Allogeneic Hematopoietic Cell Transplantation from an HLA-mismatched Family Donor: The Current Status and Future

Kyoo-Hyung Lee; Je-Hwan Lee; Jung-Hee Lee; Dae-Young Kim

doi:10.5124/jkma.2009.52.8.819

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Lee, Lee, Lee, and Kim: Allogeneic Hematopoietic Cell Transplantation from an HLA-mismatched Family Donor: The Current Status and Future

Continuing Education Column

Journal of the Korean Medical Association

Journal of the Korean Medical Association 2009; 52(8): 819-830.

Published online: 31 August 2009

DOI: https://doi.org/10.5124/jkma.2009.52.8.819

Allogeneic Hematopoietic Cell Transplantation from an HLA-mismatched Family Donor: The Current Status and Future

Kyoo-Hyung Lee, MD, Je-Hwan Lee, MD, Jung-Hee Lee, MD, Dae-Young Kim, MD

Department of Internal Medicine, University of Ulsan College of Medicine, Korea. khlee2@amc.seoul.kr

Abstract

Traditionally, human leukocyte antigen (HLA)-mismatched hematopoietic cell transplantation (HCT) has been considered ill-advised in a routine clinical practice due to excessive serious post-transplant complications, such as graft failure, graft-versus-host disease, and prolonged immunosuppression resulting in increased fatal infections. Recent introduction of new HCT techniques, especially in the area of conditioning therapy, has improved outcomes of HLA-mismatched HCT considerably. Using several regimens of reduced-intensity conditioning (RIC), it is now possible to perform allogeneic HCT in patients without HLA-matched donors in the family or in the registry from HLA-mismatched family donors. Furthermore, due to less rigorous nature of RIC therapy, elderly patients (up to 70 years of age) and patients who have been treated heavily especially with a previous HCT can also be treated. In this review, we gave a brief historical background for the development of allogeneic HCT, discussed rationale for the use RIC for HLA-mismatched HCT, and summarized trial results of HLA-mismatched HCT after RIC. Lastly, future areas of research regarding HLA-mismatched HCT were discussed.

Keywords: HLA-mismatched hematopoietic cell transplantation, Reduced-intensity conditioning, Anti-thymocyte globulin, Busufan, Fludarabine

Allogeneic Hematopoietic Cell Transplantation: Early Development

Allogeneic hematopoietic cell transplantation (HCT) is a well-established curative treatment modality for a significant proportion of patients with hematologic malignancies and bone marrow failure syndrome. The initial development of allogeneic HCT was conceptually based on the experiments using murine model, where the lethally irradiated animals were salvaged by the infusion of spleen/bone marrow cells from the other animals(1, 2), a seminal observation made in the early 1950's. Early attempts to treat patients with terminal leukemia with total body irradiation (TBI) and subsequent infusion of bone marrow cells from healthy subjects, however, were largely unsuccessful(3, 4). Systematic studies in canine transplantation models showed that the matching for the dog leukocyte antigens (DLA) between littermates was an important determinant for successful HCT(5, 6). Therefore, subsequent development of clinical allogeneic HCT techniques centered around the two premises that were assumed to be important; the first is the conditioning of patients before HCT with radiation and/or chemotherapy regimens that can ablate the bone marrow of the patients (especially for patients with leukemia). The other is that the donor and recipient should carry identical human leukocyte antigens (HLA)(7~10).

These premises, however, impeded the wider application of allogeneic HCT. Patients should be relatively young and fit to tolerate rigorous intensity of conditioning regimens. Moreover, less than one-third of patients who require allogeneic HCT have an HLAmatched family member who can donate hematopoietic cells(11).

