods Patientsmentioning

confidence: 99%

“…Twenty-eight out of 68 patients in the TAC/SIR group have been included in a phase II trial, and the results have already been published. 25 Supportive care…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

Section: Baseline Characteristics Of Patientsmentioning

confidence: 99%

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Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

Labrador

López-Corral

López‐Godino

et al. 2014

Bone Marrow Transplant

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“…Previous reports on the efficacy of sirolimus in the reduced intensity setting included between 23-91 patients transplanted with a variety of HLA-matched and -mismatched related or unrelated donors after reduced intensity conditioning with FLU combined with busulphan, [33][34][35] melphalan, [35][36][37] or cyclophosphamide. 38 Sirolimus was administered as a single loading dose between 6-12 mg followed by daily doses between 2-4 mg and targeted at a plasma level between 3-14 ng/mL.…”

Section: Cumulative Incidence (%) Hr (95% Ci); Pmentioning

confidence: 99%

“…[29][30][31] To our knowledge, the current study is the first phase II randomized trial to investigate the efficacy of sirolimus as acute GvHD prophylaxis in truly non-myeloablative HCT. However, there has been some experience in the reduced-intensity conditioning setting, and there has been a recent preliminary abstract report from a randomized phase III trial comparing tacrolimus, methotrexate and sirolimus to conventional sirolimus-free regimens.32 Data from the trial yielded results similar to ours where the addition of sirolimus reduced grade II-IV acute GvHD with no effect on grade III-IV acute GvHD, chronic GvHD or survival.Previous reports on the efficacy of sirolimus in the reduced intensity setting included between 23-91 patients transplanted with a variety of HLA-matched and -mismatched related or unrelated donors after reduced intensity conditioning with FLU combined with busulphan, [33][34][35] melphalan, [35][36][37] or cyclophosphamide. 38 Sirolimus was administered as a single loading dose between 6-12 mg followed by daily doses between 2-4 mg and targeted at a plasma level between 3-14 ng/mL.…”

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confidence: 99%

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

et al. 2014

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Research Center (FHCRC) acted as coordinating center. The study was approved by institutional review boards at the FHCRC and at collaborating centers. All patients signed consent forms approved by the local institutional review boards. The study was registered at clinicaltrials.gov (identifier: 00105001). The manuscript was prepared in accordance with the CONSORT 2010 statement (Online Supplementary Figure S1). 17 The primary objective was to determine whether either of the two experimental immunosuppressive regimens could reduce grades II-IV acute GvHD to 40% or under. Secondary objectives were to reduce the Day 200 non-relapse mortality (NRM) to 15% or under, and to lower corticosteroid use compared to the reference arm.Patients were randomized between three immunosuppressive treatment regimens and stratified according to transplant center (FHCRC vs. other), number of prior chemotherapy regimens (<3 vs. ≥3) and age (<55 vs. ≥55 years).Patients with advanced hematologic malignancies (Table 1) treatable by non-myeloablative conditioned allogeneic HCT were eligible for the study. Donors were unrelated, high-resolution typed for HLA-A, -B, -C, -DRB1 and -DQB1, allele level matched (10/10) and no more than a single allele disparity for either HLA-A, -B, or -C was allowed. 18The protocol was opened in January 2005 and closed in August 2009 after accruing 208 patients. The database was analyzed as of August 2013 and median follow up was 4.9 (range 0.5-8.4) years. TreatmentPatients were conditioned with FLU (30 mg/m 2 /day) on Days -4, -3, and -2 before receiving 2 Gy TBI at a rate of 0.06-0.07 Gy/min from a linear accelerator on the day of HCT (Day 0). Donor peripheral blood stem cells (PBSC) were collected as previously described.8 For post-grafting immunosuppression, patients were randomized between three regimens; henceforward in this report these will be referred to as arms 1-3. In arm 1, 15 mg/kg of MMF was given p.o. t.i.d. from Day 0 until Day 30, then b.i.d until Day 40 and in the absence of GvHD tapered off by Day 96. Tacrolimus 0.06 mg/kg was administered orally b.i.d. from Day -3 to 100 and in the absence of GvHD tapered off by Day 180. In arm 2, the same doses of MMF and tacrolimus were used, but MMF was b.i.d. from Day 30 to Day 150 and tapered over one month, while tacrolimus was continued to Day 100 and tapered over 50 days. In arm 3, the MMF and tacrolimus dosing schedules were the same as for arm 2, but with the addition of sirolimus started at Day -3 at 2 mg p.o. q.d. and adjusted to attain trough levels of 3-12 ng/mL. Sirolimus was stopped at Day 80 without a taper. In arms 1 and 2, tacrolimus trough levels were targeted between 10-15 ng/mL for the first 28 days and thereafter between 7.5 and 15 ng/mL. In arm 3, tacrolimus trough levels were targeted between 5 and 10 ng/mL during sirolimus administration.Eligibility criteria, patient evaluations and statistical analyses are described in the Online Supplementary Appendix. Results PatientsSixty-nine patients were randomized into arm 1, 71 int...

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Reduced‐intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

Baron

Labopin

Peniket

et al. 2014

Cancer

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BACKGROUND: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT). METHODS: The current survey compared transplantation outcomes for a cohort of 394 acute myeloid leukemia (AML) patients given bone marrow or peripheral blood stem cells from human leukocyte antigen-identical siblings after FB (n 5 218) or FM (n 5 176). Patients given manipulated grafts and those given Tcell-depleting agents (anti-thymocyte globulins or alemtuzumab) were not included. RESULTS: At the time of transplantation, 266 patients (68%) were experiencing their first complete remission (CR), 69 (18%) were experiencing a later CR, and 59 (15%) had advanced disease. The incidences of acute and chronic graft-versus-host disease were similar in the 2 groups of patients. The 2-year relapse incidence (RI), nonrelapse mortality (NRM) rate, leukemia-free survival (LFS) rate, and overall survival (OS) rate were 31% 6 3%, 18% 6 3%, 51% 6 4%, and 54% 6 4%, respectively, for FB patients and 20% 6 3% (P 5.007), 20% 6 3% (P 5.4), 60% 6 4% (P 5.08), and 62% 6 4% (P 5.2), respectively, for FM patients. Among FB patients given intravenous busulfan (n 5 81), the 2-year RI, NRM, LFS, and OS rates were 26% 6 5% (P 5.43 vs FM patients), 25% 6 6% (P 5.18), 49% 6 7% (P 5.07), and 54% 6 7% (P 5.13), respectively. In multivariate analyses, FM was associated with a lower RI (hazard ratio [HR], 0.5; P 5.01) and a trend toward higher NRM (HR, 1.6; P 5.1) with similar LFS (HR, 0.8; P 5.2) and OS (HR, 0.9; P 5.6). CONCLUSIONS: These results suggest that although FM provides better AML control than FB as an RIC regimen for allo-SCT, the 2 regimens provide similar survival. Multicenter randomized studies are needed to confirm these findings. Cancer 2015;121:1048-55.

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The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

Cited by 35 publications

References 39 publications

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

Reduced‐intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: A report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

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