Review Article
Advances in Haploidentical Hematopoetic Stem Cell Transplantation
Dimitrios Tzachanis* and Michael C. Lill
Blood and Marrow Transplant Program, Cedars-Sinai Medical Center, USA

Allogeneic Hematopoetic Stem Cell Transplantation (HSCT) is the only curative option for many malignant and inherited hematologic and non-hematologic disorders. The number of allogeneic HSCT performed has been steadily increasing worldwide. This growth can be mainly attributed to the increase in the number of eligible patients as the new less toxic nonmyeloablative and reduced intensity conditioning (RIC) regimens have allowed the transplantation of patients over the age of 50. In addition advances in graft versus host disease and infectious disease prophylaxis and treatment have continued to improve the outcomes.
Patient eligibility is mainly limited by donor availability. Ideally patients receive stem cells from a matched related (sibling) donor. But as there is only a 25% chance for a sibling to be HLA matched, there are only about 30% of patients who have a sibling matched donor. This number is expected to continue to drop as the average family size keeps going down. An alternative donor source is an unrelated HLA matched donor that can be identified through the National Marrow Donor Program. But even as the donor pool in the NMDP steadily expands and there are currently more than nine million donors in the registry, only a 60% of Caucasians and even as low as 10% of non-Northern Europeans (especially African American and other minorities) are able to find a Matched Unrelated Donor [1]. This discrepancy is due to more HLA variation in non-Europeans and to underrepresentation of ethnic minorities in the registry. The result is that approximately 5000 patients per year are in need for an alternative donor.
An alternative approach for patients without HLA-matched donors is the use of a mismatched/haploidentical donor. Haploidentical donors have one haplotype in common with the recipient, so they match in at least five out of ten HLA loci. These are most commonly relatives, such as parents, children or siblings. The advantages of this approach besides the possibility to identify a donor for almost all patients also include the avoidance of treatment delay and the higher motivation of the relative donor that facilitates research protocols [2].
The very first trials of haploidentical stem cell transplantation reported a very high incidence of graft rejection, Graft versus Host Disease (GVHD) and nonrelapse mortality (NRM) [3,4]. In order to improve these dismal outcomes strategies with both T cell depleted and T cell replete grafts have been employed [5-7]. As there is no single universally accepted way for performing a haploidentical transplantation, in the following paragraphs we will review the different strategies with a focus on the most recent advances.
Transplantation of a "mega-dose" T cell depleted Haploidentical Stem Cells
Transplantation of an ex vivo T cell depleted graft successfully avoided severe GVHD but was complicated by very high incidences of graft failure and relapse [8-10]. The Perugia group overcame the problem of graft failure by transplanting a "megadose" of T cell depleted stem cells after a conditioning regimen of enhanced myeloablation and immunosuppression [11,12] but without post-transplantation GVHD prophylaxis. This approach was based on experimental data that large dose of stem cells can overcomes MHC barriers in mice [13]. The leukemia free survival was acceptable especially for patients transplanted in remission and most importantly long term survivors had a high quality of life without GVHD and without the need for immunosuppression. A high incidence of infectious complications was observed attributed to delayed immune reconstitution after a T cell depleted graft.
The Acute Leukemia Working Party (ALWP) of the European Blood and Marrow Transplant (EBMT) Group analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a "mega-dose" T cell–depleted peripheral blood cell haploidentical HSCT [14] and reached the conclusion that haploidentical HSCT using this approach "can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor". Similarly to the previously published studies by the Perugia group the "mega-dose" of T cell depleted stem cells was associated with a high engraftment rate and minimal GVHD but the transplantation related mortality was high (36-66% at two years depending on disease status) and mainly due to infections and interstitial pneumonitis. Similar results have been published by other groups [15] and in pediatric patients [16-18].
CD3/CD19 depleted stem cells
Based on the rationale that avoidance of Anti Thymocyte Globulin (ATG) and Total Body Irradiation (TBI) will reduce NRM and that CD3/CD19 depletion of stem cells will leave tumor reactive natural killer and dendritic cells intact and facilitate the Graft versus Leukemia (GVL) effect, several groups in the US and Europe have conducted clinical trials with a RIC regimen followed by transplantation of a haploidentical CD3/C19 depleted graft [19-21]. The results appear to be very promising (especially in patients transplanted in remission) with reduced infectious complications and a higher GVL effect compared to the myeloablative T cell depleted regimen.