Hematopoietic Cell Transplantation from an HLA-mismatched Family Donor: Initial and Subsequent Clinical Studies

Nearly all patients who are in need of allogeneic HCT have at least one HLA-haploidentical family member who is willing to donate hematopoietic cells immediately, not only for the initial transplantation, but also for any additional donations that may become necessary(12). Early studies attempting to transplant allogeneic hematopoietic cells across the HLA-haplotype barrier used myeloablative conditioning regimens that were similar to those used in HLA-matched sibling HCT (Table 1)(13, 14). These trial showed high frequencies of engraftment failure, delayed neutrophil engraftment, and, when engraftment occurred, excessive graft-versus-host disease (GVHD). Even in these early observations, however, there were small portions of patients who experienced successful donor cell engraftment without serious GVHD, and achieved long-term remission of their leukemia. These findings suggested that the HLA- haplotype difference was not an absolute but a relative barrier to successful HCT. Increasing the intensity of conditioning(15) and/or depletion of donor T cells from the grafts prior to HCT (15, 16) decreased the frequency and severity of GVHD, but it also resulted in the increased graft failure, delayed immune reconstitution, and increased fatal infections, thus failing to improve overall outcomes of HLA-mismatched HCT. In subsequent clinical studies, several groups of investigators tried to improve outcomes of HLA-mismatched HCT; these efforts included the use of polyclonal(17, 18) or monoclonal(19, 20) antibodies against T cells as a part of the conditioning regimen (in vivo-T cell depletion), transplantation of higher dose of purified CD34+ cells(21), and incorporation of the concept of fetomaternal immune tolerance in selecting donors from among several available HLA-mismatched family members(Table 2)(22). Overall, these trial showed improved outcomes after HLA-mismatched HCT when compared to earlier trials. However, allogeneic HCT from an HLA-mismatched family member remained a procedure that was associated with high regimen-related toxicities and high transplantation-related mortality (TRM) ranging from 20% to 40%(17, 21, 22).

Advent of Reduced-intensity Conditioning in Allogeneic Hematopoietic Cell Transplantation

In a canine HCT model, Storb et al pioneered a concept of donor hematopoietic cell engraftment in a host after a conditioning regimen that was suppressive of immunity rather than ablative of bone marrow of the host(23). In this model, leukemia cure is dependent more upon graft-versus-leukemia effect than upon high-doses of chemo- or radiotherapy given as a part of conditioning. Various non-myeloablative, immunosuppressive conditioning regimens [collectively called reduced-intensity conditioning (RIC)] have been introduced rapidly into clinical allogeneic HCT from both HLA-matched siblings and unrelated donors. These RIC contained TBI in reduced-dose (24), busulfan in reduced-dose(25, 26), or melphalan(27), along with fludarabine. RIC for allogeneic HCT have shown to be effective in achieving successful engraftment with a reduced frequency of TRM, particularly in elderly patients and in patients with organ dysfunctions. With an advent of RIC, it became possible to perform allogeneic HCT in patients up to 70 years of age. Successful introduction of RIC in clinical HCT demonstrated that, under conditions of adequate immunosuppression of the patients but not necessarily myeloablation, donor hematopoietic cells can engraft and a complete donor hematopoietic chimerism can be achieved.

Allogeneic Hematopoietic Cell Transplantation Across MHC-barrier after Reduced-intensity Conditioning: Animal Studies

The principle shown in the success of RIC in HLA-matched allogeneic HCT, i.e. the importance of immune-suppression, but not myeloablation, for the donor cell engraftment, might be extended to HLA-mismatched HCT settings. Successful engraftment of allogeneic hematopoietic cells across major histocompatibility complex (MHC) gene-haplotype difference after RIC has been well-documented in murine(28) as well as in large animal HCT models(Table 3)(29~31). In a DLA-haploidentical littermate HCT setting(29), one of 6 dogs conditioned with TBI 450 cGy alone achieved engraftment of granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells. When posttransplant immunosuppression with mycofenolate plus cyclo-sporine was added, 3 of 6 dogs achieved sustained donor cell engraftment. When murine anti-CD44 monoclonal antibody, S5, was added to conditioning regimen of TBI, along with posttransplant immuno-suppression, 10 of 12 dogs achieved sustained engraftment. These findings suggested that DLA-haplotype barrier can be overcome after RIC. Furthermore, the addition of anti-CD44 monoclonal antibody to conditioning regimen enhanced engra-ftment potential significantly. A subsequent canine HCT study(30) showed that reducing TBI dose to 200 cGy in the conditioning along with anti-CD44 monoclonal antibody produced good initial engraftment; however over the half of the dogs experienced secondary graft failure subsequently. In a swine leukocyte antigen (SLA)-haploidentical trans-plantation study(31), results from RIC (TBI 100 cGy plus anti-CD3 immunotoxin, CRM9) with mobilized peripheral blood mononuclear cell grafting was compared to those of myeloablative conditioning (TBI 1150 cGy plus cyclophosphamide 50 mg/kg) with bone marrow cell grafting. While all of 9 animals in the RIC group achieved sustained donor cell engraft-ment, 5 of 9 animals in the myeloablative conditioning group failed to engraft. Furthermore, while only 1 animal in the RIC group developed grade 2 acute GVHD (skin rash and diarrhea), all 4 engrafted animals in the myeloablative conditioning group developed grade 3 to 4 acute GVHD. These findings suggested that RIC with TBI 100 cGy plus anti-T cell antibody in the SLA-haploidentical setting was immunosuppressive enough to facilitate efficient donor cell engraftment. In addition, acute GVHD may be decreased in the RIC group probably due to less host tissue damage and less release of proinflam-matory cytokines during conditioning and donor cell infusion.

