Abstract

Most patients who require allogeneic stem cell transplantation do not have a matched sibling donor, and many patients do not have a matched unrelated donor. In an effort to increase the applicability of transplantation, alternative donors such as mismatched adult unrelated donors, haploidentical related donors, and umbilical cord blood stem cell products are frequently used when a well matched donor is unavailable. We do not yet have the benefit of randomized trials comparing alternative donor stem cell sources to inform the choice of donor; however, the existing data allow some inferences to be made on the basis of existing observational and phase 2 studies. All 3 alternative donor sources can provide effective lymphohematopoietic reconstitution, but time to engraftment, graft failure rate, graft-versus-host disease, transplant-related mortality, and relapse risk vary by donor source. These factors all contribute to survival outcomes and an understanding of them should help guide clinicians when choosing among alternative donor sources when a matched related or matched unrelated donor is not available.

Introduction

The ability to perform hematopoietic stem cell transplantation (HSCT) hinges on the availability of a suitable donor. The best donor for HSCT is an HLA-matched sibling or unrelated donor. Unfortunately, on the basis of average family size, less than 30% of patients will have a matched sibling donor.1  As ethnic diversity increases in Europe and North America, it is imperative to have a strategy to identify an alternative stem cell source when an adult matched unrelated donor (MUD) cannot be identified. At present there are 3 alternative donor options: a partially HLA-mismatched unrelated donor (MMURD), a haploidentical related donor, and an umbilical cord blood (UCB) stem cell product.

The heterogeneity of patients in observational studies in the literature does not lend itself to direct comparisons of alternative donor sources. Until such studies as the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) randomized comparison of UCB and haploidentical transplantation (BMT-CTN 1101, NCT01597778) are complete, physicians are left to cautiously interpret the existing data in making these important decisions. There are patient-related, disease-related, and transplant protocol–related factors that together uniquely affect the clinical outcomes of an individual patient. Here we summarize the existing body of evidence in an effort to guide clinicians in using the current literature to help make a decision on donor source for an individual patient when a matched related donor (MRD) or MUD are unavailable.

Defining stem cell sources

MMURD transplantation

In this analysis, MMURD refers to an adult unrelated donor mismatched in at least one antigen or allele at HLA-A, -B, -C, or -DR. Mismatched related donor transplants are not included in this analysis. Older studies evaluated HLA compatibility on the basis of antigen matching, that is, by using anti-HLA antibodies or by low-resolution molecular typing. HLA typing precision improved to high-resolution molecular typing of the HLA locus, termed HLA allele matching, which became available over the last 2 decades. It is clear that allele-level typing gives more reliable results than antigen-level typing, so earlier observational studies using antigen level testing need to be interpreted cautiously. There is growing evidence that not all HLA mismatches are created equal. Permissive HLA mismatches seem to confer similar transplant-related outcomes when compared with matched donor sources, presumably reflecting the inability of the T cell to recognize an intrinsic HLA sequence difference,2  as well as the tendency of the mismatched HLA molecules to present similar minor histocompatibility proteins to the immune system. A nonpermissive HLA allele mismatch combination leads to poorer outcomes.2-6  MUD transplants increase donor availability but take time to organize because of donor screening and graft retrieval.

Haploidentical transplantation

In this review, haploidentical refers to a complete half mismatch (generally 3 of 6 or 4 of 8) from a related donor. These transplants have the advantage of speed because relatives are usually easy to contact for stem cell collection. The cost of collection is generally lower than in MMURD and UCB products. The major disadvantage of haploidentical donors is the HLA disparity. In T-cell–depleted haploidentical grafts, selection of a maternal over a paternal donor has been shown to result in better survival, because the maternal immune system is tolerized to fetal antigens during pregnancy.7  The benefit of maternal versus paternal donor is not as clear in T-cell–replete grafts.8  The use of a haploidentical sibling with noninherited maternal antigens has been associated with lower transplant-related mortality (TRM) and better graft-versus-host disease (GVHD) outcomes when compared with haploidentical sibling donors with noninherited paternal antigens.8 

UCB transplantation

UCB stem cell products are cryopreserved and stored so they are readily available.9  The minimal number of T cells in a UCB product allows it to be used across HLA barriers. Typically UCB stem cell products are HLA mismatched at 1 to 6 antigens or alleles. The disadvantage is the small size of the product, which limits the stem cell dose in adults and often requires the use of a second UCB product. UCB units are also expensive because each unit must be bought from a bank that needs to recoup the costs of typing, cryopreservation, and storage.

Engraftment failure

When comparable conditioning regimens and cellular products are used, total nucleated cell (TNC) dose, engraftment time, and reliability with MMURD, MRD, MUD, and haploidentical donors are similar.10-12  UCB products have the lowest effective cell dose based on the amount collected and losses incurred during cryopreservation and thawing. The median TNCs and CD34+ cells infused from a single UCB product is between 1.0 and 3.3 × 107 cells per kilogram and 0.74 and 1.2 × 105 cells per kilogram, respectively.13-18  This is 10-fold fewer stem cells compared with adult donor stem cell products. In situations where body size is large, a strategy to increase the effective stem cell dose by the use of two UCB products is generally adopted. This increases the TNC and CD34+ cell dose infused and reduces the duration of cytopenias in adults but still results in slower count recovery than anticipated in MMURD and haploidentical transplant recipients.19-21  One may reasonably anticipate at least a 7-day prolongation in time to neutrophil recovery in adults receiving a double UCB transplant when compared with peripheral blood reduced-intensity conditioning (RIC) MUD transplants (21.5 vs 13 days). Platelet recovery time is delayed from a median of 19 days in MUD to 41 days in UCB recipients.22  Research to expand stem cells in UCB units has demonstrated an improved engraftment time with these strategies,23,24  but this remains experimental.

