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• W1994461192 abstract "Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic regimen that could increase donor availability to nearly 100%. Rapid advances in medical technology and the application of novel drugs mean that most haploidentical HSCT-associated complications can now be prevented or remarkably well controlled, even cured. However, relapsing hematologic malignancy remains a major cause of death in haploidentical HSCT recipients. Haploidentical HSCT should theoretically trigger a more potent graft-versus-tumor effect compared with human leukocyte antigen-identical transplantation, due mainly to the major histocompatibility complex and minor histocompatibility anitigen disparities on donors’ immune cells and recipients’ tumor cells. The underlying mechanisms of such relapsing hematologic malignancies remain elusive. In this review, we suggest correlating factors and potential mechanisms and examine feasible therapeutic and preventive strategies for relapsing hematologic malignancies after haploidentical HSCT. Haploidentical hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic regimen that could increase donor availability to nearly 100%. Rapid advances in medical technology and the application of novel drugs mean that most haploidentical HSCT-associated complications can now be prevented or remarkably well controlled, even cured. However, relapsing hematologic malignancy remains a major cause of death in haploidentical HSCT recipients. Haploidentical HSCT should theoretically trigger a more potent graft-versus-tumor effect compared with human leukocyte antigen-identical transplantation, due mainly to the major histocompatibility complex and minor histocompatibility anitigen disparities on donors’ immune cells and recipients’ tumor cells. The underlying mechanisms of such relapsing hematologic malignancies remain elusive. In this review, we suggest correlating factors and potential mechanisms and examine feasible therapeutic and preventive strategies for relapsing hematologic malignancies after haploidentical HSCT. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative strategy for hematologic malignancies [1Park J.A. Ghim T.T. Bae K. et al.Stem cell transplant in the treatment of childhood biphenotypic acute leukemia.Pediatr Blood Cancer. 2009; 53: 444-452Crossref PubMed Scopus (25) Google Scholar], solid malignancies [2Claviez A. Canals C. Dierickx D. et al.Allogeneic hematopoietic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin’s lymphoma: an analysis of the European Group for Blood and Marrow Transplantation.Blood. 2009; 114: 2060-2067Crossref PubMed Scopus (61) Google Scholar], and other nonmalignant diseases [3Li C.K. Lee V. Shing M.M. et al.Hematopoietic stem cell transplantation for thalassaemia in Chinese patients.Hong Kong Med J. 2009; 15: 39-41PubMed Google Scholar]. This regimen has benefited patients since its emergence more than 50 years ago. In current clinical situations, a human leukocyte antigen (HLA)-matched HSCT is commonly the preferred type of transplantation, with HLA-matched sibling donors usually the first choice. For cases in which an HLA-matched related donor is not available, an HLA-matched unrelated donor is identified and selected through a donor registry. Clinical practice has demonstrated that only 50%-60% of HSCTs from HLA-matched donors are successful, with a much lower rate of success in patients of ethnic minorities [4Fuchs E.J. Huang X.J. Miller J.S. HLA-haploidentical stem cell transplantation for hematologic malignancies.Biol Blood Marrow Transplant. 