HLA-mismatched Allogeneic Hematopoietic Cell Transplantation after Reduced-intensity Conditioning: Clinical Settings

The feasibility of successful donor cell engraftment across HLA-haplotype difference after RIC in a clinical setting was first suggested in children with severe combined immunodeficiency, who were transplanted with hematopoietic cells from HLA-mismatched familial donors after RIC or even without conditioning(32~34). In these studies, durable donor cell engraftment with a full T-and B-cell function recovery after HCT was documented. As per adult patients with hematologic malignancies or bone marrow failure syndrome, other than single case reports(35, 36), there are now six hospitals worldwide which have published results of HLA-mismatched HCT after RIC(Table 4).

Massachusetts General Hospital Study

The first clinical study investigating the role of RIC in HLA-mismatched HCT in adult patients with hematologic malignancy was published by Syke et al(37). The conditioning regimen was based on murine HCT data and included cyclophosphamide (200 mg/kg), irradiation to the thymus (700 cGy), and anti-thymocyte globulin (ATG). All 5 patients in the study had advanced non-Hodgkin's lymphoma and all had grade 2~3 acute GVHD after HCT. Two patients were surviving in complete and partial remission of their lymphoma for 460 and 103 days, respectively, in full donor lymphocyte chimerism (>90%). In a subsequent study(38), anti-CD2 monoclonal antibody, Medi-507, replaced ATG. Mixed donor chimerism was achieved in most of 12 patients studied.

Kyoto University study

Ichinohe, et al(22) selected their potential hematopoietic cell donors among several HLA-mismatched family members based on the concept of fetomaternal immune tolerance (microchimerism occurring during pregnancy with subsequent immunologic tolerance between mother and offspring). Accordingly, mothers, not fathers, were preferred donors for offspring patients. Among HLA-haploidentical siblings, ones with mismatched haplotype not shared by mother were chosen as cell donors. Of 35 patients reported, 12 patients received various RIC regimens and 11 achieved successful donor cell engraftment.

Osaka University study

Ogawa, et al(39) used RIC of oral busulfan (8 mg/kg), fludarabine (180 mg/m²), and rabbit-ATG (8 mg/kg; Fresnius, Munich, Germany), a similar conditioning regimen originally used by Slavin, et al(25) for HLA-mismatched HCT in 26 patients with various hematologic malignancies. Hematopoietic cells were harvested from the donor peripheral blood after mobilization with G-CSF. Post-transplant immunosuppression for GVHD prophylaxis included FK506 and methylprednisolone. Twenty-five patients achieved primary donor cell engraftment. Five patients (20%) experienced grade 2 acute GVHD. None experienced acute GVHD over grade 2. Extensive chronic GVHD occurred only in 5 of 20 evaluated patients. Four patients died without recurrence/persistence of underlying malignancy giving TRM of 15%. Fifteen patients survived in CR with 3-year event free survival rate of 55%. Donor chimerism was achieved rapidly with all of 25 patients with primary engraftment showing 95% to 100% donor chimerism by 2 weeks after transplantation. CD8⁺ cells recovered rapidly after HCT with a median count of about 1,000/µl at 9 months although CD4⁺ cells recovered more slowly (median 100/µl at 9 months).

