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Incomplete chimerism following myeloablative and anti-thymocyte globulin-conditioned hematopoietic cell transplantation is a risk factor for relapse and chronic graft-versus-host disease

Published:September 01, 2022DOI:https://doi.org/10.1016/j.jcyt.2022.07.013

      Abstract

      Background aims

      The value of routine chimerism determination after myeloablative hematopoietic cell transplantation (HCT) is unclear, particularly in the setting of anti-thymocyte globulin (ATG)-based graft-versus-host disease (GVHD) prophylaxis.

      Methods

      Blood samples were collected at 3 months post-HCT from 558 patients who received myeloablative conditioning and ATG-based GVHD prophylaxis. Chimerism was assessed using multiplex polymerase chain reaction of short tandem repeats in sorted T cells (CD3+) and leukemia lineage cells (CD13+CD33+ for myeloid malignancies and CD19+ for B-lymphoid malignancies). ATG exposure was determined using a flow cytometry-based assay. The primary outcomes of interest were relapse and chronic GVHD (cGVHD).

      Results

      Incomplete (<95%) T-cell chimerism and leukemia lineage chimerism were present in 17% and 4% of patients, respectively. Patients with incomplete T-cell chimerism had a significantly greater incidence of relapse (36% versus 22%, subhazard ratio [SHR] = 2.03, P = 0.001) and lower incidence of cGVHD (8% versus 25%, SHR = 0.29, P < 0.001) compared with patients with complete chimerism. In multivariate modeling, patients with high post-transplant ATG area under the curve and any cytomegalovirus (CMV) serostatus other than donor/recipient seropositivity (non-D+R+) had an increased likelihood of incomplete T-cell chimerism. Patients with incomplete leukemia lineage chimerism had a significantly greater incidence of relapse (50% versus 23%, SHR = 2.70, P = 0.011) and, surprisingly, a greater incidence of cGVHD (45% versus 20%, SHR = 2.64, P = 0.003).

      Conclusions

      High post-transplant ATG exposure and non-D+R+ CMV serostatus predispose patients to incomplete T-cell chimerism, which is associated with an increased risk of relapse. The increased risk of cGVHD with incomplete B-cell/myeloid chimerism is a novel finding that suggests an important role for recipient antigen-presenting cells in cGVHD pathogenesis.

