Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Marty, Francisco M.; Bryar, Julie M.; Browne, Sarah K.; Schwarzberg, Talya; Ho, Vincent T.; Bassett, Ingrid V.; Koreth, John; Alyea, Edwin P.; Soiffer, Robert J.; Cutler, Corey; Antin, Joseph H.; Baden, Lindsey R.

doi:10.1182/blood-2007-01-069294

Cited by 134 publications

(123 citation statements)

References 49 publications

(79 reference statements)

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“…A significant reduction in the use of systemic steroids and a lower incidence of CMV reactivation was also observed in patients treated with sirolimus. Whether the lower incidence of viral reactivation was due to the reduced steroid use, specific antiviral activity of sirolimus, 22 or a combination of these factors is unknown. There was no increase in DLI use, relapse incidence or relapse-related mortality, even though donor T-cell chimerism developed significantly slower in the sirolimus-treated patients.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…This is in accordance with observations suggesting a CMV protective effect of sirolimus-based immunosuppression after solid organ transplantation 42,43 and, as recently published, also after hematopoietic SCT. 30 The mechanism(s) by which sirolimus may exert this protective effect remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…8,29 On the other hand, sirolimus exerts protection against viral infections, especially CMV reactivation. 30 On the basis of the observations mentioned, we changed the GVHD prophylaxis within the FLAMSA-RIC protocol from CYA and MMF to sirolimus, and MMF for leukemia patients with high relapse risk. This paper summarizes the results of this strategy in a first cohort of 15 consecutive patients.…”

Section: Introductionmentioning

confidence: 99%

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

Schleuning

Judith

Jedlickova

et al. 2008

Bone Marrow Transplant

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“…46,80,85 Other risk factors for CMV infection after allogeneic HSCT include the use of high-dose corticosteroids, T-cell depletion, acute and chronic GVHD, and the use of mismatched or unrelated donors. 43,46,[85][86][87][88][89] The use of sirolimus for GVHD prophylaxis seems to have a protective effect against CMV infection, possibly because of the inhibition of cellular signaling pathways that are co-opted by CMV during infection for synthesis of viral proteins. 85,90 The use of nonmyeloablative conditioning regimens generally has been reported to result in a lower rate of CMV infection and disease early after HSCT compared with standard myeloablative regimens.…”

Section: Risk Factors Allogeneic Hsct Recipientsmentioning

confidence: 99%

Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients

Ljungman

Hakki

Boeckh

2010

Infectious Disease Clinics of North America

192

207

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Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis

Cited by 134 publications

References 49 publications

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

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

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients

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