Duke University study

Rizzieri, et al(40) used RIC of cyclophosphamide (2 g/m²), fludarabine (120 mg/m²), and a humanized anti-CD52 monoclonal antibody (Alemtuzumab) 100 mg in 49 patients undergoing HCT from HLA-mismatched family donors who donated G-CSF mobilized peripheral blood mononuclear cells. Three and 4 patients experienced primary and secondary graft failure, respectively. Grade 2~4 acute GVHD was not frequent and observed in 16% of patients. Chronic GVHD occurred only in 14% of patients. Overall, 31% of patients experienced TRM, mostly due to infections.

Johns Hopkins University/Fred Hutchinson Cancer Center studies

Luznik, et al(41) used RIC of TBI 200 cGy, fludarabine 150 mg/m², and cyclophos-phamide 29 mg/kg in 68 patients undergoing HLA-mismatched HCT. Bone marrow cell grafts were used without ex vivo -T cell depletion. On days 3 to 4 of HCT, cyclophosphamide 50~100 mg/kg was given additionally. Post-transplant immunosuppression included FK506 and mycophenolate. Graft failure occurred in 9 patients (13%). Grade 2~4 acute GVHD occurred in 34%. Oneyear TRM and relapse rates were 15% and 51%, respectively. Burroughs, et al(42) applied similar RIC in 90 patients with advanced Hodgkin's disease. Of those, 38 patients were transplanted with cells from HLA-matched related donors; 24 from HLA-matched unrelated donors; and 28 from HLA-haploidentical related donors. The frequencies of acute GVHD grade 3~ 4 and extensive chronic GVHD were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). Interestingly, patients who underwent HLA-haploidentical HCT experienced significantly less disease recurrence/progression when compared to HLA-matched HCT from related or unrelated donors [2-year rates; 40% vs. 56% (P=0.01) vs. 63% (P=0.03)]. TRM was also significantly lower for HLA-haploidentical HCT when compared to HLA-matched related HCT (9% vs. 21% at 2 years; P=0.02).

University of Ulsan, Asan Medical Center study

In our hospital, an allogeneic HCT protocol for patients with high-risk hematologic disorders, utilizing an HLAmismatched family member as the donor, was initiated in April 2004(43). Thirty-one patients (median age, 34 years; range, 16~69 years) were enrolled before April 2008. The cell donors were either mother (n=14), offspring (n=9), or siblings (n=8) of these patients. The conditioning regimen consisted of busulfan 6.4 mg/kg/day intravenously, fludarabine 180 mg/m², and rabbit-ATG (12 mg/kg; Genzyme Transplant) or horse-ATG (45 mg/kg), a variation of original RIC of Slavin, et al(25). Hematopoietic cells were collected from the donors via leukapheresis after G-CSF mobilization and infused without further manipulation. Cyclosporine and methotrexate were administered for GVHD prophylaxis. Excluding 3 patients who died or relapsed with leukemia within 3 weeks after HCT, all remaining 28 patients engrafted with neutrophil (>500/µl) at a median of 16.5 days. Over 90% of evaluated patients (22/24) achieved donor chimerism 95% or over at 2 weeks after HCT and none experienced secondary graft failure. Acute GVHD grade 2~4 and moderate-severe chronic GVHD were observed in 19% and 20%, respectively. Four patients died due to transplantation related causes (3 sepsis; 1 acute GVHD) giving TRM of 13%. The patients showed a prompt recovery of their lymphocyte subset counts with mean CD4⁺ and CD8⁺ cell counts over 250/µland 1,000/µl, respectively from 2 months after HCT.

The consistent engraftment with low frequencies of acute and chronic GVHD observed following HLA-mismatched HCT after RIC, as demonstrated in the aforementioned studies, is intriguing and in contrast to the traditional concept of allogeneic HCT, where an increasing number of HLA disparities is considered as one of the most important determinants for increasing graft failure, as well for increasing GVHD(11). Decreased tissue damage induced by RIC, as opposed to myeloablative conditioning, may lead to reduced release of tissue antigens and proinflammatory cytokines, thereby favoring a post-transplant host environment with less triggering of acute GVHD. In addition, changes in the conditioning regimen given prior to allogeneic HCT can increase the contents and functions of regulatory T cells, resulting in an immune-modulatory rather than an immune-stimulating environment after HCT(44). Taken together, these findings suggest that the role of disparities in major MHC antigens as a determinant of adverse outcomes of HCT may vary according to the intensity and type of conditioning regimens.