2010; 16: S57-S63Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. With the aim of solving this conundrum and benefiting more patients, much effort has been expended in searching for feasible alternative approaches. Haploidentical HSCT appears to be a promising strategy, with a theoretically high donor availability of almost 100%. It also is less time-consuming than conventional HSCT, which requires a stringent matching process. Nevertheless, even after years of application, the high incidence of several critical complications, including severe graft-versus-host disease (GVHD), delayed engraftment, severe infection, and graft failure, still poses a barrier to the wider application of haploidentical HSCT to the benefit of more patients. In recent years, based on surprising advances in transplantation and immunology, several attempts have been made to use T cell‒depleted haploidentical bone marrow (BM) for the prevention of GVHD. The first ex vivo T cell‒depleted haploidentical HSCTs using BM were performed in 4 children with immunodeficiency syndromes more than 20 years ago; all 4 patients were healthy at 12-15 months after discharge [5Friedrich W. Goldmann S.F. Vetter U. et al.Immunoreconstitution in severe combined immunodeficiency after transplantation of HLA-haploidentical, T cell‒depleted bone marrow.Lancet. 1984; 1: 761-764Abstract PubMed Scopus (72) Google Scholar]. Since then, mega-doses of purified stem cells and T cell‒depleted grafts have been used for haploidentical HSCT, and considerable progress has been made. Today, with 2 principle protocols—T cell depletion and T cell repletion—established worldwide, an encouraging survival rate of 20% has been achieved in patients with progressive hematologic malignancies [6Handgretinger R. Lang P. The history and future prospective of haploidentical stem cell transplantation.Cytotherapy. 2008; 10: 443-451Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar]. Using this method, most complications can be prevented or remarkably well controlled, and in some cases even cured, due mainly to the application of advanced medical technologies and novel therapeutic drugs. According to traditional immunobiological theory, haploidentical HSCT could be expected to trigger a more potent graft-versus-tumor (GVT) effect compared with HLA-identical transplants due to the major histocompatibility complex (MHC) and minor histocompatibility antigen (mHA) disparities on donor immune cells and recipient tumor cells, which might facilitate the repression of tumor relapse. In fact, a high risk of relapse after haploidentical T cell‒depleted or T cell‒replete HSCT has been documented in various hematologic malignancies, including acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome, multiple myeloma, chronic myelogenous leukemia, and lymphoma, under both myeloablative and nonmyeloablative (NMA) conditioning regimens, in both children and adults [7Chen X.H. Gao L. Zhang X. et al.HLA-haploidentical blood and bone marrow transplantation with anti-thymocyte globulin: long-term comparison with HLA-identical sibling transplantation.Blood Cells Mol Dis. 2009; 43: 98-104Crossref PubMed Scopus (41) Google Scholar, 8Schwarer AP, Bollard G, Kapuscinski M, et al. Long-term follow-up of a pilot study using a chemotherapy-alone protocol for killer Ig-like receptor-ligand-mismatched haploidentical hematopoietic SCT. Bone Marrow Transplant. doi:10.1038/bmt.2010.299.Google Scholar, 9Chen Y. Liu K. Xu L. et al.HLA-mismatched hematopoietic SCT without in vitro T cell depletion for myelodysplastic syndrome.Bone Marrow Transplant. 2010; 45: 1333-1339Crossref PubMed Scopus (23) Google Scholar, 10Dellabona P, Casorati G, de Lalla C, et al. On the use of donor-derived iNKT cells for adoptive immunotherapy to prevent leukemia recurrence in pediatric recipients of HLA haploidentical HSCT for hematological malignancies. Clin Immunol. doi:10.1016/j.clim.2010.11.015.Google Scholar, 11Huang X.J. Chang Y.J. Unmanipulated HLA-mismatched/haploidentical blood and marrow hematopoietic stem cell transplantation.Biol Blood Marrow Transplan. 2011; 17: 197-204Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 12Kurokawa T. Ishiyama K. Ozaki J. et al.Haploidentical hematopoietic stem cell transplantation to adults with hematologic malignancies: analysis of 66 cases at a single Japanese center.Int J Hematol. 2010; 91: 661-669Crossref PubMed Scopus (17) Google Scholar, 13Pende D. Marcenaro S. Falco M. et al.Anti-leukemia activity of alloreactive NK cells in KIR ligand‒mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity.Blood. 