Graft failure can be mediated by cellular or humoral immunity or it may reflect insufficient or damaged stem cells. Immunologically mediated rejection can be caused by sensitization of the recipient to nonshared HLA antigens. For instance, in all 3 alternative donor sources, the risk of graft failure is higher in transplant recipients who have donor-specific anti-HLA antibodies.25-27 

MMURD transplantation

There is an approximately 10% graft failure rate in MMURD transplants, significantly higher than that observed in MRD and MUD transplants.28-31  Similar to MUD transplants, the risk of graft failure is higher with bone marrow (BM) than with peripheral blood stem cells (PBSCs) as a graft source in MMURD transplants (16% with BM vs 3% with PBSCs).32,33  The direction or vector of the HLA mismatch may also be important. In patients with an HLA nonpermissive mismatch in the host-versus-graft vector, the risk of graft failure is increased when compared with permissive or MUD transplants.6 

Haploidentical transplantation

The Perugia group has reduced graft failure rates by increasing the CD34+ cell dose (so-called “mega-dose”) with a CD34+-selected PBSC graft, in which the median CD34+ cell dose was 13.8 × 106 cells per kilogram (range, 5.1 to 29.7 × 106 cells per kilogram).34  This results in a primary engraftment failure rate of 9%. Rizzieri et al35  observed a 6% graft failure rate in RIC haploidentical transplantation by infusing similarly large CD34+ cell doses (median, 13.5 × 106 cells per kilogram), but in contrast to the Perugia regimen, they used in vivo T-cell depletion with alemtuzumab. Huang et al36  used a combination of T-cell–replete BM and granulocyte colony-stimulating factor–primed PBSCs with an augmented myeloablative (MA) conditioning regimen that included anti-thymocyte globulin (ATG), which resulted in almost no primary engraftment failures. Drobyski et al11  also observed a low graft failure rate of 4% by using augmented conditioning with an ex vivo T-cell–depleted BM graft. In patients receiving the Hopkins strategy of posttransplant cyclophosphamide with a T-cell–replete graft, the graft failure rate is 10% in MA37  and 13% in RIC38  transplants.

UCB transplantation

In UCB transplantation, there are few passively transferred T cells from the donor to protect against graft rejection, and this may be more problematic because of the low TNC and CD34+ cell doses. Graft failure is close to 10% in RIC UCB transplantation21,39-41  and as high as 20% in MA UCB transplantation.16  If engraftment failure follows UCB transplant, there is no opportunity to return to the donor for more stem cells. Thus, either additional UCB needs to be used and the recipient must survive the additional period of cytopenias, or a haploidentical donor transplant may be attempted. Salvage RIC haploidentical transplantation has been used with some success after graft failure from UCB transplantation.42 

Conclusion

UCB transplant is associated with the highest engraftment failure rate. Furthermore, options after UCB infusion for graft failure are limited because returning to the donor is not an option. Small studies have shown that haploidentical stem cells can be infused at the time of UCB transplant or at evidence of graft failure to promote engraftment.43,44  In recent years, the graft failure rate in haploidentical transplantation has improved to levels comparable to those of MUD, MRD, and MMURD. If graft rejection does occur after haploidentical transplantation, it is also difficult to retransplant patients who have become sensitized to unshared alleles or antigens. Graft failure rates for alternative donor transplants are summarized in Tables 1 and 2.45-57 

