Primary graft failure, but not relapse, may be identified by early chimerism following double cord blood unit transplantation

Rachael Hough, Andre Lopes, Pip Patrick, Nigel Russell, Kavita Raj, Eleni Tholouli, John A Snowden, Matthew Collin, Nadjet El-Mehidi, Anthony Lawrie, Laura Clifton-Hadley, Paul Veys, Charles Craddock, Stephen Mackinnon, Gordon Cook, Bronwen Shaw, David Marks, Rachael Hough, Andre Lopes, Pip Patrick, Nigel Russell, Kavita Raj, Eleni Tholouli, John A Snowden, Matthew Collin, Nadjet El-Mehidi, Anthony Lawrie, Laura Clifton-Hadley, Paul Veys, Charles Craddock, Stephen Mackinnon, Gordon Cook, Bronwen Shaw, David Marks

Abstract

Umbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double umbilical cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism after RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage-specific chimerism after DUCBT in adult patients with hematologic malignancies in the United Kingdom. Fifty-eight patients with a median age of 52 years were recruited, with overall and progression-free survivals of 59% (95% confidence interval [CI], 45%-71%) and 52% (95% CI, 39%-64%), respectively, at 2 years. Nonrelapse mortality was 4% (95% CI, 1%-13%) at day 100, and the relapse rate was 31% (95% CI, 21%-45%) at 1 year. Peripheral blood lineage-specific chimerism was feasible from day 7 after transplant onward. Five patterns of chimerism were observed including (1) complete single unit dominance (39 patients), (2) sustained donor-donor mixed chimerism (3 patients), (3) sustained donor-recipient mixed chimerism (5 patients), (4) dominance reversion (1 patient), and (5) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematologic malignancies to safely access UCBT in the United Kingdom and provided novel insights into the kinetics of donor and recipient chimerism after RIC DUCBT that are clinically relevant. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003845-41/GB as #NCT00959231 and EudraCT 2004-003845-41.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Consort diagram showing recruitment, chimerism analysis availability, and engraftment/chimerism outcomes.
Figure 2.
Figure 2.
Clinical outcomes following RIC CBT. (A) Overall and relapse-free survivals. (B) NRM and time to relapse.
Figure 3.
Figure 3.
Hematologic recovery.
Figure 4.
Figure 4.
Chimerism kinetics following RIC CBT. (A) Chimerism kinetics for PBMCs. (B) Chimerism kinetics for T cells. (C) Chimerism kinetics for B cells. (D) Chimerism kinetics for granulocytes.

