Abstract
The success of allogeneic stem cell transplant is hampered by the development of acute and chronic graft-versus-host disease (GvHD) which has direct impact on treatment-related mortality and morbidity. As a result, T cell depletion through positive selection of CD34+ cells has emerged as a promising strategy to reduce acute and chronic GvHD in these patients.
In this review, we summarize the main characteristics of allogeneic stem cell transplant with CD34+ cell selection including risks of graft failure, GvHD, infection, organ toxicity, and long-term survival. Moreover, we highlight future strategies to improve the results of this platform and to consolidate its use in clinical practice.
Article PDF
Avoid common mistakes on your manuscript.
References
Jim, HS, Barata, A, Small, BJ, Jacobsen, PB, Pidala, J. Quality of life associated with sirolimus for prevention of graft-versushost disease: results from a randomized trial. Haematologica 2014;99;548–53.
Inamoto, Y, Flowers, ME, Appelbaum, FR, et al. A retrospective comparison of tacrolimus versus cyclosporine with methotrexate for immunosuppression after allogeneic hematopoietic cell transplantation with mobilized blood cells. Biol Blood Marrow Transplant 2011;17;1088–92.
Alyea, EP, Weller, E, Fisher, DC, et al. Comparable outcome with T-cell-depleted unrelated-donor versus related-donor allogeneic bone marrow transplantation. Biol Blood Marrow Transplant 2002;8;601–7.
Pavletic, SZ, Carter, SL, Kernan, NA, et al. Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood 2005;106;3308–13.
Devine, SM, Carter, S, Soiffer, RJ, et al. Low risk of chronic graftversus- host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the blood and marrow transplant clinical trials network protocol 0303. Biol Blood Marrow Transplant 2011;17;1343–51.
Witte, T, Hoogenhout, J, Pauw, B, et al. Depletion of donor lymphocytes by counterflow centrifugation successfully prevents acute graft-versus-host disease in matched allogeneic marrow transplantation. Blood 1986;67;1302–8.
Urbano-Ispizua, A, Brunet, S, Solano, C, et al. Allogeneic transplantation of CD34+-selected cells from peripheral blood in patients with myeloid malignancies in early phase: a case control comparison with unmodified peripheral blood transplantation. Bone Marrow Transplant 2001;28;349–54.
Schumm, M, Lang, P, Bethge, W, et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy 2013;15;1253–8.
Handgretinger, R. Negative depletion of CD3(+) and TcRalphabeta(+) T cells. Curr Opin Hematol 2012;19;434–9.
Keever-Taylor, CA, Devine, SM, Soiffer, RJ, et al. Characteristics of CliniMACS(R) System CD34-enriched T cell-depleted grafts in a multicenter trial for acute myeloid leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0303. Biol Blood Marrow Transplant 2012;18;690–7.
Geyer, MB, Ricci, AM, Jacobson, JS, et al. T cell depletion utilizing CD34(+) stem cell selection and CD3(+) addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients. Br J Haematol 2012;157;205–19.
Diamond, DJ, et al. Immunohistochemical analysis of T cell phenotypes in patients with graft-versus-host disease following allogeneic bone marrow transplantation. Transplantation 1995;59; 1436–44.
Salzmann-Manrique, E, et al. Joint modeling of immune reconstitution posthaploindetical stem cell transplantation in pediatric patients with acute leukemia comparing CD34+ selected to CD3/CD19 depleted graft in a retrospective multicenter study. Front Immunol 2018;9;1841.
Bertaina, A, et al. HLA-haploidentical stem cell transplantation after removal of 𝛼𝛽+ T and B cells in children with nonmalignant disorders. Blood 2014;124;822–6.
Castro-Malaspina, H, Harris, RE, Gajewski, J, et al. Unrelated donor marrow transplantation for myelodysplastic syndromes: outcome analysis in 510 transplants facilitated by the National Marrow Donor Program. Blood 2002;99;1943–51.