Table 1

Transplant-related outcomes with MA conditioning

Reference No. of patients Graft T-cell depletion GVHD prophylaxis Graft failure (%) aGVHD grade 2 to 4 (%) aGVHD grade 3 to 4 (%) cGVHD (%) 
MMURD         
 28 28 70% BM ATG NR 27 NR NR 
 31 49 41% BM ATG or alemtuzumab CSA, MTX 14 46 NR 28 
 11 58 BM ATG, TCD CSA 46 NR 51 
 45 201 BM TCD CSA, steroid 13 NR 15 
 61 24 PBSC ATG None 34 NR 20 
 59 985 BM 24% TCD CNI based 13 NR 37 36 
 65 52 65% BM  CNI, MTX NR 85 37 48 
 29 465 60% BM  CSA, MTX 40 21 NR 
 64 118 NR  CNI based 55 28 60 
 63 334 BM  NR NR 54 24 NR 
 30 60 PB or BM  CSA, MTX 13 70 NR 60 
 68 144 70% BM  CSA, MTX 57 NR 37 
 13 83 BM  CSA based NR 52 NR 40 
Haploidentical         
 46 80 BM ATG CSA, MTX, MMF, baxilizumab 1.35 24 17 
 47 27 BM TCD TAC, MMF, CY NR 16 
 11 48 BM ATG, TCD CSA 42 NR 50 
 36 250 BM + PBSC ATG CSA, MTX, MMF 58 13 52 
 48 135 PBSC or BM ATG CSA, MMF, MTX NR 40 55 
 34 104 PBSC ATG None 
 73 756 BM + PBSC  CSA, MTX, MMF 43 14 53 
 37 50 BM  CSA, MMF, CY 10 12 NR 26 
 49 20 PBSC  TAC, MMF 30 10 35 
UCB         
 16 98 Single ATG CSA, steroid 20 26 13 30 
 80 165 Single ATG NR NR 27 NR 21 
 17 49 Single ATG CSA, MMF, or steroid 26 15 30 
 18 31 Single ATG CSA, steroid 44 17 44 
 88 514 Single  NR NR NR 36 NR 
 14 77 Single  CSA, MTX 82 25 93 
 79 100 Single  CSA, MTX 51 89 
 13 150 Single  CSA based NR 41 NR 51 
 65 128 Double  CNI, MTX NR 53 22 26 
 20 26 Double  CSA, MMF NR 65 13 23 
Reference No. of patients Graft T-cell depletion GVHD prophylaxis Graft failure (%) aGVHD grade 2 to 4 (%) aGVHD grade 3 to 4 (%) cGVHD (%) 
MMURD         
 28 28 70% BM ATG NR 27 NR NR 
 31 49 41% BM ATG or alemtuzumab CSA, MTX 14 46 NR 28 
 11 58 BM ATG, TCD CSA 46 NR 51 
 45 201 BM TCD CSA, steroid 13 NR 15 
 61 24 PBSC ATG None 34 NR 20 
 59 985 BM 24% TCD CNI based 13 NR 37 36 
 65 52 65% BM  CNI, MTX NR 85 37 48 
 29 465 60% BM  CSA, MTX 40 21 NR 
 64 118 NR  CNI based 55 28 60 
 63 334 BM  NR NR 54 24 NR 
 30 60 PB or BM  CSA, MTX 13 70 NR 60 
 68 144 70% BM  CSA, MTX 57 NR 37 
 13 83 BM  CSA based NR 52 NR 40 
Haploidentical         
 46 80 BM ATG CSA, MTX, MMF, baxilizumab 1.35 24 17 
 47 27 BM TCD TAC, MMF, CY NR 16 
 11 48 BM ATG, TCD CSA 42 NR 50 
 36 250 BM + PBSC ATG CSA, MTX, MMF 58 13 52 
 48 135 PBSC or BM ATG CSA, MMF, MTX NR 40 55 
 34 104 PBSC ATG None 
 73 756 BM + PBSC  CSA, MTX, MMF 43 14 53 
 37 50 BM  CSA, MMF, CY 10 12 NR 26 
 49 20 PBSC  TAC, MMF 30 10 35 
UCB         
 16 98 Single ATG CSA, steroid 20 26 13 30 
 80 165 Single ATG NR NR 27 NR 21 
 17 49 Single ATG CSA, MMF, or steroid 26 15 30 
 18 31 Single ATG CSA, steroid 44 17 44 
 88 514 Single  NR NR NR 36 NR 
 14 77 Single  CSA, MTX 82 25 93 
 79 100 Single  CSA, MTX 51 89 
 13 150 Single  CSA based NR 41 NR 51 
 65 128 Double  CNI, MTX NR 53 22 26 
 20 26 Double  CSA, MMF NR 65 13 23 

CNI, calcineurin inhibitor; CSA, cyclosporine A; CY, cyclophosphamide; MMF, mycophenolate mofetil; MTX, methotrexate; NR, not reported; PB, peripheral blood; TAC, tacrolimus; TCD, T-cell depletion.

Table 2

Transplant-related outcomes with RIC conditioning

Reference No. of patients Graft T-cell depletion GVHD prophylaxis Graft failure (%) aGVHD grade 2 to 4 (%) aGVHD grade 3 to 4 (%) cGVHD (%) 
MMURD         
 50 59 PBSC Alemtuzumab CSA, MMF 69 26 41 
 51 45 PBSC  TAC, MTX, bortezomib 22 29 
Haploidentical         
 35 49 PBSC Alemtuzumab CSA, MMF 16 14 
 52 26 PBSC ATG TAC, steroid 40 NR 25 
 53 61 PBSC OKT-3, TCD MMF 46 NR 18 
 86 83 PBSC ATG CSA, MTX 20 34 
 54 66 PBSC ATG TAC, steroid NR 33 
 55 33 BM + PBSC ATG CSA, MMF, anti-CD25 31 
 77 33 PB ATG TAC, MMF, CY NR 20 NR 
 77 32 BM  TAC, MMF, CY NR 11 NR 18 
 78 28 BM  CNI, MMF NR 43 11 35 
 38 68 BM  TAC, MMF, CY 13 34 25 
 40 50 BM  TAC, MMF, CY 32 13 
 56 53 60% BM  TAC, MMF 30 11 38 
UCB         
 22 64 Double ATG TAC based NR 14 22 
 19 32 Double ATG Sirolimus, TAC 13 
 91 65 Double ATG CSA, MMF NR 57 25 19 
 41 43 Double ATG CSA, MMF 11 49 NR 17 
 39 110 Double ATG CSA, MMF 59 22 23 
 21 21 Double ATG CSA, MMF 10 40 31 
 57 104 75% Single 46% ATG CSA based NR 24 18 
 40 50 Double  CNI, MMF 12 40 21 25 
 83 30 Single  CSA 27 23 23 
 90 1072 Single  NR NR 46 NR 28 
 15 119 Single or double  CSA, MMF NR 47 (RIC); 67 (MA) 16 (RIC); 31 (MA) 30 (RIC); 34 (MA) 
Reference No. of patients Graft T-cell depletion GVHD prophylaxis Graft failure (%) aGVHD grade 2 to 4 (%) aGVHD grade 3 to 4 (%) cGVHD (%) 
MMURD         
 50 59 PBSC Alemtuzumab CSA, MMF 69 26 41 
 51 45 PBSC  TAC, MTX, bortezomib 22 29 
Haploidentical         
 35 49 PBSC Alemtuzumab CSA, MMF 16 14 
 52 26 PBSC ATG TAC, steroid 40 NR 25 
 53 61 PBSC OKT-3, TCD MMF 46 NR 18 
 86 83 PBSC ATG CSA, MTX 20 34 
 54 66 PBSC ATG TAC, steroid NR 33 
 55 33 BM + PBSC ATG CSA, MMF, anti-CD25 31 
 77 33 PB ATG TAC, MMF, CY NR 20 NR 
 77 32 BM  TAC, MMF, CY NR 11 NR 18 
 78 28 BM  CNI, MMF NR 43 11 35 
 38 68 BM  TAC, MMF, CY 13 34 25 
 40 50 BM  TAC, MMF, CY 32 13 
 56 53 60% BM  TAC, MMF 30 11 38 
UCB         
 22 64 Double ATG TAC based NR 14 22 
 19 32 Double ATG Sirolimus, TAC 13 
 91 65 Double ATG CSA, MMF NR 57 25 19 
 41 43 Double ATG CSA, MMF 11 49 NR 17 
 39 110 Double ATG CSA, MMF 59 22 23 
 21 21 Double ATG CSA, MMF 10 40 31 
 57 104 75% Single 46% ATG CSA based NR 24 18 
 40 50 Double  CNI, MMF 12 40 21 25 
 83 30 Single  CSA 27 23 23 
 90 1072 Single  NR NR 46 NR 28 
 15 119 Single or double  CSA, MMF NR 47 (RIC); 67 (MA) 16 (RIC); 31 (MA) 30 (RIC); 34 (MA) 

