Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation

Robert J. Soiffer, Haesook T. Kim, Joseph McGuirk, Mitchell E. Horwitz, Laura Johnston, Mrinal M. Patnaik, Witold Rybka, Andrew Artz, David L. Porter, Thomas C. Shea, Michael W. Boyer, Richard T. Maziarz, Paul J. Shaughnessy, Usama Gergis, Hana Safah, Ran Reshef, John F. Dipersio, Patrick J. Stiff, Madhuri Vusirikala, Jeff SzerJennifer Holter, James D. Levine, Paul J. Martin, Joseph A. Pidala, Ian D. Lewis, Vincent T. Ho, Edwin P. Alyea, Jerome Ritz, Frank Glavin, Peter Westervelt, Madan H. Jagasia, Yi Bin Chen

Research output: Contribution to journalReview article

62 Citations (Scopus)

Abstract

Purpose: Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graftversus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods: Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days 23, 22, 21 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results: Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P =.004) and moderate-severe cGVHD (12% v 33%; P,.001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P =.47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [P =.04] and 59% v 74% [P =.034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P =.026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P =.01). Conclusion: In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

Original languageEnglish (US)
Pages (from-to)4003-4011
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number36
DOIs
StatePublished - Dec 20 2017

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Phase III Clinical Trials
Cell Transplantation
Graft vs Host Disease
Disease-Free Survival
T-Lymphocytes
Placebos
Survival
Antilymphocyte Serum
Myelodysplastic Syndromes
Tacrolimus
tumor-globulin
Thomsen-Friedenreich antibodies
Methotrexate
Leukemia

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. / Soiffer, Robert J.; Kim, Haesook T.; McGuirk, Joseph; Horwitz, Mitchell E.; Johnston, Laura; Patnaik, Mrinal M.; Rybka, Witold; Artz, Andrew; Porter, David L.; Shea, Thomas C.; Boyer, Michael W.; Maziarz, Richard T.; Shaughnessy, Paul J.; Gergis, Usama; Safah, Hana; Reshef, Ran; Dipersio, John F.; Stiff, Patrick J.; Vusirikala, Madhuri; Szer, Jeff; Holter, Jennifer; Levine, James D.; Martin, Paul J.; Pidala, Joseph A.; Lewis, Ian D.; Ho, Vincent T.; Alyea, Edwin P.; Ritz, Jerome; Glavin, Frank; Westervelt, Peter; Jagasia, Madan H.; Chen, Yi Bin.

In: Journal of Clinical Oncology, Vol. 35, No. 36, 20.12.2017, p. 4003-4011.

