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Clinical Trial
. 2017 Dec 20;35(36):4003-4011.
doi: 10.1200/JCO.2017.75.8177. Epub 2017 Oct 17.

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  1 , Haesook T Kim  1 , Joseph McGuirk  1 , Mitchell E Horwitz  1 , Laura Johnston  1 , Mrinal M Patnaik  1 , Witold Rybka  1 , Andrew Artz  1 , David L Porter  1 , Thomas C Shea  1 , Michael W Boyer  1 , Richard T Maziarz  1 , Paul J Shaughnessy  1 , Usama Gergis  1 , Hana Safah  1 , Ran Reshef  1 , John F DiPersio  1 , Patrick J Stiff  1 , Madhuri Vusirikala  1 , Jeff Szer  1 , Jennifer Holter  1 , James D Levine  1 , Paul J Martin  1 , Joseph A Pidala  1 , Ian D Lewis  1 , Vincent T Ho  1 , Edwin P Alyea  1 , Jerome Ritz  1 , Frank Glavin  1 , Peter Westervelt  1 , Madan H Jagasia  1 , Yi-Bin Chen  1
Affiliations
Clinical Trial

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 et al. J Clin Oncol. .

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 graft-versus-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 -3, -2, -1 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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Conflict of interest statement

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

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.

Robert J. Soiffer

Leadership: Kiadis Pharma

Consulting or Advisory Role: Sandoz, Juno Therapeutics, Gilead Sciences, MedImmune, GlaxoSmithKline

Haesook T. Kim

Consulting or Advisory Role: Neovii Biotech

Joseph McGuirk

Honoraria: Kite Pharma

Speakers’ Bureau: Kite Pharma

Research Funding: Novartis, Bellicum Pharmaceuticals, Fresenius Biotech SE & Co. KGaA, Astellas Pharma

Mitchell E. Horwitz

No relationship to disclose

Laura Johnston

No relationship to disclose

Mrinal M. Patnaik

No relationship to disclose

Witold Rybka

Consulting or Advisory Role: Merck Sharp & Dohme

Research Funding: Merck Sharp & Dohme, Seattle Genetics, Pfizer

Andrew Artz

Research Funding: Miltenyi Biotec, Neovii Biotech

David L. Porter

No relationship to disclose

Thomas C. Shea

Consulting or Advisory Role: Novartis, Merck

Michael W. Boyer

Consulting or Advisory Role: Novartis

Richard T. Maziarz

Consulting or Advisory Role: Novartis, Incyte, Juno Therapeutics, Kite Pharma

Paul J. Shaughnessy

Employment: HCA Healthcare

Honoraria: Sanofi, Millennium Pharmaceuticals

Consulting or Advisory Role: Sanofi, Millennium Pharmaceuticals

Speakers’ Bureau: Sanofi, Millennium Pharmaceuticals

Usama Gergis

Consulting or Advisory Role: Jazz Pharmaceuticals

Speakers’ Bureau: Merck, Incyte, Alexion Pharmaceuticals, Astellas Pharma, Jazz Pharmaceuticals

Travel, Accommodations, Expenses: Merck, Incyte, Astellas Pharma, Jazz Pharmaceuticals

Hana Safah

Speakers’ Bureau: Incyte, Alexion Pharmaceuticals, Celgene, Astellas Pharma, Jazz Pharmaceuticals, Sanofi

Ran Reshef

Consulting or Advisory Role: Pfizer, Concert Pharmaceuticals, Incyte, Atara Biotherapeutics, TEVA Pharmaceuticals Industries, Takeda Pharmaceuticals, Bristol-Myers Squibb, Kite Pharma

John F. DiPersio

Stock or Other Ownership: Magenta

Honoraria: Celgene, Incyte, Zymeworks, RiverVest, Cellworks, MacroGenics

Patrick J. Stiff

No relationship to disclose

Madhuri Vusirikala

Consulting or Advisory Role: Amgen

Jeff Szer

Consulting or Advisory Role: Alexion Pharmaceuticals, Sanofi, Shire, Pfizer

Travel, Accommodations, Expenses: Sanofi, Shire, Pfizer, Alexion Pharmaceuticals

Jennifer Holter

No relationship to disclose

James D. Levine

Stock or Other Ownership: Pfizer (I), Amgen

Paul J. Martin

Consulting or Advisory Role: Pfizer, Incyte

Research Funding: Neovii Biotech (Inst)