Castro-Malaspina, H, Jabubowski, AA, Papadopoulos, EB, et al. Transplantation in remission improves the disease-free survival of patients with advanced myelodysplastic syndromes treated with myeloablative T cell-depleted stem cell transplants from HLA-identical siblings. Biol Blood Marrow Transplant 2008;14; 458–68.
Small, TN, Avigan, D, Dupont, B, et al. Immune reconstitution following T-cell depleted bone marrow transplantation: effect of age and posttransplant graft rejection prophylaxis. Biol Blood Marrow Transplant 1997;3;65–75.
Tamari, R, Chung, SS, Papadopoulos, EB, et al. CD34-selected hematopoietic stem cell transplants conditioned with myeloablative regimens and antithymocyte globulin for advanced myelodysplastic syndrome: limited graft-versus-host disease without increased relapse. Biol Blood Marrow Transplant 2015;21; 2106–14.
Bayraktar, UD, de Lima, M, Saliba, RM, et al. Ex vivo T celldepleted versus unmodified allografts in patients with acute myeloid leukemia in first complete remission. Biol Blood Marrow Transplant 2013;19;898–903.
Spitzer, B, Jakubowski, AA, Papadopoulos, EB, et al. A chemotherapy-only regimen of busulfan, melphalan, and fludarabine, and rabbit antithymocyte globulin followed by allogeneic T-cell depleted hematopoietic stem cell transplantations for the treatment of myeloid malignancies. Biol Blood Marrow Transplant 2017;23;2088–95.
Jakubowski, AA, Small, TN, Young, JW, et al. T cell depleted stem-cell transplantation for adults with hematologic malignancies: sustained engraftment of HLA-matched related donor grafts without the use of antithymocyte globulin. Blood 2007;110; 4552–9.
Barba, P, Hilden, P, Devlin, SM, et al. Ex vivo CD34(+)- selected T cell-depleted peripheral blood stem cell grafts for allogeneic hematopoietic stem cell transplantation in acute leukemia and myelodysplastic syndrome is associated with low incidence of acute and chronic graft-versus-host disease and high treatment response. Biol Blood Marrow Transplant 2017; 23;452–8.
Jakubowski, AA, Small, TN, Kernan, NA, et al. T cell-depleted unrelated donor stem cell transplantation provides favorable disease-free survival for adults with hematologic malignancies. Biol Blood Marrow Transplant 2011;17;1335–42.
Hobbs, GS, Perales, MA. Effects of T-cell depletion on allogeneic hematopoietic stem cell transplantation outcomes in AML patients. J Clin Med 2015;4;488–503.
Goldberg, JD, Linker, A, Kuk, D, et al. T cell-depleted stem cell transplantation for adults with high-risk acute lymphoblastic leukemia: long-term survival for patients in first complete remission with a decreased risk of graft-versus-host disease. Biol Blood Marrow Transplant 2013;19;208–13.
Hobbs, GS, Hamdi, A, Hilden, PD, et al. Comparison of outcomes at two institutions of patients with ALL receiving ex vivo T-cell-depleted or unmodified allografts. Bone Marrow Transplant 2015;50;493–8.
Tamari, R, Oran, B, Hilden, P, et al. Allogeneic stem cell transplantation for advanced myelodysplastic syndrome: comparison of outcomes between CD34(+) selected and unmodified hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2018;24;1079–87.
Barba, P, Martino, R, Zhou, Q, et al. CD34(+) Cell selection versus reduced-intensity conditioning and unmodified grafts for allogeneic hematopoietic cell transplantation in patients age >50 years with acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant 2018;24; 964–72.
Malard, F, Labopin, M, Cho, C, Blaise, D, Papadopoulos, EB, Passweg, J, O’Reilly, R, et al. Ex-vivo and in-vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 2018;11;127.
Wagner, JE, Thompson, JS, Carter, SL, Kernan, NA. Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II-III trial. Lancet 2005;366;733–41.
Pasquini, MC, Logan, B, Jones, RJ, et al. Blood and marrow transplant clinical trials network report on the development of novel endpoints and selection of promising approaches for graftversus- host disease prevention trials. Biol Blood Marrow Transplant 2018;24;1274–80.