OKT-3, monoclonal anti-CD3 antibody.

GVHD

MMURD transplantation

The HLA disparity that results in high engraftment failure rates with alternative donors also results in a higher rate of GVHD. Woolfrey et al58  examined MMURD with PBSCs as a graft source and found an increased risk of acute grade 3 to 4 GVHD with single-allele MMURD when compared with matched transplants (relative risk [RR], 1.59; 95% CI, 1.20 to 2.09) but no difference in chronic GVHD (cGVHD). A similar study by Lee et al59  in patients receiving a BM graft showed that single-allele MMURD transplants had more grade 3 to 4 acute GVHD (aGVHD) (RR, 1.34; 95% CI, 1.12 to 1.61) than MUD transplants. The majority of patients in these studies received MA conditioning, but a similar increase in aGVHD and not cGVHD has been observed with RIC MMURD when compared with MUD transplants.60 

In MA PBSC or marrow MMURD transplants, adding ATG to calcineurin inhibitors for GVHD prophylaxis results in a rate of grade 2 to 4 aGVHD of 30% to 40%.11,28,61,62  In contrast, calcineurin inhibitor–based GVHD prophylaxis without ATG in MMURD transplants results in aGVHD rates of 50% to 80%.29,63-65 

HLA class I allele mismatched as well as HLA-DRB1 allele mismatched transplants are associated with higher rates of aGVHD when compared with MUD transplants.58,64,66  The difference in cGVHD between MMURD and MUD transplants is not as clear, but some reports do show a higher risk of cGVHD with HLA class I mismatched transplants.64,67,68  In contrast, HLA-DQ and HLA-DP mismatches have not always been shown to worsen clinical outcomes when compared with matched donor recipients.31,58,59  In patients who are otherwise matched at HLA-A, -B, -C, and -DRB1, there is no survival difference if there is an HLA-DQ mismatch, but HLA-DQ mismatch may worsen outcomes in patients who already have a 1- or 2-allele HLA mismatch.59  HLA-DPB1 mismatches are associated with lower relapse rates but with an associated increase in GVHD and TRM.69-71  HLA-C mismatched donor transplants have been associated with worse survival when compared with HLA-C matched donor transplants, likely because of more severe aGVHD.72 

Haploidentical transplantation

In studies using high-intensity conditioning by adding cytarabine and semustine to cyclophosphamide and busulfan or total-body irradiation, graft failure rates have been low, but aGVHD has been 40% to 60%, despite the use of ATG.11,36,73  Although Perugia used mega-doses of CD34+-selected stem cells, the alternative approach of using ATG for GVHD prophylaxis and standard MA conditioning demonstrated low rates of aGVHD and cGVHD (8% and 3%, respectively) but with higher graft failure rates34  as described in the “Engraftment failure” section. Both approaches continue to have drawbacks: slow posttransplant immune reconstitution in patients who receive T-cell–depleted transplants and aGVHD and cGVHD in those who receive T-cell–replete grafts.74  In RIC haploidentical transplantation, the Johns Hopkins group pioneered the use of posttransplant cyclophosphamide in an effort to reduce GVHD rates. This approach has proven to be very effective, requiring no stem cell manipulation, a simple marrow collection, and well-tolerated conditioning with modest toxicity. The rate of acute grade 2 to 4, acute grade 3 to 4, and cGVHD was 34%, 6%, and 5%, respectively.38 

UCB transplantation

The less stringent HLA matching needed when selecting a UCB unit for transplantation is not associated with an increased risk of GVHD-related mortality. The risk of aGVHD appears to be slightly lower with the use of ATG with MA conditioning, but this difference is not as appreciable with RIC UCB transplants (Tables 1 and 2).

