Comparison of reference values for immune recovery between event-free patients receiving haploidentical allografts and those receiving human leukocyte antigen-matched sibling donor allografts
1. Peking University People’s Hospital & Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China 2. Peking-Tsinghua Center for Life Sciences, Beijing 100044, China
To establish optimal reference values for recovered immune cell subsets, we prospectively investigated post-transplant immune reconstitution (IR) in 144 patients who received allogeneic stem cell transplantation (allo-SCT) and without showing any of the following events: poor graft function, grades II?IV acute graft-versus-host disease (GVHD), serious chronic GVHD, serious bacterial infection, invasive fungal infection, or relapse or death in the first year after transplantation. IR was rapid in monocytes, intermediate in lymphocytes, CD3+ T cells, CD8+ T cells, and CD19+ B cells, and very slow in CD4+ T cells in the entire patient cohort. Immune recovery was generally faster under HLA-matched sibling donor transplantation than under haploidentical transplantation. Results suggest that patients with an IR comparable to the reference values display superior survival, and the levels of recovery in immune cells need not reach those in healthy donor in the first year after transplantation. We suggest that data from this recipient cohort should be used as reference values for post-transplant immune cell counts in patients receiving HSCT.
Lum LG. The kinetics of immune reconstitution after human marrow transplantation. Blood 1987; 69(2): 369–380
pmid: 3542077
3
Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, Huang XJ. Immune reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with HLA-identical sibling transplantation. J Clin Immunol 2012; 32(2): 268–280 https://doi.org/10.1007/s10875-011-9630-7
pmid: 22173879
4
Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, Ugarte-Torres A, Khan FM, Luider J, Auer-Grzesiak I, Mansoor A, Russell JA, Daly A, Stewart DA, Maloney D, Boeckh M, Storek J. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012; 14(10): 1258–1275 https://doi.org/10.3109/14653249.2012.715243
pmid: 22985195
5
Azevedo RI, Soares MVD, Albuquerque AS, Tendeiro R, Soares RS, Martins M, Ligeiro D, Victorino RMM, Lacerda JF, Sousa AE. Long-term immune reconstitution of naive and memory T cell pools after haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19(5): 703–712 https://doi.org/10.1016/j.bbmt.2013.01.017
pmid: 23396243
6
Zhao XY, Chang YJ, Huang XJ. Conflicting impact of alloreactive NK cells on transplantation outcomes after haploidentical transplantation: do the reconstitution kinetics of natural killer cells create these differences? Biol Blood Marrow Transplant 2011; 17(10): 1436–1442 https://doi.org/10.1016/j.bbmt.2011.05.020
pmid: 21703971
7
Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP. Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 2009; 15(2): 257–265 https://doi.org/10.1016/j.bbmt.2008.11.025
pmid: 19167686
8
Wang Y, Chang YJ, Xu LP, Liu KY, Liu DH, Zhang XH, Chen H, Han W, Chen YH, Wang FR, Wang JZ, Chen Y, Yan CH, Huo MR, Li D, Huang XJ. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 2014; 124(6): 843–850 https://doi.org/10.1182/blood-2014-03-563130
pmid: 24916508
9
Wang Y, Fu HX, Liu DH, Xu LP, Zhang XH, Chang YJ, Chen YH, Wang FR, Sun YQ, Tang FF, Liu KY, Huang XJ. Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplant 2014; 49(3): 426–433 https://doi.org/10.1038/bmt.2013.191
pmid: 24292519
10
Kong Y, Chang YJ, Wang YZ, Chen YH, Han W, Wang Y, Sun YQ, Yan CH, Wang FR, Liu YR, Xu LP, Liu DH, Huang XJ. Association of an impaired bone marrow microenvironment with secondary poor graft function after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19(10): 1465–1473 https://doi.org/10.1016/j.bbmt.2013.07.014
pmid: 23879970
11
Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15(6): 825–828
pmid: 7581076
12
Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers ME. 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(12): 945–956 https://doi.org/10.1016/j.bbmt.2005.09.004
pmid: 16338616
13
Servais S, Lengline E, Porcher R, Carmagnat M, Peffault de Latour R, Robin M, Sicre de Fontebrune F, Clave E, Maki G, Granier C, Xhaard A, Dhedin N, Molina JM, Toubert A, Moins-Teisserenc H, Socie G. Long-term immune reconstitution and infection burden after mismatched hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2014; 20(4): 507–517 https://doi.org/10.1016/j.bbmt.2014.01.001
pmid: 24406505
14
Robin M, Porcher R, De Castro Araujo R, de Latour RP, Devergie A, Rocha V, Larghero J, Adès L, Ribaud P, Mary JY, Socié G. Risk factors for late infections after allogeneic hematopoietic stem cell transplantation from a matched related donor. Biol Blood Marrow Transplant 2007; 13(11): 1304–1312 https://doi.org/10.1016/j.bbmt.2007.07.007
pmid: 17950917
15
Calandra T, Cohen J; International Sepsis Forum Definition of Infection in the ICU Consensus Conference. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med 2005; 33(7): 1538–1548 https://doi.org/10.1097/01.CCM.0000168253.91200.83