      Key Words

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      References

        • Ousia S
        • Kalra A
        • Williamson TS
        • et al.
        Hematopoietic cell transplant outcomes after myeloablative conditioning with fludarabine, busulfan, low-dose total body irradiation, and rabbit antithymocyte globulin.
        Clinical transplantation. 2020; 34: e14018
        • Kharfan-Dabaja MA
        • Kumar A
        • Ayala E
        • et al.
        Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.
        Transplantation and cellular therapy. 2021; 27: 642-649
        • Doney K
        • Loken M
        • Bryant E
        • Smith A
        • Appelbaum F.
        Lack of utility of chimerism studies obtained 2–3 months after myeloablative hematopoietic cell transplantation for ALL.
        Bone marrow transplantation. 2008; 42: 271-274
        • Mossallam GI
        • Kamel AM
        • Storer B
        • Martin PJ.
        Prognostic utility of routine chimerism testing at 2 to 6 months after allogeneic hematopoietic cell transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2009; 15: 352-359
        • Bornhäuser M
        • Oelschlaegel U
        • Platzbecker U
        • et al.
        Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation.
        Haematologica. 2009; 94: 1613-1617
        • Huisman C
        • de Weger RA
        • de Vries L
        • Tilanus MG
        • Verdonck LF.
        Chimerism analysis within 6 months of allogeneic stem cell transplantation predicts relapse in acute myeloid leukemia.
        Bone marrow transplantation. 2007; 39: 285-291
        • Choi SJ
        • Lee KH
        • Lee JH
        • et al.
        Prognostic value of hematopoietic chimerism in patients with acute leukemia after allogeneic bone marrow transplantation: a prospective study.
        Bone marrow transplantation. 2000; 26: 327-332
        • Mattsson J
        • Uzunel M
        • Tammik L
        • Aschan J
        • Ringdén O.
        Leukemia lineage-specific chimerism analysis is a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation.
        Leukemia. 2001; 15: 1976-1985
        • Tang X
        • Alatrash G
        • Ning J
        • et al.
        Increasing chimerism after allogeneic stem cell transplantation is associated with longer survival time.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2014; 20: 1139-1144
        • Yeh AC
        • O’Donnell PV
        • Schoch G
        • et al.
        Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin.
        Bone Marrow Transplantation. 2021; 57: 198-206
        • Chen CT
        • Gau JP
        • Liu JH
        • Chiou TJ
        • Hsiao LT
        • Liu YC.
        Early achievement of full donor chimerism after allogeneic hematopoietic stem cell transplantation predicts lower relapse risk in patients with acute lymphoblastic leukemia.
        Journal of the Chinese Medical Association: JCMA. 2018; 81: 1038-1043
        • Thiede C
        • Bornhäuser M
        • Oelschlägel U
        • et al.
        Sequential monitoring of chimerism and detection of minimal residual disease after allogeneic blood stem cell transplantation (BSCT) using multiplex PCR amplification of short tandem repeat-markers.
        Leukemia. 2001; 15: 293-302
        • Jacque N
        • Nguyen S
        • Golmard JL
        • et al.
        Chimerism analysis in peripheral blood using indel quantitative real-time PCR is a useful tool to predict post-transplant relapse in acute leukemia.
        Bone marrow transplantation. 2015; 50: 259-265
        • Wong E
        • Mason K
        • Collins J
        • et al.
        Prognostic Limitations of Donor T Cell Chimerism after Myeloablative Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2017; 23: 840-844
        • Lee HC
        • Saliba RM
        • Rondon G
        • et al.
        Mixed T Lymphocyte Chimerism after Allogeneic Hematopoietic Transplantation Is Predictive for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2015; 21: 1948-1954
        • Deeg HJ
        • Salit RB
        • Monahan T
        • et al.
        Early Mixed Lymphoid Donor/Host Chimerism is Associated with Improved Transplant Outcome in Patients with Primary or Secondary Myelofibrosis.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2020; 26: 2197-2203
        • Qin XY
        • Li GX
        • Qin YZ
        • et al.
        Quantitative chimerism: an independent acute leukemia prognosis indicator following allogeneic hematopoietic SCT.
        Bone Marrow Transplant. 2014; 49: 1269-1277
        • Bosch M