References

    1. Rocha V, Crotta A, Ruggeri A, et al. ; Eurocord Registry . Double cord blood transplantation: extending the use of unrelated umbilical cord blood cells for patients with hematological diseases. Best Pract Res Clin Haematol. 2010;23(2):223-229.
    1. Majhail NS, Brunstein CG, Wagner JE. Double umbilical cord blood transplantation. Curr Opin Immunol. 2006;18(5):571-575.
    1. Laughlin MJ, Eapen M, Rubinstein P, et al. . Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med. 2004;351(22):2265-2275.
    1. Brunstein CG, Barker JN, Weisdorf DJ, et al. . Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007;110(8):3064-3070.
    1. Barker JN, Weisdorf DJ, DeFor TE, et al. . Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005;105(3):1343-1347.
    1. Milano F, Heimfeld S, Gooley T, Jinneman J, Nicoud I, Delaney C. Correlation of infused CD3+CD8+ cells with single-donor dominance after double-unit cord blood transplantation. Biol Blood Marrow Transplant. 2013;19(1):156-160.
    1. Verneris MR, Wagner JE. UCB and atmospheric noise. Blood. 2010;115(4):754-755.
    1. Ramirez P, Wagner JE, DeFor TE, et al. . Factors predicting single-unit predominance after double umbilical cord blood transplantation. Bone Marrow Transplant. 2012;47(6):799-803.
    1. Peterlin P, Delaunay J, Guillaume T, et al. . Complete donor T cell chimerism predicts lower relapse incidence after standard double umbilical cord blood reduced-intensity conditioning regimen allogeneic transplantation in adults. Biol Blood Marrow Transplant. 2015;21(1):180-184.
    1. Ballen KK, Spitzer TR, Yeap BY, et al. . Double unrelated reduced-intensity umbilical cord blood transplantation in adults. Biol Blood Marrow Transplant. 2007;13(1):82-89.
    1. Haspel RL, Kao G, Yeap BY, et al. . Preinfusion variables predict the predominant unit in the setting of reduced-intensity double cord blood transplantation. Bone Marrow Transplant. 2008;41(6):523-529.
    1. Gutman JA, Turtle CJ, Manley TJ, et al. . Single-unit dominance after double-unit umbilical cord blood transplantation coincides with a specific CD8+ T-cell response against the nonengrafted unit. Blood. 2010;115(4):757-765.
    1. Avery S, Shi W, Lubin M, et al. . Influence of infused cell dose and HLA match on engraftment after double-unit cord blood allografts. Blood. 2011;117(12):3277-3285, quiz 3478.
    1. Eldjerou LK, Chaudhury S, Baisre-de Leon A, et al. . An in vivo model of double-unit cord blood transplantation that correlates with clinical engraftment. Blood. 2010;116(19):3999-4006.
    1. Jaing TH, Tsay PK, Lin TL, Yang CP, Hung IJ, Wen YC. Pre-freeze and post-thaw characteristics on chimerism patterns in double-unit cord blood transplantation. Pediatr Blood Cancer. 2009;52(4):547-550.
    1. Scaradavou A, Smith KM, Hawke R, et al. . Cord blood units with low CD34+ cell viability have a low probability of engraftment after double unit transplantation. Biol Blood Marrow Transplant. 2010;16(4):500-508.
    1. Somers JA, Braakman E, van der Holt B, et al. . Rapid induction of single donor chimerism after double umbilical cord blood transplantation preceded by reduced intensity conditioning: results of the HOVON 106 phase II study. Haematologica. 2014;99(11):1753-1761.
    1. Lamers CH, Wijers R, van Bergen CA, et al. . CD4+ T-cell alloreactivity toward mismatched HLA class II alleles early after double umbilical cord blood transplantation. Blood. 2016;128(17):2165-2174.
    1. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16(2):232-236.
    1. Brunstein CG, Miller JS, McKenna DH, et al. . Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2016;127(8):1044-1051.
    1. Hashem H, Lazarus HM. Double umbilical cord blood transplantation: relevance of persistent mixed-unit chimerism. Biol Blood Marrow Transplant. 2015;21(4):612-619.
    1. Kang HJ, Yoo KH, Lee JW, et al. . Double umbilical cord blood transplantation for children and adolescents. Ann Hematol. 2010;89(10):1035-1044.
    1. Gertow J, Berglund S, Okas M, et al. . Characterization of long-term mixed donor-donor chimerism after double cord blood transplantation. Clin Exp Immunol. 2010;162(1):146-155.
    1. Yadav SP, Dhingra N, Saxena R, Sachdeva A. Persistence of both cords nine months post double cord blood transplantation for juvenile myelomonocytic leukaemia. Hematol Oncol Stem Cell Ther. 2013;6(2):79-80.