pmid: 16003060
16
Hoenigl M, Strenger V, Buzina W, Valentin T, Koidl C, Wölfler A, Seeber K, Valentin A, Strohmeier AT, Zollner-Schwetz I, Raggam RB, Urban C, Lass-Flörl C, Linkesch W, Krause R. European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) host factors and invasive fungal infections in patients with haematological malignancies. J Antimicrob Chemother 2012; 67(8): 2029–2033 https://doi.org/10.1093/jac/dks155
pmid: 22566591
17
Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, Passweg J, Roosnek E. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol 2008; 30(4): 425–437 https://doi.org/10.1007/s00281-008-0132-5
pmid: 18949477
18
DeCook LJ, Thoma M, Huneke T, Johnson ND, Wiegand RA, Patnaik MM, Litzow MR, Hogan WJ, Porrata LF, Holtan SG. Impact of lymphocyte and monocyte recovery on the outcomes of allogeneic hematopoietic SCT with fludarabine and melphalan conditioning. Bone Marrow Transplant 2013; 48(5): 708–714 https://doi.org/10.1038/bmt.2012.211
pmid: 23103674
19
Chakrabarti S, Brown J, Guttridge M, Pamphilon DH, Lankester A, Marks DI. Early lymphocyte recovery is an important determinant of outcome following allogeneic transplantation with CD34+ selected graft and limited T-cell addback. Bone Marrow Transplant 2003; 32(1): 23–30 https://doi.org/10.1038/sj.bmt.1704082
pmid: 12815474
20
Kim DH, Kim JG, Sohn SK, Sung WJ, Suh JS, Lee KS, Lee KB. Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation. Br J Haematol 2004; 125(2): 217–224 https://doi.org/10.1111/j.1365-2141.2004.04891.x
pmid: 15059145
21
Savani BN, Mielke S, Rezvani K, Montero A, Yong AS, Wish L, Superata J, Kurlander R, Singh A, Childs R, Barrett AJ. Absolute lymphocyte count on day 30 is a surrogate for robust hematopoietic recovery and strongly predicts outcome after T cell-depleted allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2007; 13(10): 1216–1223 https://doi.org/10.1016/j.bbmt.2007.07.005
pmid: 17889359
22
Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, Huang XJ. Clinical impact of absolute lymphocyte count on day 30 after unmanipulated haploidentical blood and marrow transplantation for pediatric patients with hematological malignancies. Am J Hematol 2011; 86(2): 227–230 https://doi.org/10.1002/ajh.21921
pmid: 21264916
23
Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J. Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation. Blood 1998; 91(9): 3481–3486
pmid: 9558408
24
Bayraktar UD, Milton DR, Guindani M, Rondon G, Chen J, Al-Atrash G, Rezvani K, Champlin R, Ciurea SO. Optimal threshold and time of absolute lymphocyte count assessment for outcome prediction after bone marrow transplantation. Biol Blood Marrow Transplant 2016; 22(3): 505–513 https://doi.org/10.1016/j.bbmt.2015.10.020
pmid: 26524730
25
Kim HT, Armand P, Frederick D, Andler E, Cutler C, Koreth J, Alyea EP 3rd, Antin JH, Soiffer RJ, Ritz J, Ho VT. Absolute lymphocyte count recovery after allogeneic hematopoietic stem cell transplantation predicts clinical outcome. Biol Blood Marrow Transplant 2015; 21(5): 873–880 https://doi.org/10.1016/j.bbmt.2015.01.019
pmid: 25623931
26
Bühlmann L, Buser AS, Cantoni N, Gerull S, Tichelli A, Gratwohl A, Stern M. Lymphocyte subset recovery and outcome after T-cell replete allogeneic hematopoietic SCT. Bone Marrow Transplant 2011; 46(10): 1357–1362 https://doi.org/10.1038/bmt.2010.306
pmid: 21113185
Bartelink IH, Belitser SV, Knibbe CAJ, Danhof M, de Pagter AJ, Egberts TCG, Boelens JJ. Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. Biol Blood Marrow Transplant 2013; 19(2): 305–313 https://doi.org/10.1016/j.bbmt.2012.10.010
pmid: 23092812
29
Berger M, Figari O, Bruno B, Raiola A, Dominietto A, Fiorone M, Podesta M, Tedone E, Pozzi S, Fagioli F, Madon E, Bacigalupo A. Lymphocyte subsets recovery following allogeneic bone marrow transplantation (BMT): CD4+ cell count and transplant-related mortality. Bone Marrow Transplant 2008; 41(1): 55–62 https://doi.org/10.1038/sj.bmt.1705870
pmid: 17934532
30
Kim DH, Sohn SK, Won DI, Lee NY, Suh JS, Lee KB. Rapid helper T-cell recovery above 200 × 106/L at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation. Bone Marrow Transplant 2006; 37(12): 1119–1128 https://doi.org/10.1038/sj.bmt.1705381
pmid: 16699530
31
Koehl U, Bochennek K, Zimmermann SY, Lehrnbecher T, Sörensen J, Esser R, Andreas C, Kramm C, Grüttner HP, Falkenberg E, Orth A, Bader P, Schwabe D, Klingebiel T. Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+ CD3+ count reconstitution is associated with survival. Bone Marrow Transplant 2007; 39(5): 269–278 https://doi.org/10.1038/sj.bmt.1705584
pmid: 17311085
32
Giannelli R, Bulleri M, Menconi M, Casazza G, Focosi D, Bernasconi S, Favre C. Reconstitution rate of absolute CD8+ T lymphocyte counts affects overall survival after pediatric allogeneic hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2012; 34(1): 29–34 https://doi.org/10.1097/MPH.0b013e3182127add
pmid: 21768889