        • Dhadda M
        • Hoegh-Petersen M
        • et al.
        Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation.
        Cytotherapy. 2012; 14: 1258-1275
        • 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.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2006; 12: 560-565
        • Chang YJ
        • Wang Y
        • Mo XD
        • et al.
        Optimal dose of rabbit thymoglobulin in conditioning regimens for unmanipulated, haploidentical, hematopoietic stem cell transplantation: Long-term outcomes of a prospective randomized trial.
        Cancer. 2017; 123: 2881-2892
        • Walker I
        • Panzarella T
        • Couban S
        • et al.
        Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial.
        The Lancet Oncology. 2016; 17: 164-173
        • Chang YJ
        • Wu DP
        • Lai YR
        • et al.
        Antithymocyte Globulin for Matched Sibling Donor Transplantation in Patients With Hematologic Malignancies: A Multicenter, Open-Label, Randomized Controlled Study.
        Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2020; 38: 3367-3376
        • Walker I
        • Panzarella T
        • Couban S
        • et al.
        Addition of anti-thymocyte globulin to standard graft-versus-host disease prophylaxis versus standard treatment alone in patients with haematological malignancies undergoing transplantation from unrelated donors: final analysis of a randomised, open-label, multicentre, phase 3 trial.
        The Lancet Haematology. 2020; 7: e100-e111
        • Dabas R
        • Jamani K
        • Kangarloo SB
        • et al.
        Antirelapse effect of pretransplant exposure to rabbit antithymocyte globulin.
        Blood advances. 2019; 3: 1394-1405
        • Russell JA
        • Irish W
        • Balogh A
        • et al.
        The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2010; 16: 509-514
        • Kalra A
        • Williamson T
        • Daly A
        • et al.
        Impact of Donor and Recipient Cytomegalovirus Serostatus on Outcomes of Antithymocyte Globulin-Conditioned Hematopoietic Cell Transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 1654-1663
        • Jamani K
        • MacDonald J
        • Lavoie M
        • et al.
        Zoster prophylaxis after allogeneic hematopoietic cell transplantation using acyclovir/valacyclovir followed by vaccination.
        Blood advances. 2016; 1: 152-159
        • Evernden C
        • Dowhan M
        • Dabas R
        • et al.
        High incidence of Pneumocystis jirovecii pneumonia in allogeneic hematopoietic cell transplant recipients in the modern era.
        Cytotherapy. 2020; 22: 27-34
        • Przepiorka D
        • Weisdorf D
        • Martin P
        • et al.
        1994 Consensus Conference on Acute GVHD Grading.
        Bone marrow transplantation. 1995; 15: 825-828
        • Filipovich AH
        • Weisdorf D
        • Pavletic S
        • 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.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2005; 11: 945-956
        • Whiteside S
        • Chin A
        • Tripathi G
        • et al.
        Curability and transferability of atopy with allogeneic hematopoietic cell transplantation.
        Bone marrow transplantation. 2020; 55: 1282-1289
        • Wang Y
        • Fu HX
        • Liu DH
        • et al.
        Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial.
        Bone marrow transplantation. 2014; 49: 426-433
        • Bacigalupo A
        • Lamparelli T
        • Milone G
        • et al.
        Pre-emptive treatment of acute GVHD: a randomized multicenter trial of rabbit anti-thymocyte globulin, given on day+7 after alternative donor transplants.
        Bone marrow transplantation. 2010; 45: 385-391
        • Bacigalupo A
        • Lamparelli T
        • Bruzzi P
        • et al.
        Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO).
        Blood. 2001; 98: 2942-2947
        • Khanolkar RA
        • Kalra A
        • Kinzel M
        • et al.
        A biomarker-guided, prospective, phase 2 trial of pre-emptive graft-versus-host disease therapy using anti-thymocyte globulin.
        Cytotherapy. 2021; 23: 1007-1016
        • Dabas R
        • Lee R
        • Servito MT
        • et al.
        Antithymocyte Globulin at Clinically Relevant Concentrations Kills Leukemic Blasts.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2016; 22: 815-824
        • Dabas R
        • Khan PD
        • Modi M
        • Khan FM
        • Storek J.
        More acute lymphoid leukemia than acute myeloid leukemia blasts are killed by rabbit antithymocyte globulin.
