Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors

Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial

Mahasweta Gooptu, Haesook T. Kim, Yi Bin Chen, Witold Rybka, Andrew Artz, Michael Boyer, Laura Johnston, Jim McGuirk, Thomas C. Shea, Madan Jagasia, Paul J. Shaughnessy, Carol G. Reynolds, Marie Fields, Edwin P. Alyea, Vincent T. Ho, Frank Glavin, John F. Dipersio, Peter Westervelt, Jerome Ritz, Robert J. Soiffer

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.

Original languageEnglish (US)
Pages (from-to)2216-2223
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume24
Issue number11
DOIs
StatePublished - Nov 1 2018

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Unrelated Donors
Stem Cell Transplantation
Randomized Controlled Trials
T-Lymphocytes
Cell Transplantation
Graft vs Host Disease
Regulatory T-Lymphocytes
Disease-Free Survival
Arm
Placebos
tumor-globulin
Transplants
Myelodysplastic Syndromes
CD4 Lymphocyte Count
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Double-Blind Method
Acute Myeloid Leukemia
Natural Killer Cells
Thomsen-Friedenreich antibodies
Flow Cytometry

All Science Journal Classification (ASJC) codes

  • Hematology
  • Transplantation

Cite this

Gooptu, Mahasweta ; Kim, Haesook T. ; Chen, Yi Bin ; Rybka, Witold ; Artz, Andrew ; Boyer, Michael ; Johnston, Laura ; McGuirk, Jim ; Shea, Thomas C. ; Jagasia, Madan ; Shaughnessy, Paul J. ; Reynolds, Carol G. ; Fields, Marie ; Alyea, Edwin P. ; Ho, Vincent T. ; Glavin, Frank ; Dipersio, John F. ; Westervelt, Peter ; Ritz, Jerome ; Soiffer, Robert J. / Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors : Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial. In: Biology of Blood and Marrow Transplantation. 2018 ; Vol. 24, No. 11. pp. 2216-2223.
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abstract = "We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25–127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.",
author = "Mahasweta Gooptu and Kim, {Haesook T.} and Chen, {Yi Bin} and Witold Rybka and Andrew Artz and Michael Boyer and Laura Johnston and Jim McGuirk and Shea, {Thomas C.} and Madan Jagasia and Shaughnessy, {Paul J.} and Reynolds, {Carol G.} and Marie Fields and Alyea, {Edwin P.} and Ho, {Vincent T.} and Frank Glavin and Dipersio, {John F.} and Peter Westervelt and Jerome Ritz and Soiffer, {Robert J.}",
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Gooptu, M, Kim, HT, Chen, YB, Rybka, W, Artz, A, Boyer, M, Johnston, L, McGuirk, J, Shea, TC, Jagasia, M, Shaughnessy, PJ, Reynolds, CG, Fields, M, Alyea, EP, Ho, VT, Glavin, F, Dipersio, JF, Westervelt, P, Ritz, J & Soiffer, RJ 2018, 'Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors: Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial', Biology of Blood and Marrow Transplantation, vol. 24, no. 11, pp. 2216-2223. https://doi.org/10.1016/j.bbmt.2018.07.002

Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors : Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial. / Gooptu, Mahasweta; Kim, Haesook T.; Chen, Yi Bin; Rybka, Witold; Artz, Andrew; Boyer, Michael; Johnston, Laura; McGuirk, Jim; Shea, Thomas C.; Jagasia, Madan; Shaughnessy, Paul J.; Reynolds, Carol G.; Fields, Marie; Alyea, Edwin P.; Ho, Vincent T.; Glavin, Frank; Dipersio, John F.; Westervelt, Peter; Ritz, Jerome; Soiffer, Robert J.

In: Biology of Blood and Marrow Transplantation, Vol. 24, No. 11, 01.11.2018, p. 2216-2223.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of Antihuman T Lymphocyte Globulin on Immune Recovery after Myeloablative Allogeneic Stem Cell Transplantation with Matched Unrelated Donors

T2 - Analysis of Immune Reconstitution in a Double-Blind Randomized Controlled Trial

AU - Gooptu, Mahasweta

AU - Kim, Haesook T.

AU - Chen, Yi Bin

AU - Rybka, Witold

AU - Artz, Andrew

AU - Boyer, Michael

AU - Johnston, Laura

AU - McGuirk, Jim

AU - Shea, Thomas C.

AU - Jagasia, Madan

AU - Shaughnessy, Paul J.

AU - Reynolds, Carol G.

AU - Fields, Marie

AU - Alyea, Edwin P.

AU - Ho, Vincent T.

AU - Glavin, Frank

AU - Dipersio, John F.

AU - Westervelt, Peter

AU - Ritz, Jerome

AU - Soiffer, Robert J.

PY - 2018/11/1

Y1 - 2018/11/1

N2 - We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25–127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection.

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