Van Heijst, JW, Ceberio, I, Lipuma, LB, et al. Quantitative assessment of T cell repertoire recovery after hematopoietic stem cell transplantation. Nat Med 2013;19;372–7.
Lewin, SR, Heller, G, Zhang, L, et al. Direct evidence for new T-cell generation by patients after either T-cell-depleted or unmodified allogeneic hematopoietic stem cell transplantations. Blood 2002;100;2235–42.
Barba, P, Roldán, E, Orti, G, Fox, L, Salamero, O, Bosch, F, Valcárcel, D. Resultados del trasplante alogénico vs trasplante alogénico no manipulado en pacientes con leucemia aguda y síndrome mielodisplásico. In LX Congreso Nacional SEHH XXXIV Congreso Nacional SETH, Granada, Spain 2018. Comunicación personal.
Eyrich, M, Croner, T, Leiler, C, et al. Distinct contributions of CD4(+) and CD8(+) naive and memory T-cell subsets to overall T-cell-receptor repertoire complexity following transplantation of T-cell-depleted CD34-selected hematopoietic progenitor cells from unrelated donors. Blood 2002;100; 1915–18.
Goldberg, JD, Zheng, J, Ratan, R, et al. Early recovery of T-cell function predicts improved survival after T-cell depleted allogeneic transplant. Leuk Lymphoma 2017;58;1859–71.
Perales, MA, Goldberg, JD, Yuan, J, et al. Recombinant human interleukin-7 (CYT107) promotes T-cell recovery after allogeneic stem cell transplantation. Blood 2012;120;4882–91.
Goldberg, GL, King, CG, Nejat, RA, et al. Luteinizing hormonereleasing hormone enhances T cell recovery following allogeneic bone marrow transplantation. J Immunol 2009;182;5846–54.
Velardi, E, Tsai, JJ, Holland, AM, et al. Sex steroid blockade enhances thymopoiesis by modulating Notch signaling. J Exp Med 2014;211;2341–9.
Storek, J, Gooley, T, Witherspoon, RP, Sullivan, KM, Storb, R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 1997;54;131–8.
Huang, YT, Neofytos, D, Foldi, J, et al. Cytomegalovirus Infection after CD34(+)-selected hematopoietic cell transplantation. Biol Blood Marrow Transplant 2016;22;1480–6.
Kim, SJ, Huang, YT, Foldi, J, et al. Cytomegalovirus resistance in CD34(+) -selected hematopoietic cell transplant recipients. Transplant Infect Dis 2018;20;e12881.
Huang, YT, Kim, SJ, Lee, YJ, et al. Co-infections by doublestranded DNA viruses after ex vivo T cell-depleted, CD34(+) selected hematopoietic cell transplantation. Biol Blood Marrow Transplant 2017;23;1759–66.
Lee, YJ, Chung, D, Xiao, K, et al. Adenovirus viremia and disease: comparison of T cell-depleted and conventional hematopoietic stem cell transplantation recipients from a single institution. Biol Blood Marrow Transplant 2013;19;387–92.
Lee, YJ, Huang, YT, Kim, SJ, et al. Adenovirus viremia in adult CD34(+) selected hematopoietic cell transplant recipients: low Incidence and high clinical impact. Biol Blood Marrow Transplant 2016;22;174–8.
Marty, FM, Ljungman, P, Chemaly, RF, et al. Letermovir prophylaxis for cytomegalovirus in hematopoietic-cell transplantation. N Engl J Med 2017;377;2433–44.
Hiwarkar, P, Amrolia, P, Sivaprakasam, P, et al. Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant. Blood 2017;129;2033–7.
Marty, FM, Winston, DJ, Chemaly, RF, et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic-cell transplantation. Biol Blood Marrow Transplant 2018;25;369–81.
O’Reilly, RJ, Prockop, S, Hasan, AN, Koehne, G, Doubrovina, E. Virus-specific T-cell banks for ‘off the shelf ‘ adoptive therapy of refractory infections. Bone Marrow Transplant 2016;51;1163–72.