        Cytotherapy. 2019; 21: 1161-1165
        • Dabas R
        • Dharmani-Khan P
        • Modi M
        • et al.
        Anti-thymocyte globulin's activity against acute myeloid leukemia stem cells.
        Bone marrow transplantation. 2019; 54: 549-559
        • Jiang Y
        • Wan LP
        • Qin YW
        • et al.
        Chimerism status is correlated to acute graft-versus-host disease after allogeneic stem cell transplantation.
        International journal of hematology. 2014; 99: 323-328
        • Mousavi SA
        • Javadimoghadam M
        • Ghavamzadeh A
        • et al.
        The Relationship between STR-PCR Chimerism Analysis and Chronic GvHD Following Hematopoietic Stem Cell Transplantation.
        International journal of hematology-oncology and stem cell research. 2017; 11: 24-29
        • Bortin MM
        • Truitt RL
        • Rimm AA
        • Bach FH.
        Graft-versus-leukaemia reactivity induced by alloimmunisation without augmentation of graft-versus-host reactivity.
        Nature. 1979; 281: 490-491
        • Shlomchik WD
        • Couzens MS
        • Tang CB
        • et al.
        Prevention of graft versus host disease by inactivation of host antigen-presenting cells.
        Science (New York, NY). 1999; 285: 412-415
        • Teshima T
        • Reddy P
        • Lowler KP
        • et al.
        Flt3 ligand therapy for recipients of allogeneic bone marrow transplants expands host CD8 alpha(+) dendritic cells and reduces experimental acute graft-versus-host disease.
        Blood. 2002; 99: 1825-1832
        • Mapara MY
        • Kim YM
        • Wang SP
        • Bronson R
        • Sachs DH
        • Sykes M.
        Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells.
        Blood. 2002; 100: 1903-1909
        • Chakraverty R
        • Eom HS
        • Sachs J
        • et al.
        Host MHC class II+ antigen-presenting cells and CD4 cells are required for CD8-mediated graft-versus-leukemia responses following delayed donor leukocyte infusions.
        Blood. 2006; 108: 2106-2113
        • Reddy P
        • Maeda Y
        • Liu C
        • Krijanovski OI
        • Korngold R
        • Ferrara JL.
        A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses.
        Nature medicine. 2005; 11: 1244-1249
        • Zhang Y
        • Shlomchik WD
        • Joe G
        • et al.
        APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease.
        Journal of immunology (Baltimore, Md: 1950). 2002; 169: 7111-7118
        • Chakraverty R
        • Sykes M.
        The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia.
        Blood. 2007; 110: 9-17
        • Durakovic N
        • Bezak KB
        • Skarica M
        • et al.
        Host-derived Langerhans cells persist after MHC-matched allografting independent of donor T cells and critically influence the alloresponses mediated by donor lymphocyte infusions.
        Journal of immunology (Baltimore, Md: 1950). 2006; 177: 4414-4425
        • Merad M
        • Hoffmann P
        • Ranheim E
        • et al.
        Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease.
        Nature medicine. 2004; 10: 510-517
        • Auffermann-Gretzinger S
        • Eger L
        • Bornhäuser M
        • et al.
        Fast appearance of donor dendritic cells in human skin: dynamics of skin and blood dendritic cells after allogeneic hematopoietic cell transplantation.
        Transplantation. 2006; 81: 866-873
        • Bogunovic M
        • Ginhoux F
        • Wagers A
        • et al.
        Identification of a radio-resistant and cycling dermal dendritic cell population in mice and men.
        The Journal of experimental medicine. 2006; 203: 2627-2638
        • Auffermann-Gretzinger S
        • Lossos IS
        • Vayntrub TA
        • et al.
        Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients.
        Blood. 2002; 99: 1442-1448
        • Collin MP
        • Hart DN
        • Jackson GH
        • et al.
        The fate of human Langerhans cells in hematopoietic stem cell transplantation.
        The Journal of experimental medicine. 2006; 203: 27-33
        • Billiau AD
        • Fevery S
        • Rutgeerts O
        • Landuyt W
        • Waer M.
        Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants.
        Blood. 2002; 100: 1894-1902
        • Hong C
        • Jin R
        • Dai X
        • Gao X
        Functional Contributions of Antigen Presenting Cells in Chronic Graft-Versus-Host Disease.
        Frontiers in immunology. 2021; 12614183
