[en] Purpose: A conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) combining total lymphoid irradiation (TLI) plus anti-thymocyte globulin (ATG) has been develop to induce graft-versus-tumor effects without graft-versus-host disease (GVHD). Experimental Design: We compared immune recovery in 53 patients included in a phase II randomized study comparing nonmyeloablative HCT following either fludarabine plus 2 Gy total body irradiation (TBI arm, n=28) or 8 Gy TLI plus anti-thymocyte globulin (TLI arm, n=25). Results: In comparison to TBI patients, TLI patients had a similarly low 6-month incidence of grade II-IV acute GVHD, a lower incidence of moderate/severe chronic GVHD (P=0.02), a higher incidence of CMV reactivation (P<0.001), and a higher incidence of relapse (P=0.01). While recovery of total CD8+ T cells was similar in the two groups, with median CD8+ T cell counts reaching the normal values 40-60 days after allo-HCT, TLI patients had lower percentages of naïve CD8 T cells. Median CD4+ T cell counts did not reach the lower limit of normal values the first year after allo-HCT in the two groups. Further, CD4+ T cell counts were significantly lower in TLI than in TBI patients the first 6 months after transplantation. Interestingly, while median absolute regulatory T cell (Treg) counts were comparable in TBI and TLI patients, Treg/naïve CD4+ T cell ratios were significantly higher in TLI than in TBI patients the 2 first years after transplantation. Conclusions: Immune recovery differs substantially between these two conditioning regimens possibly explaining the different clinical outcomes observed (NCT00603954).
Disciplines :
Hematology
Author, co-author :
HANNON, Muriel ; Centre Hospitalier Universitaire de Liège - CHU > Centre d'oncologie
BEGUIN, Yves ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Maris MB, Sandmaier BM, Storer BE, Maloney DG, Shizuru JA, Agura E, et al. Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgraftingmycophenolate mofetil dosing. Biol Blood Marrow Transplant 2006;12:454-65.
Baron F, Maris MB, Sandmaier BM, Storer BE, SorrorM, Diaconescu R, et al. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol 2005;23:1993-2003.
Thepot S, Zhou J, Perrot A, Robin M, Xhaard A, de Latour RP, et al. The graftversusleukemia effect is mainly restricted to NIH-defined chronic graftversushost disease after reduced intensity conditioning before allogeneic stem cell transplantation. Leukemia 2010;24:1852-8.
Storb R, Gyurkocza B, Storer BE, Sorror ML, Blume K, Niederwieser D, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clini Oncol 2013;31:1530-8.
Crooks GM, Weinberg K, Mackall C. Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 2006;12:42-6.
Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol 2012;19:324-35.
Toubert A, Glauzy S, Douay C, Clave E. Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again. Tissue Antigens 2012;79:83-9.
Peggs KS. Reconstitution of adaptive and innate immunity following allogeneic hematopoietic stem cell transplantation in humans. Cytotherapy 2006;8:427-36.
Gress RE, Emerson SG, Drobyski WR. Immune reconstitution: how it should work, what's broken, and why it matters. Biol Blood Marrow Transplant 2010;16:S133-S7.
Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 2000;355:1875-81.
Krenger W, Blazar BR, Hollander GA. Thymic T-cell development in allogeneic stem cell transplantation. Blood 2011;117:6768-76.
Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D, et al. T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 2002;99:3449-53.
Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005;115:930-9.
Clave E, Busson M, Douay C, Peffault dL, Berrou J, Rabian C, et al. Acute graft-versus-host disease transiently impairs thymic output in young patients after allogeneic hematopoietic stem cell transplantation. Blood 2009;113:6477-84.
Castermans E, Hannon M, Dutrieux J, Humblet-Baron S, Seidel L, Cheynier R, et al. Thymic recovery after allogeneic hematopoietic cell transplantation with non-myeloablative conditioning is limited to patients younger than 60 years of age. Haematologica 2011;96:298-306.
Blaise D, Tabrizi R, Boher JM, LeCorroller-Soriano AG, Bay JO, Fegueux N, et al. Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation. Cancer 2013;119:602-11.
Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, et al. Protective conditioning for acute graft-versus-host disease. N Engl J Med 2005;353:1321-31.
Kohrt HE, Turnbull BB, Heydari K, Shizuru JA, Laport GG, Miklos DB, et al. TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors. Blood 2009;114:1099-109.
Benjamin J, Chhabra S, Kohrt HE, Lavori P, Laport GG, Arai S, et al. Total Lymphoid Irradiation-Antithymocyte Globulin Conditioning and Allogeneic Transplantation for Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms. Biol Blood Marrow Transplant 2014;20:837-43.
Messina G, Giaccone L, Festuccia M, Irrera G, Scortechini I, Sorasio R, et al. Multicenter experience using total lymphoid irradiation and antithymocyte globulin as conditioning for allografting in hematological malignancies. Biol Blood Marrow Transplant 2012;18:1600-7.
Arai S, Sahaf B, Narasimhan B, Chen GL, Jones CD, Lowsky R, et al. Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 2012;119:6145-54.
Schaenman JM, Shashidhar S, Rhee C, Wong J, Navato S, Wong RM, et al. Early CMV Viremia Is Associated with Impaired Viral Control following Nonmyeloablative Hematopoietic Cell Transplantation with a Total Lymphoid Irradiation and Antithymocyte Globulin Preparative Regimen. Biol Blood Marrow Transplant 2011;17:693-702.
Pillai AB, George TI, Dutt S, Strober S. Host natural killer T cells induce an interleukin-4-dependent expansion of donor CD4+CD25+Foxp3+ T regulatory cells that protects against graft-versus-host disease. Blood 2009;113:4458-67.