2009; 113: 3119-3129Crossref PubMed Scopus (295) Google Scholar]. Studies performed within the past 5 years are summarized in Table 1, Table 2. These reports infer that relapsed hematologic malignancy after haploidentical HSCT is still the most common cause of death, although the specific incidence varies among reports, possibly due to the heterogeneity in patient series and diagnostic variations in the different cohorts. The mechanisms by which high-risk malignant cells survive under GVT effects remain elusive, however.Table 1Recent Studies of T Cell–Replete Haploidentical HSCTYear, ReferenceDisease (n)Age, Years, Median (Range)Conditioning RegimenRelapse (Median Follow-Up)2010 9Chen Y. Liu K. Xu L. et al.HLA-mismatched hematopoietic SCT without in vitro T cell depletion for myelodysplastic syndrome.Bone Marrow Transplant. 2010; 45: 1333-1339Crossref PubMed Scopus (23) Google ScholarHigh-risk MDS (36)34 (10-51)Modified Bu/Cy2 + ATG (myeloablative)18.2% in CR, 20.0% in NR (2 years)2010 12Kurokawa T. Ishiyama K. Ozaki J. et al.Haploidentical hematopoietic stem cell transplantation to adults with hematologic malignancies: analysis of 66 cases at a single Japanese center.Int J Hematol. 2010; 91: 661-669Crossref PubMed Scopus (17) Google ScholarLeukemia, multiple myeloma, MDS (66)54 (13-70)TBI (or Flu) + Bu + Me-CCNU + ATG (NMA)19.1% in high-risk group (9 months)2010 14Symons H.J. Leffell M.S. Rossiter N.D. et al.Improved survival with inhibitory killer immunoglobulin receptor (KIR) gene mismatches and KIR haplotype B donors after nonmyeloablative, HLA-haploidentical bone marrow transplantation.Biol Blood Marrow Transplant. 2010; 16: 533-542Abstract Full Text Full Text PDF PubMed Scopus (131) Google ScholarLeukemia, multiple myeloma, lymphoma, MDS (86)44 (21-69)TBI + Cy + Flu (NMA)58.0% (2 years)2010 15Xu L.P. Liu K.Y. Liu D.H. et al.The inferiority of G-PB to rhG-CSF‒mobilized blood and marrow grafts as a stem cell source in patients with high-risk acute leukemia who underwent unmanipulated HLA-mismatched/haploidentical transplantation: a comparative analysis.Bone Marrow Transplant. 2010; 45: 985-992Crossref PubMed Scopus (29) Google ScholarHigh-risk acute leukemia (14)32 (8-51)Modified Bu/Cy/ATG (myeloablative)29.6% in granulocyte colony- stimulating factor peripheral blood stem cells (2 years)2010 15Xu L.P. Liu K.Y. Liu D.H. et al.The inferiority of G-PB to rhG-CSF‒mobilized blood and marrow grafts as a stem cell source in patients with high-risk acute leukemia who underwent unmanipulated HLA-mismatched/haploidentical transplantation: a comparative analysis.Bone Marrow Transplant. 2010; 45: 985-992Crossref PubMed Scopus (29) Google ScholarHigh-risk acute leukemia (109)25 (3-56)Modified Bu + Cy + ATG (myeloablative)34.0% in granulocyte colony- stimulating factor peripheral blood stem cells/primed bone marrow (2 years)2009 16Wang H.X. Yan H.M. Liu J. et al.Haploidentical hematopoietic stem cell transplantation for non-Hodgkin lymphoma with bone marrow involvement.Leuk Lymphoma. 2009; 50: 1488-1493Crossref PubMed Scopus (13) Google ScholarRefractory non-Hodgkin lymphoma (10)19 (7-38)TBI + Ara-c + Cy or Bu + Thio + Cy (myeloablative)10.0% (60.7 months)2009 17Wang H.Y. Yan H.M. Duan L.N. et al.Haploidentical hematopoietic stem cell transplantation in child hematologic malignancies with G-CSF‒mobilized marrow grafts without T-cell depletion: a single-center report of 45 cases.Pediatr Hematol Oncol. 2009; 26: 119-128Crossref PubMed Scopus (24) Google ScholarLeukemia, non-Hodgkin lymphoma (45)35 (31-39)TBI + Ara-c + Cy + ATG or Bu + Ara-c + Cy (myeloablative)24.4% (36 months)2009 18Guo M. Sun Z. Sun Q.Y. et al.A modified haploidentical nonmyeloablative transplantation without T cell depletion for high-risk acute leukemia: successful engraftment and mild GVHD.Biol Blood Marrow Transplant. 