Grade 2 to 4 aGVHD was significantly higher in MMURD (85%) compared with UCB transplants (53%) at 100 days after HSCT for hematologic malignancies, but grade 3 to 4 aGVHD was not significantly different.65  Similarly, cGVHD rates at 2 years after HSCT were significantly higher for MMURD transplantation when compared with UCB transplants (48% vs 26%, respectively). Smaller studies have not been able to show an appreciable difference in GVHD rates after UCB or MMURD transplantation.75,76 

In parallel phase 2 trials of UCB or haploidentical transplantation using posttransplantation cyclophosphamide conducted by the BMT-CTN, the grade 2 to 4 GVHD rate was 40% for UCB transplants recipients and 32% for haploidentical transplant recipients. The grade 3 to 4 aGVHD rates were 21% and 0% for UCB and haploidentical transplants, respectively. cGVHD was also higher in UCB transplants: 25% compared with 13% at 1 year after transplant.40 

Conclusion

GVHD is most frequent in MMURD transplants and is comparable between UCB and haploidentical transplants when posttransplant cyclophosphamide is used for the latter. Studies in alternative donor transplants use a variety of GVHD prophylaxis strategies, which complicates a comparative analysis. With the high degree of HLA mismatch in haploidentical transplants, novel techniques to reduce GVHD are necessary such as high stem cell doses, in vivo or ex vivo T-cell depletion, and posttransplant cyclophosphamide. None of these strategies have been compared directly with each other, and the risk of graft failure needs to be weighed against the benefit of graft-versus-leukemia effect in each of these strategies. Tables 1 and 2 summarize GVHD rates in alternative donor transplants.

TRM

The reported TRM is highly variable and likely accounted for by the diversity in conditioning regimens, underlying disease, use of PBSCs or BM, and comorbidities at time of transplantation. Most studies do not account for these differences when reporting an overall TRM.

MMURD transplantation

Multiple studies have demonstrated that the long-term nonrelapse mortality is significantly higher in MMURD when compared with MUD transplants. In a large Center for International Blood and Marrow Transplant Research (CIBMTR) study of more than 4000 patients receiving a transplant for chronic myeloblastic leukemia in chronic phase, the 5-year TRM was 31% in MRD, 38% in MUD, 50% in 1 HLA class I MMURD, and 48% in 1 HLA class II MMURD.67  In another large retrospective study of 1800 patients, the RR of an allele MMURD was 1.4 (95% CI, 1.09 to 1.81) when compared with HLA allele-MUDs,58  and this observation is consistent among other studies.29,59,64 

Haploidentical transplantation

In a study of patients receiving MA conditioning for a haploidentical transplant with ex vivo T-cell–depleted BM, the 2-year TRM in haploidentical transplants was 42%, which was not significantly different from MMURD (45%) but significantly higher than MUD transplants (23%).11  In a more recent analysis by Wang et al12  in which patients with acute monoblastic leukemia (AML) or acute lymphoblastic leukemia received MA conditioning with ATG as part of GVHD prophylaxis, there was no appreciable difference in TRM between haploidentical (34%) and MRD transplant recipients (38%) at 2 years after transplant. Another study examined the impact of T-cell depletion with ATG on transplant outcomes and found that the use of ATG increased the TRM significantly from 16% to 42%.77  In patients receiving the Perugia regimen, the TRM was 36.5%,34  mostly because of infection, which reflected impaired T-cell immune reconstitution. In patients receiving posttransplant cyclophosphamide without ATG to prevent GVHD, the TRM has been reported as 16% at 100 days after transplant.37 

In heavily pretreated patients with Hodgkin disease, the TRM with RIC haploidentical transplant was 8% at 2 years, significantly better than MUD and MRD transplants in the study by Burroughs et al.78  Low TRM has also been reported in RIC haploidentical transplants for patients receiving posttransplant cyclophosphamide (4% to 6%).38,40  A small study in high-risk patients with AML who received RIC haploidentical transplantation did not demonstrate a difference in TRM when compared with MMURD transplants (10.1% vs 17.9%, respectively).10 

UCB transplantation

Long-term TRM of UCB transplants has been comparable to MUD and MRD transplants in some studies,13,41,79  but the upfront mortality associated with UCB transplants is higher.80,81  Small studies that have compared TRM of UCB to MMURD could not demonstrate a significant difference, but these were small studies that were likely underpowered.65,76 

The TRM in RIC UCB transplant recipients is reportedly higher than that observed in MUD and haploidentical transplants. In a study of 2 phase 2 parallel trials, the 2-year TRM with UCB was 24% compared with 7% in haploidentical transplant recipients.40  It is difficult to compare stem cell sources because this was not a randomized trial, and posttransplant immune suppression differed by stem cell source. Nevertheless, the data do suggest that early TRM with UCB is higher than that with haploidentical transplants. This is likely due to the slower UCB transplant lymphohematopoietic reconstitution.82  This higher rate of TRM in UCB is also observed when compared with MUD transplants.21,22,39,41,83 

Conclusion

In all alternative donor transplants, the TRM is generally higher than that observed in matched donor transplants when similar conditioning regimens are used. In the MA setting, the TRM from haploidentical and UCB transplants is comparable with that for MMURD transplants. RIC reduces the risk of TRM in haploidentical and UCB transplants. Comparing RIC haploidentical and UCB transplants suggests that UCB has a higher TRM than haploidentical transplants, likely related to the slower engraftment and risk of infection-related fatality with UCB. Tables 3 and 4 summarize TRM rates in alternative donor transplants.