        • Schober K
        • Buchholz VR
        • Busch DH.
        TCR repertoire evolution during maintenance of CMV-specific T-cell populations.
        Immunological reviews. 2018; 283: 113-128
        • Day EK
        • Carmichael AJ
        • ten Berge IJ
        • Waller EC
        • Sissons JG
        • Wills MR.
        Rapid CD8+ T cell repertoire focusing and selection of high-affinity clones into memory following primary infection with a persistent human virus: human cytomegalovirus.
        Journal of immunology (Baltimore, Md: 1950). 2007; 179: 3203-3213
        • Iancu EM
        • Corthesy P
        • Baumgaertner P
        • et al.
        Clonotype selection and composition of human CD8 T cells specific for persistent herpes viruses varies with differentiation but is stable over time.
        Journal of immunology (Baltimore, Md: 1950). 2009; 183: 319-331
        • Ugarte-Torres A
        • Hoegh-Petersen M
        • Liu Y
        • et al.
        Donor serostatus has an impact on cytomegalovirus-specific immunity, cytomegaloviral disease incidence, and survival in seropositive hematopoietic cell transplant recipients.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2011; 17: 574-585
        • Randolph SSB
        • Gooley TA
        • Warren EH
        • Appelbaum FR
        • Riddell SR.
        Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.
        Blood. 2004; 103: 347-352
        • Stern M
        • Passweg JR
        • Locasciulli A
        • et al.
        Influence of donor/recipient sex matching on outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia.
        Transplantation. 2006; 82: 218-226
        • Randolph SS
        • Gooley TA
        • Warren EH
        • Appelbaum FR
        • Riddell SR.
        Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA-matched, related hematopoietic stem cell transplants.
        Blood. 2004; 103: 347-352
        • Nakasone H
        • Tian L
        • Sahaf B
        • et al.
        Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans.
        Blood. 2015; 125: 3193-3201
        • Antin JH
        • Childs R
        • Filipovich AH
        • et al.
        Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2001; 7: 473-485
        • Lion T.
        Detection of impending graft rejection and relapse by lineage-specific chimerism analysis.
        Methods in molecular medicine. 2007; 134: 197-216
        • Storek J
        • Dawson MA
        • Storer B
        • et al.
        Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation.
        Blood. 2001; 97: 3380-3389
        • Schmid C
        • Labopin M
        • Schaap N
        • et al.
        Long-term results and GvHD after prophylactic and preemptive donor lymphocyte infusion after allogeneic stem cell transplantation for acute leukemia.
        Bone Marrow Transplantation. 2021; 57: 215-223
        • Sairafi D
        • Remberger M
        • Uhlin M
        • Ljungman P
        • Ringdén O
        • Mattsson J.
        Leukemia lineage-specific chimerism analysis and molecular monitoring improve outcome of donor lymphocyte infusions.
        Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation. 2010; 16: 1728-1737
        • Shahzad M
        • Anwar I
        • Siddiqui RS
        • et al.
        Outcomes with CD34 stem cell boost for poor graft function after allogeneic hematopoietic stem cell transplantation for hematologic malignancies: A systemic review and meta-analysis.
        Journal of Clinical Oncology. 2021; 39: e19021
        • Rosenow F
        • Berkemeier A
        • Krug U
        • et al.
        CD34(+) lineage specific donor cell chimerism for the diagnosis and treatment of impending relapse of AML or myelodysplastic syndrome after allo-SCT.
        Bone marrow transplantation. 2013; 48: 1070-1076
        • Wang L
        • Wang LN
        • Zhou JF
        • et al.
        Low-Dose Decitabine Monotherapy Reverses Mixed Chimerism in Adult Patients After Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimen: A Pilot Phase II Study.
        Frontiers in medicine. 2021; 8627946
        • Armand Philipe
        • Kim Haesook T
        • Logan Brent R
        • et al.
        Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation.
        Blood. 2014; 123 (32): 3664-3671https://doi.org/10.1182/blood-2014-01-552984
        • Sorror Mohamed L
        • Maris Michael B
        • Storb Rainer
        • et al.
        Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
        Blood. 2005; 106: 2912-2919https://doi.org/10.1182/blood-2005-05-2004