2009; 15: 930-937Abstract Full Text Full Text PDF PubMed Scopus (50) Google ScholarHigh-risk acute leukemia (33)23 (7-43)Flu + Ara-c + Cy + ATG + TBI (NMA)18.2% (2-7.5 months)2009 7Chen X.H. Gao L. Zhang X. et al.HLA-haploidentical blood and bone marrow transplantation with anti-thymocyte globulin: long-term comparison with HLA-identical sibling transplantation.Blood Cells Mol Dis. 2009; 43: 98-104Crossref PubMed Scopus (41) Google ScholarLeukemia (56)TBI (or CCNU + Bu) + Cy + Ara-C + ATG (myeloablative)22.0% (207 days)2009 19Huang X.J. Liu D.H. Liu K.Y. et al.Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematologic malignancies in children.Biol Blood Marrow Transplant. 2009; 15: 91-94Abstract Full Text Full Text PDF PubMed Scopus (21) Google ScholarLeukemia, MDS (58)N/A (3-14)Bu/Cy2 + ATG + Ara-c + Me-CCNU(myeloablative)44.6% in high-risk group, 11.3% in standard-risk group (3 years)2009 20Chen X.H. Zhang C. Zhang X. et al.Role of antithymocyte globulin and granulocyte-colony stimulating factor‒mobilized bone marrow in allogeneic transplantation for patients with hematologic malignancies.Biol Blood Marrow Transplant. 2009; 15: 266-273Abstract Full Text Full Text PDF PubMed Scopus (37) Google ScholarLeukemia (46)25 (5-54)TBI (or Bu + CCNU) + Ara-c + Cy + ATG (myeloablative)23.9% (2 years)2009 21Huang X.J. Liu D.H. Liu K.Y. et al.Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation.Biol Blood Marrow Transplant. 2009; 15: 257-265Abstract Full Text Full Text PDF PubMed Scopus (225) Google ScholarAcute leukemia (250)N/AAra-c + Bu/Cy + ATG + semustine(myeloablative)11.9% and 24.3% for AML and ALL in standard-risk group; 20.2% and 48.5% for AML and ALL in high-risk group (3 years)2008 22Luznik 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.Biol Blood Marrow Transplant. 2008; 14: 641-650Abstract Full Text Full Text PDF PubMed Scopus (1144) Google ScholarLeukemia, MDS, lymphoma, paroxysmal nocturnal hemoglobinuria (68)46 (1-71)TBI + Cy + Flu (NMA)58.0% (2 years)2008 23Liu D.H. Huang X.J. Liu K.Y. et al.Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children.Biol Blood Marrow Transplant. 2008; 14: 469-477Abstract Full Text Full Text PDF PubMed Scopus (63) Google ScholarAcute and chronic leukemia (42)N/A (3-14)Ara-c + BuCy + Me-CCNU + ATG(myeloablative)37.0% in high-risk group ALL, 0 in AML and CML (2 years)2008 24Hiroyasu O. Kazuhiro I. Katsuji K. et al.Unmanipulated HLA 2-3 antigen–mismatched (haploidentical) bone marrow transplantation using only pharmacological GVHD prophylaxis.Exp Hematol. 2008; 36: 1-8Abstract Full Text Full Text PDF PubMed Scopus (54) Google ScholarLeukemia, lymphoma, and MDS (30)30 (16-42)TBI + Flu + Cy + Ara-c (myeloablative)20.9% (3 years)2008 25Huang X.J. Xu L.P. Liu K.Y. et al.HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for chronic myeloid leukemia: improved outcomes in patients in accelerated phase and blast crisis phase.Ann Med. 2008; 40: 444-455Crossref PubMed Scopus (52) Google ScholarCML (93)29 (9-54)Bu + Cy + ATG (myeloablative)3.29% in CML chronic phase, 31.45% in non–chronic phase (4 years)2007 26Takao Y. Keiko O. Michihiro K. et al.Outcome of non–T-cell–depleted HLA-haploidentical hematopoietic stem cell transplantation from family donors in children and adolescents.Int J Hematol. 2007; 85: 246-255Crossref PubMed Scopus (10) Google ScholarHematologic malignancies (68); solid tumors (4)7 (0.5-19)TBI-based or no TBI (myeloablative or NMA)0 in CR group, 57.0% in NR (26 months)2007 27Dong L.J. Wu T. Zhang M.J. et al.CD3+ cell dose and disease status are important factors determining clinical outcomes in patients undergoing unmanipulated haploidentical blood and marrow transplantation after conditioning including antithymocyte globulin.Biol Blood Marrow Transplant. 2007; 13: 1515-1524Abstract Full Text Full Text PDF PubMed Scopus (29) Google ScholarLeukemia, MDS (157)25 (6-50)Ara-c + Bu/Cy + ATG (myeloablative)18.0% (2 years)2006 28Lu D.P. Dong L.J. 