Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Cutler, Corey; Stevenson, Kristen E.; Kim, Haesook T.; Richardson, Paul G.; Ho, Vincent T.; Linden, Erica; Revta, Carolyn; Ebert, Ruth; Warren, Diane; Choi, Sung Won; Koreth, John; Armand, Philippe; Alyea, Edwin P.; Carter, Shelly; Horowitz, Mary M.; Antin, Joseph H.; Soiffer, Robert J.

doi:10.1182/blood-2008-07-169342

Cited by 141 publications

(109 citation statements)

References 49 publications

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“…In contrast to previously published evidence in the setting of busulfan/cyclophosphamide conditioning, 27 or that of largely intravenous busulfan/fludarabine but with the combination of TAC/everolimus, 29 we did not observe a significantly increased risk of hepatic VOD among patients treated with SIR/TAC and busulfan-based conditioning. However, the overall incidence of this complication was low and this risk was likely mitigated by avoiding cyclophosphamide, pharmacokinetic targeting of intravenous busulfan, initiation of SIR on day -1 after conditioning therapy was completed, and VOD prophylaxis with ursodeoxycholic acid in all patients.…”

Section: Discussioncontrasting

confidence: 56%

“…Notably, the incidence of VOD observed in this study is lower than that previously reported. 27 The cumulative incidence of TMA did not differ significantly between the two groups [SIR/TAC 25% (95% CI: 14-44%) versus MTX/TAC 20% (95% CI: 10-38%)] (P=0.48). TMA occurred in nine SIR/TAC-treated patients and seven MTX/TAC-treated patients (P=0.57).…”

Section: Engraftment and Early Toxicitymentioning

confidence: 99%

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A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundThere is evidence suggesting that sirolimus, in combination with tacrolimus, is active in the prevention of graft-versus-host disease. Sirolimus-based immune suppression may suppress alloreactive T cells, while sparing the survival and function of regulatory T cells. Design and MethodsWe conducted a randomized trial to compare the impact of sirolimus/tacrolimus against that of methotrexate/tacrolimus on the prevention of graft-versus-host disease and regulatory T-cell reconstitution. ResultsSeventy-four patients were randomized 1:1 to sirolimus/tacrolimus or methotrexate/ tacrolimus, stratified for type of donor (sibling or unrelated) and the patients' age. The rate of grade II-IV acute graft-versus-host disease at 100 days was 43% (95% CI: 27-59%) in the sirolimus/tacrolimus group and 89% (95% CI: 72-96%) in the methotrexate/tacrolimus group (P<0.001). The rate of moderate/severe chronic graft-versus-host disease was 24% (95% CI: 7-47%) in the sirolimus/tacrolimus group and 64% (95% CI: 41-79%) in the methotrexate/tacrolimus group (P=0.008). Overall survival and patient-reported quality of life did not differ between the two groups. On days 30 and 90 post-transplant, sirolimus-treated patients had a significantly greater proportion of regulatory T cells among the CD4 + cells in the peripheral blood, and isolated regulatory T cells were functional. ConclusionsThese data demonstrate that sirolimus/tacrolimus prevents grade II-IV acute graft-versus-host disease and moderate-severe chronic graft-versus-host disease more effectively than does methotrexate/tacrolimus, and supports regulatory T-cell reconstitution following allogeneic hematopoietic cell transplantation. ABSTRACT© F e r r a t a S t o r t i F o u n d a t i o n

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Section: Discussioncontrasting

confidence: 56%

Section: Engraftment and Early Toxicitymentioning

confidence: 99%

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

et al. 2012

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“…24,25 The efficacy of sirolimus has been demonstrated in solid organ transplantation, but a definite role in allogeneic HCT has yet to be defined. In the setting of high-dose conditioning, the addition of sirolimus to calcineurin-based acute GvHD prophylaxis has been associated with lower levels of acute GvHD compared to historical data.…”

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

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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“…One of the major problems with sirolimus is its toxicity profile in combination with calcineurin inhibitors, including the development of microangiopathy or veno-occlusive disease, especially among patients receiving myeloablative conditionings. 33,34 We have previously reported that bortezomib induces selective depletion of alloreactive T cells, 25 while Treg are resistant to this pro-apoptotic effect. Furthermore, bortezomib allows the expansion of a suppressive T-cell subpopulation in vitro.…”

Section: Discussionmentioning

confidence: 99%

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

et al. 2012

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The online version of this article has a Supplementary Appendix. BackgroundWe have previously shown that bortezomib induces a depletion of alloreactive T cells and allows the expansion of T cells with suppressive properties. In the current study, we analyzed the potential synergistic effect of bortezomib in conjunction with sirolimus in order to reducegraft-versus-host disease without hampering graft-versus-leukemia effect in the allogeneic transplant setting. Design and MethodsWe evaluated the effect of sirolimus, bortezomib or the combination of both in the proliferation and activation of in vitro stimulated T lymphocytes. Pathways involved in this synergy were also analyzed using Western blot assays. Finally, BALB/c mice receiving C57BL/6 allogeneic donor bone marrow with splenocytes were used to measure in vivo the effect of this novel combination on the risk of graft-versus-host disease. ResultsThe combination of both drugs synergistically inhibited both activation and proliferation of stimulated T cells. Also, the production of Th1 cytokines (IFN γ, IL-2 and TNF) was significantly inhibited. This effect was due, at least in part, to the inhibition of Erk and Akt phosphorylation. In vivo, the combination reduced the risk of graft-versus-host disease without hampering graft-versus-leukemia effect, as shown in mice receiving graft-versus-host disease prophylaxis with sirolimus plus bortezomib being infused with tumor WEHI cells plus C57BL/6 donor BM and splenocytes. ConclusionsThe current study reveals a synergistic effect of the combination sirolimus and bortezomib to prevent graft-versus-host disease while maintaining the graft-versus-leukemia effect.Key words: allogeneic transplant, sirolimus, bortezomib, graft-versus-host, graft-versusleukemia. Haematologica 2012;97(9):1329-1337. doi:10.3324/haematol.2011 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n Citation: Caballero-Velázquez T, Sánchez-Abarca LI, Gutierrez-Cosio S, Blanco B, Calderon C, Herrero C, Carrancio S, Serrano C, del Cañizo C, San Miguel JF, and Pérez-Simón JA. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graftversus-leukemia effect after allogeneic transplantation. The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

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Sirolimus is associated with veno-occlusive disease of the liver after myeloablative allogeneic stem cell transplantation

Cited by 141 publications

References 49 publications

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

A randomized phase II study to evaluate tacrolimus in combination with sirolimus or methotrexate after allogeneic hematopoietic cell transplantation

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

The novel combination of sirolimus and bortezomib prevents graft-versus-host disease but maintains the graft-versus-leukemia effect after allogeneic transplantation

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