HLA-mismatched Hematopoietic Cell Transplantation: The Future

The fact that it is now possible to perform allogeneic HCT from an HLA-mismatched family member using RIC without excessive morbidity and mortality to the patients is likely to change the way we apply allogeneic HCT in clinic in a major way. Allogeneic HCT now can be used in patients with high-risk hematologic malignancies and bone marrow failure syndrome, even when an HLA-matched donor is not available or when allogeneic HCT is needed urgently (therefore there is no time for unrelated donor search and coordination for cell collection). Moreover, due to the less intense nature of conditioning regimen, elderly patients (up to 70 years of age) and patients who have been treated a great deal, particularly with a previous HCT, can also be treated.

Stronger graft-versus-leukemia effect after HLAmismatched HCT compared to HLA-matched HCT was shown in a murine model; (45) the same effect was also suggested in a clinical trial(42). Therefore, further prospective clinical studies are needed to determine whether a stronger graft-versus-leukemia effect would result from HLA-mismatched HCT compared with HLA-matched HCT. Finally, HLA-mismatched HCT may provide a clinical setting where donor natural killer cell infusion therapy may be utilized for effective immunotherapy for advanced malignancies (46) (and unpublished data, Lee K-H and Choi I).

Figures and Tables

Table 1

Early studies of HLA-mismatched HCT from a family member

HCT, hematopoietic cell transplantation; AL, acute leukemia; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; CP, chronic phase; BC, blastic crisis; Cy, cyclophosphamide; TBI, total body irradiation; Mel, melphalan; MPD, methylprednisolone; CR1, first complete remission; CR2, second complete remission; TCD, T-cell depletion; BM, bone marrow cells; CSA, cyclosporine; MTX, methotrexate; GVHD, graft-versus-host disease; gr, grade; BMT, bone marrow transplantation.

Table 2

Recent studies of HLA-mismatched HCT from a family member after myeloablative conditioning therapy

HCT, hematopoietic cell transplantation; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; NHL, non-Hodgkin's lymphoma; Cy, cyclophosphamide; TBI, total body irradiation; Mel, melphalan; ATG, anti-thymocyte globulin; MeCCNU, methyl CCNU; TCD, T-cell depletion; G-PB, growth factor-mobilized peripheral blood mononuclear cells; BM, bone marrow cells; CSA, cyclosporine; MTX, methotrexate; MMF, mycophenolate mofetil; aGVHD, acute graft-versus-host disease; gr, grade; cGVHD, chronic graft-versus-host disease; BMT, bone marrow transplantation; TRM, transplantation-related mortality

Table 3

Animal transplantation models where donor cells engrafted across MHC-barrier after reduced-intensity conditioning

TBI, total body irradiation; Cy, cyclophosphamide; GVHD, graft-versus-host disease; PBMC, peripheral blood mononuclear cells; BM, bone marrow cells; G-CSF, granulocyte colony-stimulating factor; aGVHD, acute graft-versus-host disease.

Table 4

HLA-mismatched HCT from a family member after reduced-intensity conditioning therapy

HCT, hematopoietic cell transplantation; NHL, non-Hodgkin's lymphoma; AML, acute myelogenous leukemia; HD, Hodgkin's disease; RIC, reduced-intensity conditioning; MDS, myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; AL, acute leukemia; MM, multiple myeloma; MPD, myelodysplastic syndrome; PNH, paroxysmal nocturnal hemoglobinuria; Cy, cyclophosphamide; XRT, radiotherapy; ATG, anti-thymocyte globulin; Bu, busulfan; Flu, fludarabine; BM, bone marrow cells; TCD, T-cell depletion; G-PB, growth factor-mobilized peripheral blood mononuclear cells; CSA, cyclosporine; MTX, methotrexate; MPD, methylprednisolone; MMF, mycophenolate mofetil; aGVHD, acute graft-versus-host disease; gr, grade; cGVHD, chronic graft-versus-host disease; CR, complete remission; PR, partial remission; MC, mixed chimerism; TRM, transplantation-related mortality; NRM, non-relapse mortality ; UD, unrelated donor

References

1. Jacobson LO, Marks EK, Robson MJ, Gaston EO, Zirke RE. Effect of spleen protection on mortality following X- irradiation. J Laboratory Clin Med. 1949. 34:1538–1543.