Table 3

Survival outcomes with MA conditioning

Reference No. of patients Graft OS DFS TRM 
MMURD      
 28 28 70% BM 19% at 3 y 19% at 3 y 40% at 3 y 
 45 201 BM 19% at 5 y 18% at 5 y 51% at 5 y 
 13 83 BM 20% at 3 y 19% at 3 y 65% at 3 y 
 59 985 >93% BM 29% at 5 y 38% at 1 y 45% at 1 y 
 84 1854 60% BM 30% at 5 y 30% at 5 y 30% at 5 y 
 30 60 BM or PB 35% at 5 y 30% at 5 y 42% at 5 y 
 68 144 BM 38% at 3 y 40% at 3 y NR 
 61 24 PB 40% at 2 y 40% at 2 y 35% at 1 y 
 67 215 BM or PB 40% at 5 y 38% at 5 y 50% at 5 y 
 31 49 40% BM 64% at 5 y 45% at 5 y 24% at 2 y 
 65 52 65% BM NR 38% at 5 y 27% at 5 y 
Haploidentical      
 11 48 BM 21% at 2 y NR 42% at 2 y 
 34 104 PB 40% at 22 mo 25% at 6 mo 36.5% at 1 y 
 46 80 BM 45% at 3 y 38% at 3 y 36% at 3 y 
 47 27 BM 48% at 3 y NR 11% at 3 y 
 37 50 BM 62% at 1.5 y 51% at 1.5 y 16% at 100 d 
 73 756 BM + PB 67% at 3 y 63% at 3 y 18% at 3 y 
 49 20 PBSC 69% at 20 mo 40% at 20 mo 10% at 100 d 
 86 132 BM + PB 77.5% at 4 y 73.1% at 4 y NR 
UCB      
 13 150 Single 26% at 3 y 23% at 3 y 63% at 3 y 
 16 98 Single 36% at 2 y 33% at 2 y 44% at 2 y 
 88 514 Single 37% at 1 y 51% at 1 y 34% at 1 y 
 18 31 Single 37% at 3 y 37% at 3 y NR 
 80 165 Single NR 53% at 2.5 y 19% at 2.5 y 
 17 49 Single NR 42% at 2 y 39% at 2 y 
 14 77 Single NR 63% at 5 y 9.7% at 5 y 
 79 100 Single NR 70% at 3 y 9% at 1 y 
 65 128 Double NR 51% at 5 y 34% at 5 y 
Reference No. of patients Graft OS DFS TRM 
MMURD      
 28 28 70% BM 19% at 3 y 19% at 3 y 40% at 3 y 
 45 201 BM 19% at 5 y 18% at 5 y 51% at 5 y 
 13 83 BM 20% at 3 y 19% at 3 y 65% at 3 y 
 59 985 >93% BM 29% at 5 y 38% at 1 y 45% at 1 y 
 84 1854 60% BM 30% at 5 y 30% at 5 y 30% at 5 y 
 30 60 BM or PB 35% at 5 y 30% at 5 y 42% at 5 y 
 68 144 BM 38% at 3 y 40% at 3 y NR 
 61 24 PB 40% at 2 y 40% at 2 y 35% at 1 y 
 67 215 BM or PB 40% at 5 y 38% at 5 y 50% at 5 y 
 31 49 40% BM 64% at 5 y 45% at 5 y 24% at 2 y 
 65 52 65% BM NR 38% at 5 y 27% at 5 y 
Haploidentical      
 11 48 BM 21% at 2 y NR 42% at 2 y 
 34 104 PB 40% at 22 mo 25% at 6 mo 36.5% at 1 y 
 46 80 BM 45% at 3 y 38% at 3 y 36% at 3 y 
 47 27 BM 48% at 3 y NR 11% at 3 y 
 37 50 BM 62% at 1.5 y 51% at 1.5 y 16% at 100 d 
 73 756 BM + PB 67% at 3 y 63% at 3 y 18% at 3 y 
 49 20 PBSC 69% at 20 mo 40% at 20 mo 10% at 100 d 
 86 132 BM + PB 77.5% at 4 y 73.1% at 4 y NR 
UCB      
 13 150 Single 26% at 3 y 23% at 3 y 63% at 3 y 
 16 98 Single 36% at 2 y 33% at 2 y 44% at 2 y 
 88 514 Single 37% at 1 y 51% at 1 y 34% at 1 y 
 18 31 Single 37% at 3 y 37% at 3 y NR 
 80 165 Single NR 53% at 2.5 y 19% at 2.5 y 
 17 49 Single NR 42% at 2 y 39% at 2 y 
 14 77 Single NR 63% at 5 y 9.7% at 5 y 
 79 100 Single NR 70% at 3 y 9% at 1 y 
 65 128 Double NR 51% at 5 y 34% at 5 y 

DFS, disease-free survival.

