Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning

a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)

F Javier Bolanos Meade, Ran Reshef, Raphael Fraser, Mingwei Fei, Sunil Abhyankar, Zaid Al-Kadhimi, Amin M. Alousi, Joseph H. Antin, Sally Arai, Kate Bickett, Yi Bin Chen, Lloyd E. Damon, Yvonne A. Efebera, Nancy L. Geller, Sergio A. Giralt, Parameswaran Hari, Shernan G. Holtan, Mary M. Horowitz, David A. Jacobsohn, Richard J Jones & 14 others Jane L. Liesveld, Brent R. Logan, Margaret L. MacMillan, Marco Mielcarek, Pierre Noel, Joseph Pidala, David L. Porter, Iskra Pusic, Ronald Sobecks, Scott R. Solomon, Daniel J. Weisdorf, Juan Wu, Marcelo C. Pasquini, John Koreth

Research output: Contribution to journalArticle

Abstract

Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. Methods: In this prospective multicentre phase 2 trial, adult patients aged 18–75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m 2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day −3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m 2 intravenous bolus on day 1 and 10 mg/m 2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day −3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5–15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3–4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54–0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76–1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86–1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

Original languageEnglish (US)
Pages (from-to)e132-e143
JournalThe Lancet Haematology
Volume6
Issue number3
DOIs
StatePublished - Mar 1 2019

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Mycophenolic Acid
Cell Transplantation
Tacrolimus
Graft vs Host Disease
Methotrexate
Cyclophosphamide
Control Groups
Transplantation
Bortezomib
maraviroc
trans-crotonin
Recurrence
Survival

ASJC Scopus subject areas

  • Hematology

Cite this

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning : a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). / Bolanos Meade, F Javier; Reshef, Ran; Fraser, Raphael; Fei, Mingwei; Abhyankar, Sunil; Al-Kadhimi, Zaid; Alousi, Amin M.; Antin, Joseph H.; Arai, Sally; Bickett, Kate; Chen, Yi Bin; Damon, Lloyd E.; Efebera, Yvonne A.; Geller, Nancy L.; Giralt, Sergio A.; Hari, Parameswaran; Holtan, Shernan G.; Horowitz, Mary M.; Jacobsohn, David A.; Jones, Richard J; Liesveld, Jane L.; Logan, Brent R.; MacMillan, Margaret L.; Mielcarek, Marco; Noel, Pierre; Pidala, Joseph; Porter, David L.; Pusic, Iskra; Sobecks, Ronald; Solomon, Scott R.; Weisdorf, Daniel J.; Wu, Juan; Pasquini, Marcelo C.; Koreth, John.

In: The Lancet Haematology, Vol. 6, No. 3, 01.03.2019, p. e132-e143.