Joseph A. Pidala

No relationship to disclose

Ian D. Lewis

Consulting or Advisory Role: Neovii Biotech, Amgen, Roche, Pfizer

Vincent T. Ho

Consulting or Advisory Role: Jazz Pharmaceuticals

Edwin P. Alyea

No relationship to disclose

Jerome Ritz

Consulting or Advisory Role: Biothera, Celgene, Juno Therapeutics, Amgen, Draper Laboratory, ZIOPHARM Oncology

Research Funding: Roche

Frank Glavin

Employment: Neovii Biotech, Orphan Technologies

Leadership: Orphan Technologies

Peter Westervelt

No relationship to disclose

Madan H. Jagasia

No relationship to disclose

Yi-Bin Chen

Consulting or Advisory Role: Jazz Pharmaceuticals, REGiMMUNE, Takeda Pharmaceuticals, INSYS Therapeutics, Magenta Therapeutics, EnGeneIC

Research Funding: Seattle Genetics, Novartis, Celgene

Figures

Fig 1.
Fig 1.
CONSORT diagram. ATLG, anti–T-lymphocyte globulin; TBI, total body irradiation.
Fig 2.
Fig 2.
Cumulative incidence of (A) grade 2 to 4 acute graft-versus-host disease (GVHD), (B) grades 3 to 4 acute GVHD, (C) chronic GVHD (cGVHD), and (D) moderate-severe cGVHD. ATLG, anti–T-lymphocyte globulin.
Fig 3.
Fig 3.
(A) Moderate-severe chronic graft-versus-host disease (cGVHD)–free survival. (B) Overall survival (OS). (C) cGVHD and relapse-free survival (cGRFS). (D) Progression-free survival (PFS). (E) Nonrelapse mortality (NRM). (F) Disease relapse. Log-rank test was used for group comparison for (A) to (D) and Gray test for (E) and (F). ATLG, anti–T-lymphocyte globulin.
Fig 4.
Fig 4.
Outcomes according to day −3 absolute lymphocyte count (ALC) level and treatment arm. (A) Progression-free survival (PFS). (B) Overall survival (OS). Log-rank test was used for four group comparisons. A:D −3, anti–T-lymphocyte globulin day −3; P:D −3, placebo day −3.
Fig A1.
Fig A1.
Cumulative incidence of neutrophil and platelet engraftment. (A) Absolute neutrophil count (ANC) ≥ 500/μL. (B) Platelets ≥ 20,000/μL. Gray test was used for group comparisons. ATLG, anti–T-lymphocyte globulin.
Fig A2.
Fig A2.
(A) Percent low absolute lymphocyte count (ALC) according to treatment arm and conditioning regimen. (B) Percent low ALC according to treatment arm in patients administered cyclophosphamide and total body irradiation (Cy-TBI) on the basis of order of TBI. ATLG, anti–T-lymphocyte globulin; Bu-Cy, busulfan and cyclophosphamide; Bu-Flu, busulfan and fludarabine.
Fig A3.
Fig A3.
Overall survival by arm in each conditioning regimen. (A) Cyclophosphamide and total body irradiation (Cy-TBI). (B) Busulfan and cyclophosphamide (Bu-Cy). (C) Busulfan and fludarabine (Bu-Flu). Log-rank test was used for group comparisons. ATLG, anti–T-lymphocyte globulin.
Fig A4.
Fig A4.
Moderate-severe chronic graft-versus-host disease–free survival by arm in each conditioning regimen. (A) Cyclophosphamide and total body irradiation (Cy-TBI). (B) Busulfan and cyclophosphamide (Bu-Cy). (C) Busulfan and fludarabine (Bu-Flu). Log-rank test was used for group comparisons. ATLG, anti–T-lymphocyte globulin.
Fig A5.
Fig A5.
Heat map of T-cell reconstitution. (A) Day 30. (B) Day 100. (C) One year. All values are absolute counts and normalized by subtracting by row median and divided by row median absolute deviation. Each column represents a single patient sample. Red indicates higher absolute counts. ATLG, anti–T-lymphocyte globulin.
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References

    1. Anasetti C, Logan BR, Lee SJ, et al. : Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 367:1487-1496, 2012 - PMC - PubMed
    1. Wingard JR, Majhail NS, Brazauskas R, et al. : Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol 29:2230-2239, 2011 - PMC - PubMed
    1. Holtan SG, DeFor TE, Lazaryan A, et al. : Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333-1338, 2015 - PMC - PubMed
    1. Lee SJ, Kim HT, Ho VT, et al. : Quality of life associated with acute and chronic graft-versus-host disease. Bone Marrow Transplant 38:305-310, 2006 - PubMed
    1. Bacigalupo A, Lamparelli T, Barisione G, et al. : Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: Long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant 12:560-565, 2006 - PubMed

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