Table 4

Survival outcomes with RIC conditioning

Reference No. of patients Graft OS DFS TRM 
MMURD      
 50 59 PB 29% at 2 y 28% at 2 y 36% at 1 y 
 51 45 PB 64% at 2 y 51% at 2 y 11% at 2 y 
Haploidentical      
 53 61 PB 28% at 2 y 25% at 2 y 42% at 2 y 
 35 49 PB 31% at 1 y 43% at 1 y 10.2% at 100 d 
 38 68 BM 36% at 2 y 26% at 2 y 15% at 1 y 
 78 28 BM 58% at 2 y 51% at 2 y 8% at 2 y 
 87 16 PB 60% at 2 y 60% at 2 y 18% at 2 y 
 40 50 BM 62% at 1 y 48% at 1 y 7% at 1 y 
 56 53 60% BM 64% at 2 y 60% at 2 y 7% at 2 y 
UCB      
 83 30 Single 33% at 1 y 22% at 1 y 27% at 100 d 
 41 43 Double 34% at 3 y 34% at 3 y 28% at 6 mo 
 39 110 Double 45% at 3 y 38% at 3 y 26% at 3 y 
 22 64 Double 46% at 3 y 30% at 3 y 27% at 3 y 
 57 104 75% Single 48% at 1 y 40% at 1 y 28% at 1 y 
 19 32 Double 53% at 2 y 31.2% at 2 y 34% at 2 y 
 40 50 Double 54% at 1 y 46% at 1 y 24% at 1 y 
 91 65 Double 55% at 3 y 34% at 3 y 15% at 3 y 
 21 21 Double 71% at 2 y 55% at 2 y 19% at 6 mo 
Reference No. of patients Graft OS DFS TRM 
MMURD      
 50 59 PB 29% at 2 y 28% at 2 y 36% at 1 y 
 51 45 PB 64% at 2 y 51% at 2 y 11% at 2 y 
Haploidentical      
 53 61 PB 28% at 2 y 25% at 2 y 42% at 2 y 
 35 49 PB 31% at 1 y 43% at 1 y 10.2% at 100 d 
 38 68 BM 36% at 2 y 26% at 2 y 15% at 1 y 
 78 28 BM 58% at 2 y 51% at 2 y 8% at 2 y 
 87 16 PB 60% at 2 y 60% at 2 y 18% at 2 y 
 40 50 BM 62% at 1 y 48% at 1 y 7% at 1 y 
 56 53 60% BM 64% at 2 y 60% at 2 y 7% at 2 y 
UCB      
 83 30 Single 33% at 1 y 22% at 1 y 27% at 100 d 
 41 43 Double 34% at 3 y 34% at 3 y 28% at 6 mo 
 39 110 Double 45% at 3 y 38% at 3 y 26% at 3 y 
 22 64 Double 46% at 3 y 30% at 3 y 27% at 3 y 
 57 104 75% Single 48% at 1 y 40% at 1 y 28% at 1 y 
 19 32 Double 53% at 2 y 31.2% at 2 y 34% at 2 y 
 40 50 Double 54% at 1 y 46% at 1 y 24% at 1 y 
 91 65 Double 55% at 3 y 34% at 3 y 15% at 3 y 
 21 21 Double 71% at 2 y 55% at 2 y 19% at 6 mo 

Relapse rates

MMURD transplantation

In MMURD, regardless of the indication for transplant and the conditioning regimen, patients generally have relapse rates comparable to those of MUD and MRD transplant recipients. A large retrospective CIBMTR analysis compared 521 patients who received a 1 or more allele MMURD to 3514 patients who received an MRD transplant. Relapse rates at 5 years were 14% in MRD, 12% in MUD, 11% in single class I mismatch and 9% in single class II mismatched donors, and these were not significantly different in multivariate analysis.67 

Haploidentical transplantation

Relapse in haploidentical transplants is highly variable based on the GVHD and graft failure strategies used. In patients receiving an RIC haploidentical transplant with posttransplant cyclophosphamide to reduce GVHD, the relapse rate was 45% at 1 year after transplant.40  The relapse rate for MA haploidentical transplant with posttransplant cyclophosphamide was 22% at a median follow-up of about 11 months, suggesting that the higher intensity conditioning can improve relapse rates in patients receiving posttransplant cyclophosphamide. In patients receiving the Perugia regimen, the cumulative incidence of relapse at 6 months was 25% for all patients but was significantly higher in patients transplanted in relapse (51%) when compared with those transplanted in remission (16%).34 

UCB transplantation

Patients receiving MA UCB transplants are associated with a lower risk of relapse (16%) when compared with matched and mismatched transplants (37% to 52%).65  In patients receiving an RIC double UCB transplant, the 1-year relapse incidence was 31%. This appeared to be lower than the 45% observed in the parallel haploidentical transplant study40 ; however, patients who received UCB had a higher TRM. Therefore, the relapse rates are not directly comparable, because more haploidentical patients were at risk for relapse.

Conclusion

Disease risk stratification and status at time of transplantation are ultimately very important in determining risk of relapse or progression after transplant, and it is difficult to compensate for these issues in noncomparative trials.

OS

MMURD transplantation

A large retrospective study of about 1300 patients receiving an HSCT for malignant hematologic diseases showed a 3-year survival of 40% in MMURD, a 20% disadvantage when compared with MUD transplants.64  This relationship has been observed in multiple other studies of MMURD compared with matched donor sources (Tables 3 and 4). When comparing RIC and MA conditioning regimens, Woolfrey et al58  were not able to demonstrate a difference in survival based on regimen intensity. Woolfrey et al went on to compare the results of their study with PBSC MMURD, and the results were reported by Lee et al59  in which patients had a similar MMURD transplant but with a BM graft. No difference in overall survival (OS) was observed in single-antigen MMURD transplants with PBSCs when compared with single-antigen MMURD with BM (RR, 1.13; 95% CI, 0.93 to 1.40).

In RIC MMURD transplants, the OS difference when compared with matched donor sources is not as clear. Koreth et al60  recently reported a large retrospective analysis of the CIBMTR in which a 3-year OS of 30.9% for RIC-allele MMURD was seen, significantly lower than that observed in MUD transplants (37.4%). A CIBMTR analysis of patients with non-Hodgkin lymphoma receiving RIC MMURD transplant showed that older age, shorter time from diagnosis to transplant, non–total-body irradiation conditioning regimen, ex vivo T-cell depletion, and HLA mismatch were associated with mortality.85 

Haploidentical transplantation

The largest analysis to date in 756 adults receiving an MA haploidentical transplant for AML, chronic myeloblastic leukemia, or acute lymphoblastic leukemia had an excellent 3-year OS of 67%.73  In patients with intermediate- or high-risk AML in first complete remission (CR1), 4-year OS was 77.5% and was significantly better than that for patients receiving chemotherapy alone.86  Other studies have demonstrated similar survival outcomes with MA haploidentical transplants (Tables 3 and 4). When compared with patients who received MUD and MMURD transplants, patients who received a haploidentical transplant with an ex vivo T-cell–depleted BM graft had an OS at 2 years of 21%, significantly lower than both MUD (58%) and single-antigen MMURD (34%),11  indicating that GVHD prevention strategy is an important variable.

