Review on Haploidentical Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies

William A Fabricius, Muthalagu Ramanathan, William A Fabricius, Muthalagu Ramanathan

Abstract

Allogenic hematopoietic cell transplantation (HSCT) is typically the preferred curative therapy for adult patients with acute myeloid leukemia, but its use has been reduced as a consequence of limited donor availability in the form of either matched-related donors (MRD) or matched-unrelated donors (MUD). Alternative options such as unrelated umbilical cord blood (UCB) transplantation and haploidentical HSCT have been increasingly studied in the past few decades to overcome these obstacles. A human leukocyte antigen- (HLA-) haploidentical donor is a recipient's relative who shares an exact haplotype with the recipient but is mismatched for HLA genes on the unshared haplotype. These dissimilarities pose several challenges to the outcomes of the patient receiving such a type of HSCT, including higher rates of bidirectional alloreactivity and graft failure. In the past 5 years, however, several nonrandomized studies have shown promising results in terms of graft success and decreased rates of alloreactivity, in part due to newer grafting techniques and graft-versus-host disease (GVHD) prophylaxis. We present here a summary and review of the latest results of these studies as well as a brief discussion on the advantages and challenges of haploidentical HSCT.

References

    1. Bejanyan N., Haddad H., Brunstein C. Alternative donor transplantation for acute myeloid leukemia. Journal of Clinical Medicine. 2015;4(6):1240–1268. doi: 10.3390/jcm4061240.
    1. Kanakry C. G., de Lima M. J., Luznik L. Alternative donor allogeneic hematopoietic cell transplantation for acute myeloid leukemia. Seminars in Hematology. 2015;52(3):232–242. doi: 10.1053/j.seminhematol.2015.03.005.
    1. Gragert L., Eapen M., Williams E., et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. The New England Journal of Medicine. 2014;371(4):339–348. doi: 10.1056/nejmsa1311707.
    1. Mehta J., Frankfurt O., Altman J., et al. Optimizing the CD34 + cell dose for reduced-intensity allogeneic hematopoietic stem cell transplantation. Leukemia and Lymphoma. 2009;50(9):1434–1441. doi: 10.1080/10428190903085944.
    1. Barker J. N., Scaradavou A., Stevens C. E. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood. 2010;115(9):1843–1849. doi: 10.1182/blood-2009-07-231068.
    1. Raiola A. M., Dominietto A., di Grazia C., et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biology of Blood and Marrow Transplantation. 2014;20(10):1573–1579. doi: 10.1016/j.bbmt.2014.05.029.
    1. Wang Y., Liu Q.-F., Xu L.-P., et al. Haploidentical vs identical-sibling transplant for AML in remission: a multicenter, prospective study. Blood. 2015;125(25):3956–3962. doi: 10.1182/blood-2015-02-627786.
    1. Ciurea S. O., Zhang M. J., Bacigalupo A. A., et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033–1040. doi: 10.1182/blood-2015-04-639831.
    1. Ringden O., Labopin M., Ciceri M., et al. Is there a stronger graft-versus-leukemia effect using HLA-haploidentical donors compared with HLA-identical siblings? Leukemia. 2015 doi: 10.1038/leu.2015.232.
    1. Kasamon Y. L., Luznik L., Leffell M. S., et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biology of Blood and Marrow Transplantation. 2010;16(4):482–489. doi: 10.1016/j.bbmt.2009.11.011.
    1. Bashey A., Zhang X., Sizemore C. A., et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. Journal of Clinical Oncology. 2013;31(10):1310–1316. doi: 10.1200/jco.2012.44.3523.
    1. Lu D.-P., Dong L., Wu T., et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107(8):3065–3073. doi: 10.1182/blood-2005-05-2146.
    1. Aversa F., Tabilio A., Terenzi A., et al. Successful engraftment of T-cell-depleted haploidentical “three-loci” incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994;84(11):3948–3955.
    1. Aversa F., Tabilio A., Velardi A., et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. The New England Journal of Medicine. 1998;339(17):1186–1193. doi: 10.1056/nejm199810223391702.
    1. Aversa F., Terenzi A., Tabilio A., et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. Journal of Clinical Oncology. 2005;23(15):3447–3454. doi: 10.1200/jco.2005.09.117.
    1. Ciceri F., Labopin M., Aversa F., et al. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008;112(9):3574–3581. doi: 10.1182/blood-2008-02-140095.
    1. Lang P., Greil J., Bader P., et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells, Molecules, and Diseases. 2004;33(3):281–287. doi: 10.1016/j.bcmd.2004.08.017.