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: 3065-3073Crossref PubMed Scopus (409) Google ScholarLeukemia, MDS (135)37 (5-50)BuCy2 + ATG (myeloablative)18.0% (2 years)2006 29Huang 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: 291-297Crossref PubMed Scopus (325) Google ScholarLeukemia, MDS (171)23 (2-56)Me-CCNU + BuCy + Ara-C + ATG (myeloablative)12.2% in standard-risk group, 38.9% in high-risk group (2 years)HSCT indicates hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; Bu, busulfan; Cy, cyclophosphamide; ATG, antithymocyte globulin; CR, complete remission; NR, no remission; TBI, total-body irradiation; Me-CCNU, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea; Flu, fludarabine; Ara-c, cytarabine; NMA, nonmyeloablative; Thio, thiotepa; N/A, not available; AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia. Open table in a new tab Table 2Recent Studies of T Cell‒Depleted Haploidentical HSCTYear, ReferenceDisease (n)Age, Years, Median (Range)Conditioning RegimenRelapse Rate (Median Follow-Up)2010 30Klingebiel 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: 3437-3446Crossref PubMed Scopus (135) Google ScholarALL (102)8.7 (0.64-16)TBI-based or not (unknown)36.0% in CR (5 years)2010 31Ciurea S.O. Saliba R. Rondon G. et al.Reduced-intensity conditioning using fludarabine, melphalan and thiotepa for adult patients undergoing haploidentical SCT transplantation from family donors in children and adolescents.Bone Marrow Transplant. 2010; 45: 429-436Crossref PubMed Scopus (48) Google ScholarLeukemia, MDS, lymphoma (28)36 (6-56)Melphalan + Thio + Flu + ATG (NMA)44.0% in advance, 0 in CR (72 days)2010 32Federmann B. Hagele M. Pfeiffer M. et al.Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reducedintensity conditioning and CD3/CD19 depleted grafts.Leukemia. 2011; 25: 121-129Crossref PubMed Scopus (55) Google ScholarLeukemia, lymphoma(28)45 (19-65)Flu (cladribine) + Thio + melphalan + OKT-3 (NMA)28.6% (748 days)2008 33Stern M. Ruggeri L. Mancusi A. et al.Survival after T cell‒depleted haploidentical stem cell transplantation is improved using the mother as donor.Blood. 2008; 112: 2990-2995Crossref PubMed Scopus (188) Google ScholarLeukemia (118)18 (2-52)TBI + Thio + Flu (or Cy) + ATG (myeloablative)22.7% in mother donor, 46.5% in father donor (3.4 years)2008 34Ciceri 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: 3574-3581Crossref PubMed Scopus (228) Google ScholarLeukemia (266)31 (16-66)TBI-based regimen(myeloablative)AML: 16% in CR1, 23% in CR2, 32% in advance; ALL: 26% in CR1, 27% in CR2, 49% in advance (2 years)2007 35Ruggeri L. Mancusi A. Capanni M. et al.Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value.Blood. 2007; 110: 433-440Crossref PubMed Scopus (489) Google ScholarAML (112)N/ATBI + Flu (methotrexate) + ATG (myeloablative)25.0% (5.07 years)2007 36Rizzieri D.A. Koh L.P. Long G.D. et al.Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.J Clin Oncol. 2007; 25: 690-697Crossref PubMed Scopus (168) Google ScholarHematologic malignancies or advanced myeloproliferative disorder (49)48 (17-66)Alemtuzumab + Flu + Cy(NMA)49.0% (unknown)2006 37Marks D.I. Khattry N. Cummins M. et al.Haploidentical stem cell transplantation for children with acute leukaemia.Br J Haematol. 2006; 134: 196-201Crossref PubMed Scopus (67) Google ScholarALL, AML (34)11 (1-16)TBI + Cy-based (myeloablative)13.0 in CR, 100.0 in NR (62 months)HSCT indicates hematopoietic stem cell transplantation; ALL, acute lymphocytic leukemia; TBI, total-body irradiation; CR, complete remission; MDS, myelodysplastic syndrome; Thio, thiotepa; Flu, fludarabine; ATG, antithymocyte globulin; NMA, nonmyeloablative; Cy, cyclophosphamide; AML, acute myelogenous leukemia; N/A, not available. Open table in a new tab HSCT indicates hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; Bu, busulfan; Cy, cyclophosphamide; ATG, antithymocyte globulin; CR, complete remission; NR, no remission; TBI, total-body irradiation; Me-CCNU, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea; Flu, fludarabine; Ara-c, cytarabine; NMA, nonmyeloablative; Thio, thiotepa; N/A, not available; AML, acute myelogenous leukemia; ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia. HSCT indicates hematopoietic stem cell transplantation; ALL, acute lymphocytic leukemia; TBI, total-body