Tzannou, I, Papadopoulou, A, Naik, S, et al. Off-the-shelf virus-specific T cells to treat BK virus, human herpesvirus 6, cytomegalovirus, epstein-barr virus, and adenovirus infections after allogeneic hematopoietic stem-cell transplantation. J Clin Oncol 2017;35;3547–57.
Kosuri, S, Adrianzen Herrera, D, Scordo, M, et al. The impact of toxicities on first-year outcomes after ex vivo CD34(+)-selected allogeneic hematopoietic cell transplantation in adults with hematologic malignancies. Biol Blood Marrow Transplant 2017;23;2004–11.
Rondon-Clavo, C, Scordo, M, Hilden, P, et al. Early fluid overload is associated with an increased risk of nonrelapse mortality after ex vivo CD34-selected allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2018;24;2517–22.
Cho, C, Hsu, M, Barba, P, et al. Long-term prognosis for 1-year relapse-free survivors of CD34+ cell-selected allogeneic hematopoietic stem cell transplantation: a landmark analysis. Bone Marrow Transplant 2017;52;1629–36.
Armand, P, Kim, HT, Sainvil, MM, et al. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial. Br J Haematol 2016;173;96–104.
Pinana, JL, Perez-Pitarch, A, Garcia-Cadenas, I, et al. A timeto- event model for acute kidney injury after reduced-intensity conditioning stem cell transplantation using a tacrolimus- and sirolimus-based graft-versus-host disease prophylaxis. Biol Blood Marrow Transplant 2017;23;1177–85.
Shah, GL, Scordo, M, Kosuri, S, et al. Impact of toxicity on survival for older adult patients after CD34(+) selected allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2018;24;142–9.
Jakubowski, AA, Petrlik, E, Maloy, M, et al. T cell depletion as an alternative approach for patients 55 years or older undergoing allogeneic stem cell transplantation as curative therapy for hematologic malignancies. Biol Blood Marrow Transplant 2017;23;1685–94.
Sorror, ML, Maris, MB, Storb, R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106;2912–19.
Barba, P, Ratan, R, Cho, C, et al. Hematopoietic cell transplantation comorbidity index predicts outcomes in patients with acute myeloid leukemia and myelodysplastic syndromes receiving CD34(+) selected grafts for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2017;23;67–74.
Dahi, PB, Morawa, E, Perales, MA, et al. Low incidence of GvHD with T-cell depleted allografts facilitates further treatments for post-transplantation relapse in AML and MDS. Bone Marrow Transplant 2016;51;991–3.
Sehn, LH, Alyea, EP, Weller, E, et al. Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion. J Clin Oncol 1999;17;561–8.
Perales, MA, Jenq, R, Goldberg, JD, et al. Second-line age-adjusted International Prognostic Index in patients with advanced non- Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT. Bone Marrow Transplant 2010;45;1408–16.
Bryant, A, et al. Efficacy of donor lymphocyte infusion in CD34+ allogeneic hematopoietic stem cell transplant for myeloid and lymphoid malignancies: a single center experience. Biol Blood Marrow Transplant 2018;24;S303–4.
Pasquini, MC, Devine, S, Mendizabal, A, Baden, LR, Wingard, JR, Lazarus, HM, et al. Comparative outcomes of donor graft CD34+ selection and immune suppressive therapy as graftversus- host disease prophylaxis for patients with acute myeloid leukemia in complete remission undergoing HLA-matched sibling allogeneic hematopoietic cell transplantation. J Clin Oncol 2012;30;3194–201.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Peer review under responsibility of the International Academy for Clinical Hematology
Rights and permissions
This is an open access article distributed under the CC BY-NC 4.0 license (https://doi.org/creativecommons.org/licenses/by-nc/4.0/).
About this article
Cite this article
Roldan, E., Perales, M.A. & Barba, P. Allogeneic Stem Cell Transplantation with CD34+ Cell Selection. Clin Hematol Int 1, 154–160 (2019). https://doi.org/10.2991/chi.d.190613.001
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.2991/chi.d.190613.001