    1. Klingebiel T., Cornish J., Labopin M., et al. Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood. 2010;115(17):3437–3446. doi: 10.1182/blood-2009-03-207001.
    1. Walker I., Shehata N., Cantin G., et al. Canadian multicenter pilot trial of haploidentical donor transplantation. Blood Cells, Molecules, and Diseases. 2004;33(3):222–226. doi: 10.1016/j.bcmd.2004.08.006.
    1. Martelli M. F., Di Ianni M., Ruggeri L., et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood. 2014;124(4):638–644. doi: 10.1182/blood-2014-03-564401.
    1. Waller E. K., Giver C. R., Rosenthal H., et al. Facilitating T-cell immune reconstitution after haploidentical transplantation in adults. Blood Cells, Molecules, and Diseases. 2004;33(3):233–237. doi: 10.1016/j.bcmd.2004.08.009.
    1. Bethge W. A., Faul C., Bornhäuser M., et al. Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. Blood Cells, Molecules, and Diseases. 2008;40(1):13–19. doi: 10.1016/j.bcmd.2007.07.001.
    1. 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(10):1253–1258. doi: 10.1016/j.jcyt.2013.05.014.
    1. Airoldi I., Bertaina A., Prigione I., et al. γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ +/CD19+ lymphocytes. Blood. 2015;125(15):2349–2358. doi: 10.1182/blood-2014-09-599423.
    1. Perruccio K., Tosti A., Burchielli E., et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood. 2005;106(13):4397–4406. doi: 10.1182/blood-2005-05-1775.
    1. Martelli M. F., Di Ianni M., Ruggeri L., et al. ‘Designed’ grafts for HLA-haploidentical stem cell transplantation. Blood. 2014;123(7):967–973. doi: 10.1182/blood-2013-10-531764.
    1. Bonini C., Ferrari G., Verzeletti S., et al. HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia. Science. 1997;276(5319):1719–1724. doi: 10.1126/science.276.5319.1719.
    1. Ciceri F., Bonini C., Stanghellini M. T. L., et al. Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study. The Lancet Oncology. 2009;10(5):489–500. doi: 10.1016/s1470-2045(09)70074-9.
    1. Di Stasi A., Tey S.-K., Dotti G., et al. Inducible apoptosis as a safety switch for adoptive cell therapy. The New England Journal of Medicine. 2011;365(18):1673–1683. doi: 10.1056/nejmoa1106152.
    1. Huang X. J., Liu D. H., Liu K. Y., et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006;38(4):291–297. doi: 10.1038/sj.bmt.1705445.
    1. Liu D., Huang X., Liu K., et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children. Biology of Blood and Marrow Transplantation. 2008;14(4):469–477. doi: 10.1016/j.bbmt.2008.02.007.
    1. Di Bartolomeo P., Santarone S., De Angelis G., et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood. 2013;121(5):849–857. doi: 10.1182/blood-2012-08-453399.
    1. Luznik L., O'Donnell P. V., Symons H. J., et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biology of Blood and Marrow Transplantation. 2008;14(6):641–650. doi: 10.1016/j.bbmt.2008.03.005.
    1. O'Donnell P. V., Luznik L., Jones R. J., et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biology of Blood and Marrow Transplantation. 2002;8(7):377–386. doi: 10.1053/bbmt.2002.v8.pm12171484.
    1. McCurdy S. R., Kanakry J. A., Showel M. M., et al. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015;125(19):3024–3031. doi: 10.1182/blood-2015-01-623991.
    1. Shook D. R., Triplett B. M., Eldridge P. W., Kang G., Srinivasan A., Leung W. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatric Blood and Cancer. 2015;62(4):666–673. doi: 10.1002/pbc.25352.
    1. Triplett B. M., Shook D. R., Eldridge P., et al. Rapid memory T-cell reconstitution recapitulating CD45RA-depleted haploidentical transplant graft content in patients with hematologic malignancies. Bone Marrow Transplantation. 2015;50:968–977. doi: 10.1038/bmt.2014.324.
    1. Kanda Y., Chiba S., Hirai H., et al. Allogeneic hematopoietic stem cell transplantation from family members other than HLA-identical siblings over the last decade (1991–2000) Blood. 2003;102(4):1541–1547. doi: 10.1182/blood-2003-02-0430.
    1. Wang Y., Liu D.-H., Xu L.-P., et al. Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. Biology of Blood and Marrow Transplantation. 2011;17(6):821–830. doi: 10.1016/j.bbmt.2010.08.023.
    1. Szydlo R., Goldman J. M., Klein J. P., et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings. Journal of Clinical Oncology. 1997;15(5):1767–1777.
    1. Ash R. C., Horowitz M. M., Gale R. P., et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Transplantation. 1991;7(6):443–452.

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