Baron F, Zachee P, Maertens J, Kerre T, Ory A, Seidel L, et al. Non-myeloablative allogeneic hematopoietic cell transplantation following fludarabine plus 2 Gy TBI or ATG plus 8 Gy TLI: a phase II randomized study from the Belgian Hematological Society. J Hematol Oncology 2015;8:4.
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2005;11:945-56.
Baron F, Baker JE, Storb R, Gooley TA, Sandmaier BM, Maris MB, et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood 2004;104:2254-62.
Kakhniashvili I, Filicko J, Kraft WK, Flomenberg N. Heterogeneous clearance of antithymocyte globulin after CD34+-selected allogeneic hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 2005;11:609-18.
Podgorny PJ, Ugarte-Torres A, Liu Y, Williamson TS, Russell JA, Storek J. High rabbit-antihuman thymocyte globulin levels are associated with low likelihood of graft-vs-host disease and high likelihood of posttransplant lymphoproliferative disorder. Biol Blood Marrow Transplant 2010;16:915-26.
Chawla S, Dharmani-Khan P, Liu Y, Prokopishyn N, AmlishMunir M, Griffiths C, et al. High Serum Level of Antithymocyte Globulin Immediately before Graft Infusion Is Associated with a Low Likelihood of Chronic, But Not Acute, Graft-versus-Host Disease. Biol Blood Marrow Transplant 2014;20:1156-62.
Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity 2008;29:848-62.
De Bock M, Fillet M, Hannon M, Seidel L, Merville MP, Gothot A, et al. Kinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning. PLoS ONE 2013;8:e55876.
Thiant S, Yakoub-Agha I, Magro L, Trauet J, Coiteux V, Jouet JP, et al. Plasma levels of IL-7 and IL-15 in the first month after myeloablative BMT are predictive biomarkers of both acute GVHD and relapse. Bone Marrow Transplant 2010;45:1546-52.
Thiant S, Labalette M, Trauet J, Coiteux V, de BE, Dessaint JP, et al. Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD. Bone Marrow Transplant 2011;46:1374-81.
Edinger M, Hoffman P, Ermann J, Drago K, Beilhack A, Fathman CG, et al. Donor CD4+CD25+ regulatory T cells suppress acute GVHD lethality without loss of GVL activity. Blood 2002;100:142a, #535.
Hannon M, Lechanteur C, Lucas S, Somja J, Seidel L, Belle L, et al. Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease. Transfusion 2014;54:353-63.
Xhaard A, Moins-Teisserenc H, Busson M, Robin M, Ribaud P, Dhedin N, et al. Reconstitution of regulatory T-cell subsets after allogeneic hematopoietic SCT. Bone Marrow Transplant 2014;49:1089-92.
Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J, et al. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J Clin Invest 2010;120:1479-93.
Nador RG, Hongo D, Baker J, Yao Z, Strober S. The changed balance of regulatory and naive T cells promotes tolerance after TLI and anti-T-cell antibody conditioning. Am J Transplant 2010;10:262-72.
Pierson W, Cauwe B, Policheni A, Schlenner SM, Franckaert D, Berges J, et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3 (+) regulatory T cells. Nature Immunology. 2013;14:959-65.
Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. SciTranslMed 2013;5:179ra43.
Kennedy-Nasser AA, Ku S, Castillo-Caro P, Hazrat Y, Wu MF, Liu H, et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Can Res 2014;20:2215-25.
Kohrt HE, Pillai AB, Lowsky R, Strober S. NKT cells, Treg, and their interactions in bone marrow transplantation. Eur J Immunol 2010;40:1862-9.
Rubio MT, Moreira-Teixeira L, Bachy E, Bouillie M, Milpied P, Coman T, et al. Early posttransplantation donor-derived invariant natural killer T-cell recovery predicts the occurrence of acute graft-versus-host disease and overall survival. Blood 2012;120:2144-54.
Baron F, Storer B, Maris MB, Storek J, Piette F, Metcalf M, et al. Unrelated donor status and high donor age independently affect immunologic recovery after nonmyeloablative conditioning. Biol Blood Marrow Transplant 2006;12:1176-87.
Sarantopoulos S, Stevenson KE, Kim HT, Cutler CS, Bhuiya NS, Schowalter M, et al. Altered B-cellhomeostasis and excess BAFF inhuman chronic graftversushost disease. Blood 2009;113:3865-74.
Servais S, Lengline E, Porcher R, Carmagnat M, Peffault de Latour R, Robin M, et al. Long-Term Immune Reconstitution and Infection Burden after Mismatched Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2014;20:507-17.
Vukicevic M, Chalandon Y, Helg C, Matthes T, Dantin C, Huard B, et al. CD56bright NK cells after hematopoietic stem cell transplantation are activated mature NK cells that expand in patients with low numbers of T cells. Eur J Immunol 2010;40:3246-54.
Vago L, Forno B, Sormani MP, Crocchiolo R, Zino E, Di Terlizzi S, et al. Temporal, quantitative, and functional characteristics of single-KIR-positive alloreactive natural killer cell recovery account for impaired graftversusleukemia activity after haploidentical hematopoietic stem cell transplantation. Blood 2008;112:3488-99.
Kornblit B, Maloney DG, Storer BE, Maris MB, Vindelov L, Hari P, et al. A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after nonmyeloablative unrelated donor transplantation. Haematologica 2014;99:1624-31.
Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012;14:1258-75.
Baron F, Labopin M, Niederwieser D, Vigouroux S, Cornelissen JJ, Malm C, et al. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European group for blood and marrow transplantation. Leukemia 2012;26:2462-8.