2. Lorenz E, Uphoff D, Reid TR, Shelton E. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst. 1951. 12:197–201.

3. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intra-venous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957. 257:491–496.

4. Bortin MM. A compendium of reported human bone marrow transplants. Transplantation. 1970. 9:571–587.

5. Epstein RB, Storb R, Ragde H, Thomas ED. Cytotoxic typing antisera for marrow grafting in littermate dogs. Transplantation. 1968. 6:45–58.

6. Storb R, Rudolph RH, Thomas ED. Marrow grafts between canine siblings matched by serotyping and mixed leukocyte culture. J Clin Invest. 1971. 50:1272–1275.

7. Buckner CD, Epstein RB, Rudolph RH, Clift RA, Storb R, Thomas ED. Allogeneic marrow engraftment following whole body irradiation in a patient with leukemia. Blood. 1970. 35:741–750.

8. Thomas ED, Storb R, Fefer A, Slichter SJ, Bryant JI, Buckner CD, Neiman PE, Clift RA, Funk DD, Lerner KE. Aplastic anaemia treated by marrow transplantation. Lancet. 1972. 1:284–289.

9. Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, Goodell BW, Hickman RO, Lerner KG, Neiman PE, Sale GE, Sanders JE, Singer J, Stevens M, Storb R, Weiden PL. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1972. 49:511–533.

10. Graw RG Jr, Santos GW. Bone marrow transplantation in patients with leukemia. Incidence and severity of graft-versushost disease in successful HL-A-matched transplants. Transplantation. 1971. 11:197–199.

11. Martin PJ. Blume KG, Forman SJ, Appelbaum FR, editors. Overview of hematopoietic cell transplantation immunology. Thomas' Hematopoietic Cell Transplantation. 2004. 3rd ed. Blackwell Publishing;16–30.

12. Koh LP, Rizzieri DA, Chao NJ. Allogeneic hematopoietic stem cell transplant using mismatched/haploidentical donors. Biol Blood Marrow Transplant. 2007. 13:1249–1267.

13. Powles RL, Morgenstern GR, Kay HE, McElwain TJ, Clink HM, Dady PJ, Barrett A, Jameson B, Depledge MH, Watson JG, Sloane J, Leigh M, Lumley H, Hedley D, Lawler SD, Filshie J, Robinson B. Mismatched family donors for bone-marrow transplantation as treatment for acute leukaemia. Lancet. 1983. 1:612–615.

14. Beatty PG, Clift RA, Mickelson EM, Nisperos BB, Flournoy N, Martin PJ, Sanders JE, Stewart P, Buckner CD, Storb R, et al. Marrow transplantation from related donors other than HLAidentical siblings. N Engl J Med. 1985. 313:765–771.

15. Henslee-Downey PJ, Abhyankar SH, Parrish RS, Pati AR, Godder KT, Neglia WJ, Goon-Johnson KS, Geier SS, Lee CG, Gee AP. Use of partially mismatched related donors extends access to allogeneic marrow transplant. Blood. 1997. 89:3864–3872.

16. Lacerda JF, Martins C, Carmo JA, Lourenco F, Juncal C, Rodrigues A, Vilalobos I, Moura MC, Ligeiro D, Martinho A, Lacerda JM. Haploidentical stem cell transplantation with purified CD34 cells after a chemotherapy-alone conditioning regimen. Biol Blood Marrow Transplant. 2003. 9:633–642.

17. Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, Chen H, Liu DH, Gao ZY, Chen YH, Xu LP, Zhang YC, Ren HY, Li D, Liu KY. 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. 107:3065–3073.

18. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Wang JZ, Gao ZY, Zhang YC, Jiang Q, Shi HX, Lu DP. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006. 38:291–297.

19. Kanda Y, Oshima K, Asano-Mori Y, Kandabashi K, Nakagawa M, Sakata-Yanagimoto M, Izutsu K, Hangaishi A, Tsujino S, Ogawa S, Motokura T, Chiba S, Hirai H. In vivo alemtuzumab enables haploidentical human leukocyte antigen-mismatched hematopoietic stem-cell transplantation without ex vivo graft manipulation. Transplantation. 2005. 79:1351–1357.

20. Chen HR, Ji SQ, Wang HX, Yan HM, Zhu L, Liu J, Xue M, Xun CQ. Humanized anti-CD25 monoclonal antibody for prophylaxis of graft-vs-host disease (GVHD) in haploidentical bone marrow transplantation without ex vivo T-cell depletion. Exp Hematol. 2003. 31:1019–1025.

21. Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. 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. 23:3447–3454.

22. Ichinohe T, Uchiyama T, Shimazaki C, Matsuo K, Tamaki S, Hino M, Watanabe A, Hamaguchi M, Adachi S, Gondo H, Uoshima N, Yoshihara T, Hatanaka K, Fujii H, Kawa K, Kawanishi K, Oka K, Kimura H, Itoh M, Inukai T, Maruya E, Saji H, Kodera Y. Feasibility of HLA-haploidentical hematopoietic stem cell transplantation between noninherited maternal antigen (NIMA)-mismatched family members linked with long-term fetomaternal microchimerism. Blood. 2004. 104:3821–3828.

23. Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem HP, Leisenring W, Shulman H. Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood. 1997. 89:3048–3054.

24. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers ME, Georges GE, Grumet FC, Kiem HP, Torok-Storb B, Yu C, Blume KG, Storb RF. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001. 97:3390–3400.

25. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998. 91:756–763.

26. Lee KH, Lee JH, Kim WK, Chi HS, Lee JS. Non-myeloablative conditioning regimen of fludarabine, busulfan, anti-thymocyte globulin, and methylprednisolone for allogeneic peripheral blood hematopoietic cell transplantation. Haematologica. 2001. 86:999–1001.

27. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P, O'Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Korbling M, Keating M, Kantarjian H, Champlin R. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood. 1997. 89:4531–4536.

28. Vanclee A, Lutgens LC, Oving EB, Deutz NE, Gijbels MJ, Schouten HC, Bos GM. Keratinocyte growth factor ameliorates acute graft -versus-host disease in a novel nonmyeloablative haploidentical transplantation model. Bone Marrow Transplant. 2005. 36:907–915.

29. Sandmaier BM, Fukuda T, Gooley T, Yu C, Santos EB, Storb R. Dog leukocyte antigen-haploidentical stem cell allografts after anti-CD44 therapy and reduced-intensity conditioning in a preclinical canine model. Exp Hematol. 2003. 31:168–175.

30. Fukuda T, Kerbauy FR, Gooley T, Santos EB, Storb R, Sandmaier BM. Dog leukocyte antigen-haploidentical stem cell allografts after anti-CD44 therapy and nonmyeloablative conditioning in a preclinical canine model. Transplantation. 2006. 82:332–339.

31. Cina RA, Wikiel KJ, Lee PW, Cameron AM, Hettiarachy S, Rowland H, Goodrich J, Colby C, Spitzer TR, Neville DM Jr, Huang CA. Stable multilineage chimerism without graft versus host disease following nonmyeloablative haploidentical hematopoietic cell transplantation. Transplantation. 2006. 81:1677–1685.

32. Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham-Rundles S, Dupont B, Hodes MZ, Good RA, O'Reilly RJ. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood. 1983. 61:341–348.

33. Fischer A, Durandy A, de Villartay JP, Vilmer E, Le Deist F, Gerota I, Griscelli C. HLA-haploidentical bone marrow transplantation for severe combined immunodeficiency using E rosette fractionation and cyclosporine. Blood. 1986. 67:444–449.