irradiation; CR, complete remission; MDS, myelodysplastic syndrome; Thio, thiotepa; Flu, fludarabine; ATG, antithymocyte globulin; NMA, nonmyeloablative; Cy, cyclophosphamide; AML, acute myelogenous leukemia; N/A, not available. In our opinion, haploidentical HSCT has merit in improving survival probability, and haploidentical donors likely would be one of the main stem cell sources. In this review, we suggest correlating factors and potential mechanisms causing relapse of hematologic malignancies after haploidentical HSCT, then address the newly identified indications for relapse, as well as feasible therapeutic and preventive strategies. In ideal haploidentical HSCT, the initiating conditioning therapy, especially the myeloablative regimen, eradicates the majority of malignant hematologic cells. In addition, the posttransplantation GVT effects then eradicate any residual malignant cells remaining after conditioning therapy. Thus, in the case of in situ relapse, the residual malignant cells must survive ablation of the hematopoietic system, which includes malignant hematologic cells, and also survive the GVT reaction [38Cairo M.S. Jordan C.T. Maley C.C. et al.NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse After Allogeneic Hematopoietic Stem Cell Transplantation. Report from the Committee on the Biological Considerations of Hematological Relapse Following Allogeneic Stem Cell Transplantation Unrelated to Graft-Versus-Tumor Effects: state of the science.Biol Blood Marrow Transplant. 2010; 16: 709-728Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar]. According to recent reports, malignant cell resistance to conditioning therapy demonstrated a similar process to that involved in drug resistance in chemotherapy [39Katzir H. Yeheskely-Hayon D. Regev R. et al.Role of the plasma membrane leaflets in drug uptake and multidrug resistance.FEBS J. 2010; 277: 1234-1244Crossref PubMed Scopus (15) Google Scholar, 40Michelle J.H. Seoyeon C. Alex H.B. et al.Mechanism of relapse in pediatric acute lymphoblastic leukemia.Cell Cycle. 2008; 7: 1315-1320Crossref PubMed Scopus (20) Google Scholar, 41Bram E.E. Stark M. Raz S. et al.Chemotherapeutic drug‒induced ABCG2 promoter demethylation as a novel mechanism of acquired multidrug resistance.Neoplasia. 2009; 11: 1359-1370Abstract Full Text PDF PubMed Scopus (96) Google Scholar], and certain factors might influence malignancy relapse, including, but not limited to, the cancerous microenvironment, cancer stem cells, gene polymorphisms, host ages, GVHD prevention strategies, disease status at transplantation, and gene mutations. Here we discuss corresponding factors and potential immune mechanisms involved in the emergence of relapsing malignancies after haploidentical HSCT (Figure 1). Siblings, parents, and offspring are all potential haploidentical donors. Maternal tolerance and/or immunization should make consideration of maternal transplants a priority. The immune systems of mother and child are in close contact during pregnancy and achieve a delicate equilibrium, which might exert an influence on haploidentical transplantation later in life. The maternal immune system, unlike that of the fetus, is mature and usually functional and thus is capable of being immunized by paternal histocompatibility antigens transmitted from the fetus. Antibodies directed against paternal HLA antigens [42van Rood J.J. Eernisse J.G. van Leeuwen A. Leucocyte antibodies in sera from pregnant women.Nature. 1958; 181: 1735-1736Crossref PubMed Scopus (260) Google Scholar] and memory type T lymphocytes directed against paternal major and minor histocompatibility antigens [43Van Kampen C.A. Versteeg-van der Voort Maarschalk M.F. Langerak-Langerak J. et al.Pregnancy can induce long-persisting primed CTLs specific for inherited paternal HLA antigens.Hum Immunol. 2001; 62: 201-207Crossref PubMed Scopus (84) Google Scholar, 44Verdijk R.M. Kloosterman A. Pool J. et al.Pregnancy induces minor histocompatibility antigen‒specific cytotoxic T cells: implications for stem cell transplantation and immunotherapy.Blood. 