    1. Cornelissen JJ, Kalin B, Lamers CHJ. Graft predominance after double umbilical cord blood transplantation: a review. Stem Cell Investig. 2017;4(6):47.
    1. Gyger M, Baron C, Forest L, et al. . Quantitative assessment of hematopoietic chimerism after allogeneic bone marrow transplantation has predictive value for the occurrence of irreversible graft failure and graft-vs.-host disease. Exp Hematol. 1998;26(5):426-434.
    1. Dubovsky J, Daxberger H, Fritsch G, et al. . Kinetics of chimerism during the early post-transplant period in pediatric patients with malignant and non-malignant hematologic disorders: implications for timely detection of engraftment, graft failure and rejection. Leukemia. 1999;13(12):2059–, 2060-2069..
    1. Baron F, Sandmaier BM. Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia. 2006;20(10):1690-1700.
    1. Liesveld JL, Rothberg PG. Mixed chimerism in SCT: conflict or peaceful coexistence? Bone Marrow Transplant. 2008;42(5):297-310.
    1. Konuma T, Kato S, Oiwa-Monna M, Ishii H, Tojo A, Takahashi S. Early phase mixed chimerism in bone marrow does not affect long-term outcomes of myeloablative single-unit cord blood transplantation for adult patients with hematological malignancies. Leuk Lymphoma. 2016;57(12):2848-2854.
    1. Yokohata E, Kuwatsuka Y, Ohashi H, et al. . Impact of T-cell chimerism on relapse after cord blood transplantation for hematological malignancies: Nagoya Blood and Marrow Transplantation Group study. Bone Marrow Transplant. 2017;52(4):612-614.
    1. Tomizawa D, Aoki Y, Nagasawa M, et al. . Novel adopted immunotherapy for mixed chimerism after unrelated cord blood transplantation in Omenn syndrome. Eur J Haematol. 2005;75(5):441-444.
    1. Tanoue S, Konuma T, Takahashi S, et al. . Long-term persistent donor-recipient mixed chimerism without disease recurrence after myeloablative single-unit cord blood transplantation in adult acute myeloid leukemia following myelodysplastic syndrome. Leuk Lymphoma. 2017;58(12):2973-2975.
    1. Wagner JE, Barker JN, DeFor TE, et al. . Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100(5):1611-1618.
    1. Moscardó F, Sanz J, Senent L, et al. . Impact of hematopoietic chimerism at day +14 on engraftment after unrelated donor umbilical cord blood transplantation for hematologic malignancies. Haematologica. 2009;94(6):827-832.
    1. Elkaim E, Picard C, Galambrun C, et al. . Peripheral blood cells chimerism after unrelated cord blood transplantation in children: kinetics, predictive factors and impact on post-transplant outcome. Br J Haematol. 2014;166(4):557-565.
    1. Chan KW, Grimley MS, Taylor C, Wall DA. Early identification and management of graft failure after unrelated cord blood transplantation. Bone Marrow Transplant. 2008;42(1):35-41.
    1. Hanley PJ, Cruz CR, Savoldo B, et al. . Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes. Blood. 2009;114(9):1958-1967.
    1. Introna M, Pievani A, Borleri G, et al. . Feasibility and safety of adoptive immunotherapy with CIK cells after cord blood transplantation. Biol Blood Marrow Transplant. 2010;16(11):1603-1607.
    1. Song K, Sun Z, Liu H, et al. . Primary research on unrelated double umbilical cord blood transplantation and implantation kinetics. Hematology. 2013;18(5):253-259.
    1. Somers JA, Brand A, van Hensbergen Y, et al. . Double umbilical cord blood transplantation: a study of early engraftment kinetics in leukocyte subsets using HLA-specific monoclonal antibodies. Biol Blood Marrow Transplant. 2013;19(2):266-273.
    1. Kang HJ, Kho SH, Jang MK, Lee SH, Shin HY, Ahn HS. Early engraftment kinetics of two units cord blood transplantation. Bone Marrow Transplant. 2006;38(3):197-201.
    1. Newell LF, Milano F, Nicoud IB, et al. . Early CD3 peripheral blood chimerism predicts the long-term engrafting unit following myeloablative double-cord blood transplantation. Biol Blood Marrow Transplant. 2012;18(8):1243-1249.
    1. Avery S, Voss MH, Gonzales AM, et al. . Importance of day 21 BM chimerism in sustained neutrophil engraftment following double-unit cord blood transplantation. Bone Marrow Transplant. 2012;47(8):1056-1060.
    1. Abedin S, Peres E, Levine JE, Choi S, Yanik G, Couriel DR. Double umbilical cord blood transplantation after novel myeloablative conditioning using a regimen of fludarabine, busulfan, and total lymphoid irradiation. Biol Blood Marrow Transplant. 2014;20(12):2062-2066.

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