34. Haddad E, Landais P, Friedrich W, Gerritsen B, Cavazzana-Calvo M, Morgan G, Bertrand Y, Fasth A, Porta F, Cant A, Espanol T, Muller S, Veys P, Vossen J, Fischer A. Long-term immune reconstitution and outcome after HLA-nonidentical T-cell-depleted bone marrow transplantation for severe combined immunodeficiency: a European retrospective study of 116 patients. Blood. 1998. 91:3646–3653.

35. Umeda K, Adachi S, Ishihara H, Higashi Y, Shiota M, Watanabe KI, Hishizawa M, Ichinohe T, Kitoh T, Maruya E, Saji H, Uchiyama T, Nakahata T. Successful T-cell-replete peripheral blood stem cell transplantation from HLA-haploidentical microchimeric mother to daughter with refractory acute lymphoblastic leukemia using reducedintensity conditioning. Bone Marrow Transplant. 2003. 31:1061–1063.

36. Fuchida S, Nakano S, Yamada N, Uchida R, Okano A, Okamoto M, Maruya E, Saji H, Shimazaki C. Successful non-T-cell-depleted HLA-haploidentical stem cell transplantation (SCT) with reduced-intensity conditioning from a second child for late graft failure after the first HLA-haploidentical SCT for MDS/overt leukemia based on feto-maternal microchimerism. Bone Marrow Transplant. 2005. 35:1031–1032.

37. Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM, Colby C, Sackstein R, Sachs DH, Spitzer TR. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet. 1999. 353:1755–1759.

38. Spitzer TR, McAfee SL, Dey BR, Colby C, Hope J, Grossberg H, Preffer F, Shaffer J, Alexander SI, Sachs DH, Sykes M. Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation. 2003. 75:1748–1751.

39. Ogawa H, Ikegame K, Yoshihara S, Kawakami M, Fujioka T, Masuda T, Taniguchi Y, Hasei H, Kaida K, Inoue T, Kim EH, Kawase I. Unmanipulated HLA 2-3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning. Biol Blood Marrow Transplant. 2006. 12:1073–1084.

40. Rizzieri DA, Koh LP, Long GD, Gasparetto C, Sullivan KM, Horwitz M, Chute J, Smith C, Gong JZ, Lagoo A, Niedzwiecki D, Dowell JM, Waters-Pick B, Liu C, Marshall D, Vredenburgh JJ, Gockerman J, Decastro C, Moore J, Chao NJ. Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution. J Clin Oncol. 2007. 25:690–697.

41. Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttrans-plantation cyclophosphamide. Biol Blood Marrow Transplant. 2008. 14:641–650.

42. Burroughs L, O'Donnell P, Sandmeier BM, Storer B, Luznik L, Symons H, Maris M, Blume KG, Niederwieser DW, Bruno B, Maziarz T, Pulsipher M, Petersen F, McSweeney PA, Chauncey T, Agura E, Wade JC, Storb RF, Fuchs EJ, Maloney DG. Comparison of allogeneic hematopoietic cell transplantation (HCT) after nonmy-eloablative conditioning with HLA-matched related (MRD), unrelated (URD), and related haploidentical (Haplo) donors for relapsed or refractory Hodgkins lymphoma (HL). Blood. 2007. 110:S. 58–59.

43. Lee KH, Lee JH, Kim DY, Kim SH, Shin HJ, Lee YS, Kang YA, Seol M, Ryu SG. Hematopoietic cell transplantation from an HLA-mismatched familial donor is feasible without ex vivo-T cell depletion after reduced-intensity conditioning with busulfan, fludarabine, and antithymocyte globulin. Biol Blood Marrow Transplant. 2009. 15:61–72.

44. Lowsky R, Takahashi T, Liu YP, Dejbakhsh-Jones S, Grumet FC, Shizuru JA, Laport GG, Stockerl-Goldstein KE, Johnston LJ, Hoppe RT, Bloch DA, Blume KG, Negrin RS, Strober S. Protective conditioning for acute graft-versus-host disease. N Engl J Med. 2005. 353:1321–1331.

45. Aizawa S, Sado T. Graft-versus-leukemia effect in MHC-compatible and-incompatible allogeneic bone marrow transplantation of radiation-induced, leukemia-bearing mice. Transplantation. 1991. 52:885–889.

46. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005. 105:3051–3057.

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