Sirolimus, Tacrolimus, and Low-Dose Methotrexate as Graft-versus-Host Disease Prophylaxis in Related and Unrelated Donor Reduced-Intensity Conditioning Allogeneic Peripheral Blood Stem Cell Transplantation

Alyea, Edwin P.; Li, Shuli; Kim, Haesook T.; Cutler, Corey; Ho, Vincent T.; Soiffer, Robert J.; Antin, Joseph H.

doi:10.1016/j.bbmt.2008.05.024

Cited by 51 publications

(53 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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. 33,34,[36][37][38] Sirolimus was given in combination with tacrolimus with or without methotrexate and antithymocyte globulin. Grade II-IV acute GvHD rates were between 10-37% and chronic GvHD rates were between 40-74% at two years, 33,34,36,37 with a trend towards better outcome in patients who did not receive methotrexate.…”

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

confidence: 99%

“…Grade II-IV acute GvHD rates were between 10-37% and chronic GvHD rates were between 40-74% at two years, 33,34,36,37 with a trend towards better outcome in patients who did not receive methotrexate. 33,34 Most of the studies did not clearly state for how long GvHD prophylaxis was planned, except for Claxton et al; 38 they discontinued sirolimus on Day 30 post transplantation and 43% of patients experienced grade II-IV acute GvHD and 77% chronic GvHD.Perez-Simon et al have compared a prospective cohort of 50 patients treated with sirolimus and tacrolimus with an equivalent retrospective cohort of 45 patients treated with CSP and MMF GvHD prophylaxis. Sirolimus was given until Day 180 post transplantion.…”

mentioning

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.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2014

View full text Add to dashboard Cite

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...

show abstract

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

confidence: 99%

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

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[13][14][15][16] To overcome these limitations, several novel strategies are currently under investigation. The synergistic effects of mTor (mammalian target of rapamycin) and calcineurin inhibitors 17 or mTor inhibitors and mycophenolate mofetil 18 have been explored in prophylaxis regimens. Similarly, specific anti-T-and B-cell antibodies (such as alemtuzumab, 19 antithymocyte globulin, 20 rituximab 21,22 ) or antibodies against soluble GvHD effectors (such as infliximab and etanercept; see below) have been tested to prevent GvHD with some success, counterbalanced by a high incidence of severe opportunistic infections and disease relapse.…”

Section: Prospectsmentioning

confidence: 99%