Post-transplant T cell infusion
Adoptive immunotherapy with post-transplant infusion of pathogen specific T cells has been attempted as a way to reduce the infectious complications associated with haploidentical HSCT. Several groups have created T cell populations in vitro with specificity against adenovirus [22], EBV [23] (or both [24]), CMV [25] and Aspergillus [26]. Infusion of these cells has been shown to be safe, effective and not cause GVHD [27] but as this technique has not found wider application yet as it is time consuming, expensive and requires expert skills and specialized facilities [28].
Another promising technique is the infusion of donor T cells that have been genetically modified in order to express a suicide gene. The suicide gene can be turned on by the administration of a medication in case the patient develops GVHD. In clinical trials infusion of these cells accelerated immune reconstitution both directly and indirectly by driving the recovery of thymic activity and the few cases of GVHD were very rapidly and effectively controlled by turning on the suicide gene [29-31]. As with the previous technique, technical limitations make a wider application difficult.
Depletion of donor alloreactive T cells
Donor anti-host alloreactive T cells can be activated in vitro in a mixed lymphocyte reaction with donor-derived PBMCs and then depleted with the use an antibody targeting activated T cells such as an immunotoxin that reacts with CD25. The allodepleted T cell product can be safely infused to the donor and may improve T cell recovery as was demonstrated in two trials from Europe [32,33]. Photodepletion of host-reactive T cells is another selective method of allodepletion currently under study [34,35].
Unmanipulated T cell replete haploidentical transplants
A group from China has published on performing unmanipulated haploidentidentical HSCT with the use of intense GVHD prophylaxis and a graft that was composed of GSCF primed harvested marrow and collected peripheral stem cells. In their experience the outcomes with this procedure were comparable to HLA-identical sibling transplantation [36,37]. The same group published the results of a prospective trial in patients with intermediate or high risk Acute Myeloid Leukemia (AML) in first complete remission (CR1) that showed a clear superiority in terms of Overall and Disease Free Survival of the unmanipulated haploidentical HSCT over chemotherapy [38]. A group from Europe also showed that transplantation of unmanipulated GCSF primed bone marrow following either a myeloablative or even a RIC conditioning regimen is feasible with vigorous pre- and posttransplant GVHD prophylaxis [39].
Another group from China has reported on the infusion of haploidentical GCSF mobilized peripheral blood stem cells following not a preparative regimen but conventional chemotherapy [40,41]. Their patients had an impressively high leukemia free and overall survival at six years (84.4% and 89.5% respectively for patients with low or intermediated risk AML in CR1), no patient developed GVHD and nobody engrafted [40]. For elderly patients with AML they showed in a prospective randomized study that their approach was superior to conventional chemotherapy [41]. Presumably the resulting transient microchimerism was just enough for a GVL effect but not sufficient to induce GVHD, although there are still many unanswered questions [42].
T cell replete haploidentical HSCT with Post transplantantion High Dose Cyclophosphamide
Donor and host alloreactive T cells can be depleted in vivo with the post transplantation administration of high dose cyclophopshamide (PTCy) [43]. PTCy needs to be administered within a very short window after the stem cell infusion. Hematoopetic stem cells are relatively spared by the toxic effects of high dose cyclophosphamide thanks to the high expression of aldehyde dehydrogenase [44]. The Hopkins and the Seattle groups have pioneered the use of high dose Cyclophosphamide (50 mg/kg on days +3 and +4) following a reduced intensity regimen (Cyclophosphamide 14.5 mg/kg/day i.v. on days −6 and −5, fludarabine 30 mg/m2/day i.v. on days −6 to −2, and 200 cGy of TBI on day −1) and haploidentical donor marrow infusion [45]. Among 210 patients treated at Hopkins 87% had sustained engraftment and the cumulative incidences of grades II-IV acute GVHD and chronic GVHD were 27% and 13%, respectively. Fiveyear cumulative incidence of non-relapse mortality was 18%, relapse 55%, and overall survival 35% [46]. The relatively low observed infectious mortality suggests that memory T cells are spared by PTCy [6].