Research output: Contribution to journalArticle

Bolanos Meade, FJ, Reshef, R, Fraser, R, Fei, M, Abhyankar, S, Al-Kadhimi, Z, Alousi, AM, Antin, JH, Arai, S, Bickett, K, Chen, YB, Damon, LE, Efebera, YA, Geller, NL, Giralt, SA, Hari, P, Holtan, SG, Horowitz, MM, Jacobsohn, DA, Jones, RJ, Liesveld, JL, Logan, BR, MacMillan, ML, Mielcarek, M, Noel, P, Pidala, J, Porter, DL, Pusic, I, Sobecks, R, Solomon, SR, Weisdorf, DJ, Wu, J, Pasquini, MC & Koreth, J 2019, 'Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)', The Lancet Haematology, vol. 6, no. 3, pp. e132-e143. https://doi.org/10.1016/S2352-3026(18)30221-7
Bolanos Meade, F Javier ; Reshef, Ran ; Fraser, Raphael ; Fei, Mingwei ; Abhyankar, Sunil ; Al-Kadhimi, Zaid ; Alousi, Amin M. ; Antin, Joseph H. ; Arai, Sally ; Bickett, Kate ; Chen, Yi Bin ; Damon, Lloyd E. ; Efebera, Yvonne A. ; Geller, Nancy L. ; Giralt, Sergio A. ; Hari, Parameswaran ; Holtan, Shernan G. ; Horowitz, Mary M. ; Jacobsohn, David A. ; Jones, Richard J ; Liesveld, Jane L. ; Logan, Brent R. ; MacMillan, Margaret L. ; Mielcarek, Marco ; Noel, Pierre ; Pidala, Joseph ; Porter, David L. ; Pusic, Iskra ; Sobecks, Ronald ; Solomon, Scott R. ; Weisdorf, Daniel J. ; Wu, Juan ; Pasquini, Marcelo C. ; Koreth, John. / Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning : a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203). In: The Lancet Haematology. 2019 ; Vol. 6, No. 3. pp. e132-e143.
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title = "Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)",
abstract = "Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. Methods: In this prospective multicentre phase 2 trial, adult patients aged 18–75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m 2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day −3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m 2 intravenous bolus on day 1 and 10 mg/m 2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day −3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5–15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3–4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90{\%} CI 0·54–0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76–1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86–1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13{\%}) had grade 3 and 67 (73{\%}) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11{\%}) had grade 3 and 68 (76{\%}) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20{\%}) had grade 3 and 63 (68{\%}) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84{\%}] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82{\%}] for tacrolimus, methotrexate, and bortezomib; and 78 [85{\%}] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47{\%}], 44 [49{\%}], and 43 [47{\%}], respectively). Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.",
author = "{Bolanos Meade}, {F Javier} and Ran Reshef and Raphael Fraser and Mingwei Fei and Sunil Abhyankar and Zaid Al-Kadhimi and Alousi, {Amin M.} and Antin, {Joseph H.} and Sally Arai and Kate Bickett and Chen, {Yi Bin} and Damon, {Lloyd E.} and Efebera, {Yvonne A.} and Geller, {Nancy L.} and Giralt, {Sergio A.} and Parameswaran Hari and Holtan, {Shernan G.} and Horowitz, {Mary M.} and Jacobsohn, {David A.} and Jones, {Richard J} and Liesveld, {Jane L.} and Logan, {Brent R.} and MacMillan, {Margaret L.} and Marco Mielcarek and Pierre Noel and Joseph Pidala and Porter, {David L.} and Iskra Pusic and Ronald Sobecks and Solomon, {Scott R.} and Weisdorf, {Daniel J.} and Juan Wu and Pasquini, {Marcelo C.} and John Koreth",
year = "2019",
month = "3",
day = "1",
doi = "10.1016/S2352-3026(18)30221-7",
language = "English (US)",
volume = "6",
pages = "e132--e143",
journal = "The Lancet Haematology",
issn = "2352-3026",
publisher = "Lancet Publishing Group",
number = "3",

}

TY - JOUR

T1 - Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning

T2 - a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)

AU - Bolanos Meade, F Javier

AU - Reshef, Ran

AU - Fraser, Raphael

AU - Fei, Mingwei

AU - Abhyankar, Sunil

AU - Al-Kadhimi, Zaid

AU - Alousi, Amin M.

AU - Antin, Joseph H.

AU - Arai, Sally

AU - Bickett, Kate

AU - Chen, Yi Bin

AU - Damon, Lloyd E.

AU - Efebera, Yvonne A.

AU - Geller, Nancy L.

AU - Giralt, Sergio A.

AU - Hari, Parameswaran

AU - Holtan, Shernan G.

AU - Horowitz, Mary M.

AU - Jacobsohn, David A.

AU - Jones, Richard J

AU - Liesveld, Jane L.

AU - Logan, Brent R.

AU - MacMillan, Margaret L.

AU - Mielcarek, Marco

AU - Noel, Pierre

AU - Pidala, Joseph

AU - Porter, David L.

AU - Pusic, Iskra

AU - Sobecks, Ronald

AU - Solomon, Scott R.

AU - Weisdorf, Daniel J.

AU - Wu, Juan

AU - Pasquini, Marcelo C.

AU - Koreth, John

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. Methods: In this prospective multicentre phase 2 trial, adult patients aged 18–75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m 2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day −3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m 2 intravenous bolus on day 1 and 10 mg/m 2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day −3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5–15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3–4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54–0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76–1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86–1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

AB - Background: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. Methods: In this prospective multicentre phase 2 trial, adult patients aged 18–75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m 2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day −3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m 2 intravenous bolus on day 1 and 10 mg/m 2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day −3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5–15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3–4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. Findings: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54–0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76–1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86–1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). Interpretation: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. Funding: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

UR - http://www.scopus.com/inward/record.url?scp=85061920512&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061920512&partnerID=8YFLogxK

U2 - 10.1016/S2352-3026(18)30221-7

DO - 10.1016/S2352-3026(18)30221-7

M3 - Article

VL - 6

SP - e132-e143

JO - The Lancet Haematology

JF - The Lancet Haematology

SN - 2352-3026

IS - 3

ER -