Research output: Contribution to journalReview article

Soiffer, RJ, Kim, HT, McGuirk, J, Horwitz, ME, Johnston, L, Patnaik, MM, Rybka, W, Artz, A, Porter, DL, Shea, TC, Boyer, MW, Maziarz, RT, Shaughnessy, PJ, Gergis, U, Safah, H, Reshef, R, Dipersio, JF, Stiff, PJ, Vusirikala, M, Szer, J, Holter, J, Levine, JD, Martin, PJ, Pidala, JA, Lewis, ID, Ho, VT, Alyea, EP, Ritz, J, Glavin, F, Westervelt, P, Jagasia, MH & Chen, YB 2017, 'Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation', Journal of Clinical Oncology, vol. 35, no. 36, pp. 4003-4011. https://doi.org/10.1200/JCO.2017.75.8177
Soiffer, Robert J. ; Kim, Haesook T. ; McGuirk, Joseph ; Horwitz, Mitchell E. ; Johnston, Laura ; Patnaik, Mrinal M. ; Rybka, Witold ; Artz, Andrew ; Porter, David L. ; Shea, Thomas C. ; Boyer, Michael W. ; Maziarz, Richard T. ; Shaughnessy, Paul J. ; Gergis, Usama ; Safah, Hana ; Reshef, Ran ; Dipersio, John F. ; Stiff, Patrick J. ; Vusirikala, Madhuri ; Szer, Jeff ; Holter, Jennifer ; Levine, James D. ; Martin, Paul J. ; Pidala, Joseph A. ; Lewis, Ian D. ; Ho, Vincent T. ; Alyea, Edwin P. ; Ritz, Jerome ; Glavin, Frank ; Westervelt, Peter ; Jagasia, Madan H. ; Chen, Yi Bin. / Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 36. pp. 4003-4011.
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title = "Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation",
abstract = "Purpose: Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graftversus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods: Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days 23, 22, 21 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results: Despite a reduction in grade 2 to 4 acute GVHD (23{\%} v 40{\%}; P =.004) and moderate-severe cGVHD (12{\%} v 33{\%}; P,.001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48{\%} v 44{\%}, respectively; P =.47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47{\%} v 65{\%} [P =.04] and 59{\%} v 74{\%} [P =.034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95{\%} CI, 1.05 to 2.28; P =.026) and OS (hazard ratio, 1.74; 95{\%} CI, 1.12 to 2.71; P =.01). Conclusion: In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.",
author = "Soiffer, {Robert J.} and Kim, {Haesook T.} and Joseph McGuirk and Horwitz, {Mitchell E.} and Laura Johnston and Patnaik, {Mrinal M.} and Witold Rybka and Andrew Artz and Porter, {David L.} and Shea, {Thomas C.} and Boyer, {Michael W.} and Maziarz, {Richard T.} and Shaughnessy, {Paul J.} and Usama Gergis and Hana Safah and Ran Reshef and Dipersio, {John F.} and Stiff, {Patrick J.} and Madhuri Vusirikala and Jeff Szer and Jennifer Holter and Levine, {James D.} and Martin, {Paul J.} and Pidala, {Joseph A.} and Lewis, {Ian D.} and Ho, {Vincent T.} and Alyea, {Edwin P.} and Jerome Ritz and Frank Glavin and Peter Westervelt and Jagasia, {Madan H.} and Chen, {Yi Bin}",
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month = "12",
day = "20",
doi = "10.1200/JCO.2017.75.8177",
language = "English (US)",
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TY - JOUR

T1 - Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation

AU - Soiffer, Robert J.

AU - Kim, Haesook T.

AU - McGuirk, Joseph

AU - Horwitz, Mitchell E.

AU - Johnston, Laura

AU - Patnaik, Mrinal M.

AU - Rybka, Witold

AU - Artz, Andrew

AU - Porter, David L.

AU - Shea, Thomas C.

AU - Boyer, Michael W.

AU - Maziarz, Richard T.

AU - Shaughnessy, Paul J.

AU - Gergis, Usama

AU - Safah, Hana

AU - Reshef, Ran

AU - Dipersio, John F.

AU - Stiff, Patrick J.

AU - Vusirikala, Madhuri

AU - Szer, Jeff

AU - Holter, Jennifer

AU - Levine, James D.

AU - Martin, Paul J.

AU - Pidala, Joseph A.

AU - Lewis, Ian D.

AU - Ho, Vincent T.

AU - Alyea, Edwin P.

AU - Ritz, Jerome

AU - Glavin, Frank

AU - Westervelt, Peter

AU - Jagasia, Madan H.

AU - Chen, Yi Bin

PY - 2017/12/20

Y1 - 2017/12/20

N2 - Purpose: Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graftversus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods: Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days 23, 22, 21 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results: Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P =.004) and moderate-severe cGVHD (12% v 33%; P,.001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P =.47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [P =.04] and 59% v 74% [P =.034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P =.026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P =.01). Conclusion: In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

AB - Purpose: Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graftversus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods: Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days 23, 22, 21 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results: Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P =.004) and moderate-severe cGVHD (12% v 33%; P,.001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P =.47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [P =.04] and 59% v 74% [P =.034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P =.026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P =.01). Conclusion: In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

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