As this approach is technically simple and cost-effective, it has been adopted by many other centers. A group from Atlanta compared their center's outcomes of haploidentical HSCT using PTCy with those of conventional HLA-matched sibling donor (MRD) or HLA-matched unrelated donor (MUD) HSCT and reported that they were not inferior [47]. The same group has also showed that using a myeloablative preparative regimen and peripheral blood stem cells (PBSCs) as the graft source in conjunction with haploidentical HSCT and PCTy is safe and feasible [48].
The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) recently published the results of 2 parallel multicenter phase 2 trials (BMT-CTN 0603 and 0604) for patients with hematologic malignancies and no suitable related donor [49]. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or haploidentical HSCT with PTCY. The outcomes in terms of engraftment, GVHD, NRM and RFS at one year were similar and comparable to those reported after matched unrelated donor transplantation. These results set the stage for BMT-CTN 1101, a multicenter randomized phase 3 trial of dUCB vs haplo.
Tolerance induction
The achievement of specific tolerance to host but not tumor or infectious alloantigens by selectively inactivating the indicated subsets of alloantigen-specific T-lymphocytes has been the goal of transplant immunology [50]. Our currently expanding understanding of the biochemical and molecular basis of T-cell tolerance provides great promise towards reaching this goal.
The two signal model of T cell activation dictates that for T cell activation to proceed two signals are required: one through the antigen specific T cell receptor (TCR) and the second though the non-antigen specific engagement of a costimulatory molecule by its counterpart on an antigen presenting cell [51]. Engagement of the TCR in the absence of costimulation leads to T cell anergy and to peripheral tolerance formation [52]. Regulatory T cells are believed to abrogate GVHD and enhance immune reconstitution without blocking the GVL effect [53,54].
A group from Harvard conducted a clinical trial where a haploidentical marrow was infused after in vitro co-culture with recipient cells in the presence of CTLA4Ig, which is an antibody that blocks the second costimulatory signal rendering the alloreactive T cells in the culture anergic [55]. 95% of the treated patients engrafted, the GVHD rate was low and the immune reconstitution was rapid resulting in very few viral infections [56]. After the in vitro treatment the frequency of helper T cells that were reactive against the recipient fell by one to four orders of magnitude, whereas third party alloreactivity remained unaffected.
The Perugia group studied the infusion of haploidentical donor derived regulatory T cells (Tregs) followed by CD34+ cells and donor mature T cells in the setting of T cell depleted haploidentical HSCT [57]. Almost all patients engrafted, acute GVHD rate was low, there was no chronic GVHD, immune recovery was rapid and the GVL effect appeared preserved [58].
Rapamycin is an immunosuppressive medication that exerts its action through mTOR inhibition. mTOR inhibitors unlike calcineurin inhibitors (CNI) facilitate immunologic tolerance by inducing T cell anergy, promoting the expansion of regulatory T cells and inhibiting the maturation of dendritic cells [59,60]. In addition rapamycin has a direct antineoplastic effect that might be of clinical significance in the setting of HSCT [61]. The Milan group developed a CNI-free T cell replete haploidentical protocol with GVHD prophylaxis based on rapamycin, mycophenolate mofetil (MMF), ATG and rituximab [62]. Their purpose was to promote a rapid immune recovery with preferential accumulation of regulatory T cells. Their preliminary results look promising with most patients engrafting and acceptable rates of GVHD, NRM and relapse [63]. Furthermore they were able to demonstrate an early T-cell immune reconstitution characterized by the in-vivo expansion of Tregs.
Haploidentical HSCT has evolved from a desperate "Hail Mary" attempt for patients with no other options to a reliable procedure with results comparable to those of HSCT with the use of a matched related or unrelated donor. Furthermore it is now in the forefront of exciting research in immunology with the promise to abrogate GVHD while strengthening GVL.

  1. National Marrow Donor Program. 2013.
  2. Oevermann L, Handgretinger R New strategies for haploidentical transplantation. Pediatr Res 2012; 71: 418-426.
  3. Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, et al. Marrow transplantation from related donors other than HLAidentical siblings. N Engl J Med 1985; 313: 765-771.