2004; 103: 1961-1964Crossref PubMed Scopus (166) Google Scholar] are frequently found in multiparous women. Under such circumstances, humoral and cellular immunity against HLA and mHA in the offspring might mediate enhanced GVT effects after maternal donor transplantation. For patients undergoing T cell‒depleted haploidentical HSCT, even though the majority of T cells have been removed, the small population of contaminant memory T cells transferred with the graft could still spontaneously undergo unopposed proliferation and play a vital role in the GVT process by virtue of the absence of pharmacologic GVHD prophylaxis [33Stern M. Ruggeri L. Mancusi A. et al.Survival after T cell‒depleted haploidentical stem cell transplantation is improved using the mother as donor.Blood. 2008; 112: 2990-2995Crossref PubMed Scopus (188) Google Scholar]. Stern et al. [33Stern M. Ruggeri L. Mancusi A. et al.Survival after T cell‒depleted haploidentical stem cell transplantation is improved using the mother as donor.Blood. 2008; 112: 2990-2995Crossref PubMed Scopus (188) Google Scholar] found relapse rates of 22.7% with maternal donors and 46.5% with paternal donors after T cell depletion in vitro excluding the sex effect, supporting the notion that the use of immunized maternal donors is associated with reduced relapse mortality with both T cell‒depleted and T cell‒replete HSCT. In contrast, for maternal donors who were not immunized but tolerized during pregnancy, low immune reactivity would weaken the recipient’s GVT effect, contributing to the higher relapse rate than seen with immunized maternal donors. The situation might be different when considering reciprocal transplantation, in which the mother is the recipient and the offspring is the donor. It is assumed that the fetus has an immature immune system, incapable of initiating immunity against noninherited maternal alloantigens. As a result, no decreased risk of relapse has been reported with the use of offspring as haploidentical donors. The use of noninherited maternal alloantigen‒mismatched and noninherited paternal alloantigen‒mismatched sibling donors also has been found to have no statistically significant effect on the outcome of relapse [33Stern M. Ruggeri L. Mancusi A. et al.Survival after T cell‒depleted haploidentical stem cell transplantation is improved using the mother as donor.Blood. 2008; 112: 2990-2995Crossref PubMed Scopus (188) Google Scholar]. Unfortunately, currently no detailed information is available on donor humoral and cellular immune reactivity against mismatched HLA on recipient cells before transplantation, and we cannot yet exclude the possibility that some family members might be immunized by different HLA molecules expressed in patients through as-yet unclarified pathways. In any case, when assessing the maternal factors recorded during pregnancy, stem cell donor alloimmune status should be determined when selecting a haploidentical donor from among family members or other relatives, to achieve a potent GVT effect after haploidentical HSCT. The frequency of HLA-mismatched loci in haploidentical donors ranges from 1 to 5 in 10/10 alleles. HLA mismatches can involve different numbers of mismatched locus sites and different combinations of HLA mismatches. HLA-mismatched donor‒recipient combinations have widely varying effects on the risk of relapse post-HSCT, particularly with respect to HLA-DPB1 and HLA-Cw disparities [45Shaw B.E. Mayor N.P. Russell N.H. et al.Diverging effects of HLA-DPB1 matching status on outcome following unrelated donor trans" @default.
• W1994461192 created "2016-06-24" @default.
• W1994461192 creator A5046198649 @default.
• W1994461192 creator A5064376232 @default.
• W1994461192 creator A5079625742 @default.
• W1994461192 creator A5090013547 @default.
• W1994461192 date "2011-08-01" @default.
• W1994461192 modified "2023-09-25" @default.
• W1994461192 title "Relapsing Hematologic Malignancies after Haploidentical Hematopoietic Stem Cell Transplantation" @default.
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