  4. Powles RL, Morgenstern GR, Kay HE, McElwain TJ, Clink HM, Dady PJ,et al. Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia. Lancet 1983; 1: 612-615.
  5. Fernandez Vina M, Heslop HE, Barker JN. New approaches in alternative donor transplantation. Biol Blood Marrow Transplant 2013; 19: S91-96.
  6. Fuchs EJ. Haploidentical transplantation for hematologic malignancies:where do we stand? Hematology Am Soc Hematol Educ Program 2012; 2012: 230-236.
  7. Reisner Y, Hagin D, Martelli MF. Haploidentical hematopoietic transplantation: current status and future perspectives. Blood 2011; 118: 6006-6017.
  8. Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120-2130.
  9. Ash RC, Horowitz MM, Gale RP, van Bekkum DW, Casper JT, Gordon-Smith EC, et al. Bone marrow transplantation from related donors other than HLA-identical siblings: effect of T cell depletion. Bone Marrow Transplant 1991; 7: 443-452.
  10. O'Reilly RJ, Keever C, Kernan NA, Brochstein J, Collins N, Flomenberg N, et al. HLA nonidentical T cell depleted marrow transplants: a comparison of results in patients treated for leukemia and severe combined immunodeficiency disease. Transplant Proc 1987; 19: 55-60.
  11. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, et al.Full haplotype-mismatched hematopoietic stem-cell transplantation:a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005; 23: 3447-54.
  12. Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, et al.Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998; 339: 1186-93.
  13. Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med 1995; 1: 1268-1273.
  14. Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, 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: 3574-3581.
  15. Mehta J, Singhal S, Gee AP, Chiang KY, Godder K, Rhee Fv Fv, et al. Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients. Bone Marrow Transplant 2004; 33: 389-396.
  16. Klingebiel T, Cornish J, Labopin M, Locatelli F, Darbyshire P,Handgretinger R, 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: 3437-3446.
  17. Marks DI, Khattry N, Cummins M, Goulden N, Green A, Harvey J, et al. Haploidentical stem cell transplantation for children with acute leukaemia. Br J Haematol 2006; 134: 196-201.
  18. Lang P, Greil J, Bader P, Handgretinger R, Klingebiel T, Schumm M, et al. Long-term outcome after haploidentical stem cell transplantation in children. Blood Cells Mol Dis 2004; 33: 281-287.
  19. Bader P, Soerensen J, Jarisch A, Ponstingl E, Krenn T, Faber J, et al. Rapid immune recovery and low TRM in haploidentical stem cell transplantation in children and adolescence using CD3/CD19- depleted stem cells. Best Pract Res Clin Haematol 2011; 24: 331-337.
  20. González-Vicent M, Molina B, Andión M, Sevilla J, Ramirez M, et al. Allogeneic hematopoietic transplantation using haploidentical donor vs. unrelated cord blood donor in pediatric patients: a single-center retrospective study. Eur J Haematol. 2011; 87: 46-53.
  21. Chen X, Hale GA, Barfield R, Benaim E, Leung WH, et al. Rapid immune reconstitution after a reduced-intensity conditioning regimen and a CD3-depleted haploidentical stem cell graft for paediatric refractory haematological malignancies. Br J Haematol. 2006; 135: 524-32.
  22. Comoli P, Schilham MW, Basso S, van Vreeswijk T, Bernardo ME, Maccario R, et al. T-cell lines specific for peptides of adenovirus hexon protein and devoid of alloreactivity against recipient cells can be obtained from HLA-haploidentical donors. J Immunother 2008; 31:529-536.
  23. Comoli P, Basso S, Zecca M, Pagliara D, Baldanti F, Bernardo ME, et al.Preemptive therapy of EBV-related lymphoproliferative disease after pediatric haploidentical stem cell transplantation. Am J Transplant 2007; 7: 1648-1655.
  24. Leen AM, Christin A, Myers GD, Liu H, Cruz CR, Hanley PJ, et al. Cytotoxic T lymphocyte therapy with donor T cells prevents and treats adenovirus and Epstein-Barr virus infections after haploidentical and matched unrelated stem cell transplantation. Blood 2009; 114: 4283-4292.
  25. Feuchtinger T, Opherk K, Bethge WA, Topp MS, Schuster FR, Weissinger EM, et al. Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation. Blood 2010; 116: 4360-4367.
  26. Perruccio K, Tosti A, Burchielli E, Topini F, Ruggeri L, Carotti A, et al. Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation. Blood 2005; 106: 4397-4406.
  27. Melenhorst JJ, Leen AM, Bollard CM, Quigley MF, Price DA, Rooney CM,et al. Allogeneic virus-specific T cells with HLA alloreactivity do not produce GVHD in human subjects. Blood 2010; 116: 4700-4702.
  28. Sellar RS, Peggs KS The role of virus-specific adoptive T-cell therapy in hematopoietic transplantation. Cytotherapy 2012; 14: 391-400.
  29. Vago L, Oliveira G, Bondanza A, Noviello M, Soldati C, Ghio D, et al. T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation. Blood 2012; 120: 1820-1830.
  30. Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med 2011; 365: 1673-1683.
  31. Ciceri F, Bonini C, Stanghellini MT, Bondanza A, Traversari C, Salomoni M, 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. Lancet Oncol 2009; 10: 489-500.
  32. Amrolia PJ, Muccioli-Casadei G, Huls H, Adams S, Durett A, Gee A, et al.Adoptive immunotherapy with allodepleted donor T-cells improves immune reconstitution after haploidentical stem cell transplantation. Blood 2006; 108: 1797-1808.
  33. André-Schmutz I, Le Deist F, Hacein-Bey-Abina S, Vitetta E, Schindler J, Chedeville G, et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet 2002; 360: 130-137.
  34. McIver ZA, Melenhorst JJ, Grim A, Naguib N, Weber G, Fellowes V, et al. Immune reconstitution in recipients of photodepleted HLA-identical sibling donor stem cell transplantations: T cell subset frequencies predict outcome. Biol Blood Marrow Transplant 2011; 17: 1846-1854.
  35. Roy DC, et al, Reduction in Incidence of Severe Infections by Transplantation of High Doses of Haploidentical T Cells Selectively Depleted of Alloreactive Units. ASH Annual Meeting Abstracts. 2011; 118: 3020.
  36. Huang X, Liu D. Related HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: observations of a single Chinese center. Clin Transpl 2011; .
  37. Lu, D.P., et al., Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLAidentical sibling transplantation. Blood, 2006. 107(8): p. 3065-73.
  38. Huang XJ, Zhu HH, Chang YJ, Xu LP, Liu DH, Zhang XH, et al. The superiority of haploidentical related stem cell transplantation over chemotherapy alone as postremission treatment for patients with intermediate- or high-risk acute myeloid leukemia in first complete remission. Blood 2012; 119: 5584-5590.
  39. Di Bartolomeo P, Santarone S, De Angelis G, Picardi A, Cudillo L,Cerretti R, et al. Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies. Blood 2013; 121: 849-857.
  40. Guo M, Hu KX, Liu GX, Yu CL, Qiao JH, Sun QY, et al. HLA-mismatched stem-cell microtransplantation as postremission therapy for acute myeloid leukemia: long-term follow-up. J Clin Oncol 2012; 30: 4084-4090.
  41. Guo M, Hu KX, Yu CL, Sun QY, Qiao JH, Wang DH, et al. Infusion of HLAmismatched peripheral blood stem cells improves the outcome of chemotherapy for acute myeloid leukemia in elderly patients. Blood 2011; 117: 936-941.
  42. Spitzer TR. Microtransplantation: a new paradigm for the separation of graft versus host disease and graft versus tumor? J Clin Oncol 2012;30: 4051-4052.
  43. Luznik L, O'Donnell PV, Fuchs EJ. Post-transplantation cyclophosphamide for tolerance induction in HLA-haploidentical bone marrow transplantation. Semin Oncol 2012; 39: 683-693.
  44. Jones RJ, Barber JP, Vala MS, Collector MI, Kaufmann SH, Ludeman SM, et al. Assessment of aldehyde dehydrogenase in viable cells. Blood 1995; 85: 2742-2746.
  45. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and highdose,posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641-650.
  46. Munchel A, Kesserwan C, Symons HJ, Luznik L, Kasamon YL,Jones RJ, et al. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep 2011; 3 Suppl 2: e15.
  47. Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, 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. J Clin Oncol 2013; 31: 1310-1316.
  48. Solomon SR, Sizemore CA, Sanacore M, Zhang X, Brown S, et al. Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with highrisk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012; 18: 1859-66.
  49. Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011; 118: 282-8.
  50. Appleman LJ, Tzachanis D, Grader-Beck T, Van Puijenbroek AA, Boussiotis VA. Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation. Leuk Lymphoma 2002; 43: 1159- 1167.
  51. Tzachanis D, Lafuente EM, Li L, Boussiotis VA. Intrinsic and extrinsic regulation of T lymphocyte quiescence. Leuk Lymphoma 2004; 45:1959-1967.
  52. Kuklina EM Molecular mechanisms of T-cell anergy. Biochemistry (Mosc) 2013; 78: 144-156.
  53. Nguyen VH, Shashidhar S, Chang DS, Ho L, Kambham N, Bachmann M,et al. The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. Blood 2008; 111: 945-953.
  54. Jones SC, Murphy GF, Korngold R. Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant 2003; 9: 243-256.
  55. Guinan EC, Boussiotis VA, Neuberg D, Brennan LL, Hirano N, Nadler LM, et al. Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 1999; 340: 1704-1714.
  56. Davies JK, Gribben JG, Brennan LL, Yuk D, Nadler LM, Guinan EC. Outcome of alloanergized haploidentical bone marrow transplantation after ex vivo costimulatory blockade: results of 2 phase 1 studies. Blood 2008; 112: 2232-2241.
  57. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E, et al. Tregs prevent GVHD and promote immune reconstitution in HLAhaploidentical transplantation. Blood 2011; 117: 3921-3928.
  58. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Del Papa B, Perruccio K, et al. Immunoselection and clinical use of T regulatory cells in HLAhaploidentical stem cell transplantation. Best Pract Res Clin Haematol 2011; 24: 459-466.
  59. Powell JD, Zheng Y. Dissecting the mechanism of T-cell anergy with immunophilin ligands. Curr Opin Investig Drugs 2006; 7: 1002-1007.
  60. McMahon G, Weir MR, Li XC, Mandelbrot DA. The evolving role of mTOR inhibition in transplantation tolerance. J Am Soc Nephrol 2011; 22: 408-415.
  61. Armand P, Gannamaneni S, Kim HT, Cutler CS, Ho VT, Koreth J, et al.Improved survival in lymphoma patients receiving sirolimus for graftversus-host disease prophylaxis after allogeneic hematopoietic stemcell transplantation with reduced-intensity conditioning. J Clin Oncol 2008; 26: 5767-5774.
  62. Ciceri F, Bregni M, Peccatori J. Innovative platforms for haploidentical stem cell transplantation: the role of unmanipulated donor graft. J Cancer 2011; 2: 339-340.
  63. Peccatori, J., et al., In-Vivo Expansion of T Regulatory Cells by Rapamycin in a Calcineurin-Inhibitor Free GVHD Prophylaxis in Unmanipulated Haploidentical Stem Cell Transplantation (SCT). Biol Blood Marrow Transplant, 2011. 17(2): p. S170.
  64. Charpentier B. Belatacept: a novel immunosuppressive agent for kidney transplant recipients. Expert Rev Clin Immunol 2012; 8: 719-728.
  65. Martin ST, Tichy EM, Gabardi S. Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation. Pharmacotherapy 2011; 31: 394-407.
  66. Furuzawa-Carballeda J, Lima G, Alberú J, Palafox D, Uribe-Uribe N,Morales-Buenrostro LE, et al. Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A. Clin Exp Immunol 2012; 167: 330-337.

Cite this article: Tzachanis D, Lill MC (2013) Advances in Haploidentical Hematopoetic Stem Cell Transplantation. J Hematol Transfus 1(1): 1003.
Right Table
Content:   Home  |  Aims & Scope  |  Early Online  |  Current Issue  | 
Journal Info:   Editorial Board  |  Article Processing Charges  |  FAQs
Contact Us
2952 Market Street, Suite 140
San Diego, California 92102, USA
Tel: 1-619-373-8030
Fax: 1-619-793-4845
Toll free number: 1-800-762-9856
Copyright © 2013 JSciMed Central. All rights reserved.