In 83 patients with AML or myelodysplastic syndrome who received RIC haploidentical transplants with busulfan and fludarabine, including ATG as part of GVHD prophylaxis,87  OS at a median follow up of 26 months was 60% in leukemia in CR1, 53% in CR2 and CR3, and 53% in myelodysplastic syndrome. Patients with refractory leukemia had a significantly lower OS at 9%. In high-risk patients with AML who received RIC haploidentical transplants and ATG for GVHD prophylaxis, 3-year OS was 65.7%,10  comparable to that in patients receiving a well-matched or partially matched MA HSCT in that study. In refractory or relapsed patients with Hodgkin disease, for most of whom a previous autologous transplant had failed, no difference in OS at 2 years was observed in MRD, MUD, or haploidentical transplants with RIC.78 Table 4 summarizes the reported OS rates in RIC haploidentical transplants.

UCB transplantation

In two studies of patients receiving MA UCB transplants compared with MMURD transplants, the 3-year OS was 66% for UCB, significantly higher than that for MMURD transplants. In both studies, the TRM was lower and progression-free survival was higher with UCB compared with MMURD.75,76  A CIBMTR observational analysis was not able to show a significant OS difference between UCB and MMURD transplants in patients receiving MA conditioning.13  In another study of UCB MA conditioning that included more than 500 patients, a 1-year OS of 37% was observed.88  Other studies that reported OS in UCB HSCT with MA conditioning are summarized in Table 3. As in MMURD, the direction of HLA mismatch may be important in UCB transplantation. Unidirectional mismatch in the graft-versus-host direction alone may result in less TRM and better OS when compared with host-versus-graft unidirectional mismatches and bidirectional mismatches.89 

OS in patients receiving RIC UCB is between 34% and 63% in patients with hematologic malignancies.39,41,90,91  In the BMT-CTN phase 2 parallel studies of UCB and haploidentical transplants, UCB appeared to have higher TRM (24% vs 7%) with comparable disease-free survival rates, resulting in an apparent OS benefit with haploidentical transplants (62% vs 54% with UCB transplants) at 1 year after transplantation. More TRM has also been observed with UCB transplants compared with MUD transplants, but similar disease-free survival and OS rates were observed.22 

Conclusion

OS is a compound outcome of transplant-related complications and disease relapse. Patients receiving an MMURD have a higher rate of TRM than those receiving matched donor transplants, resulting in an overall lower OS. The range of OS rates after haploidentical transplants likely relates to the differences in transplant indication, severity of disease, and GVHD prophylaxis strategies. Compared with haploidentical and MMURD transplants, UCB transplantation results in higher TRM but similar progression-free survival and OS rates. Tables 3 and 4 summarize survival outcomes in alternative donor transplants.

Making a decision

Despite the large number of phase 2 and observational studies in the literature, the dearth of randomized trials makes the prioritization of an alternative donor difficult. The decision may in part reflect the research agenda of the transplantation center because no one source of stem cells is clearly superior to another. The anticipated outcomes of alternative donor transplantation are relatively predictable, and they are similar enough that randomized controlled trials will be critical to resolving the remaining issues. However, the large number of variables that influence outcomes makes it unrealistic to expect such trials to be conducted quickly enough or in large enough numbers to provide definitive recommendations. Nevertheless, there are themes that can be inferred by the current data to inform a decision.

If a donor is urgently required, UCB and haploidentical transplantation have the advantage over adult volunteer MMURD. In general, UCB products can be obtained promptly because they are cryopreserved and in inventory. Haploidentical family members are usually evaluated and scheduled for stem cell collection more promptly than unrelated donors. If upfront cost is a major concern, haploidentical donors have a clear advantage over both UCB products and MMURD. For patients who have had problems with Epstein-Barr virus, cytomegalovirus, or other infections, UCB may be less desirable because of both the delay in hematopoietic recovery and the lack of passively transferred cellular immunity. Strategies to speed hematopoietic recovery in UCB transplantation are very interesting, but they are unlikely to improve immunologic function, and they are likely to be quite expensive.

All MMURD transplants are not equal. Although in general, there is a higher risk of GVHD and outcomes similar to those of UCB and haploidentical transplantation, the ability to recognize permissive and nonpermissive mismatches and choosing donors with mismatches in the graft rejection direction rather than the GVHD direction may allow for graft vs leukemia effect with a risk of GVHD similar to that observed using matched donors.

Physicians are left with the current evidence to help them decide on what type of transplant would be best for their patient. Diagnosis, disease severity, disease status at time of transplant, conditioning regimens, graft source, and GVHD prophylaxis strategies are the factors that together influence clinical outcomes after transplantation. The outcomes have significantly improved with alternative donor transplantation, but much work remains to be done until they are proven to be noninferior to matched related and unrelated donor transplants.

Authorship

Contribution: N.K. and J.H.A. performed the literature review and wrote and edited the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Joseph H. Antin, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215; e-mail: jantin@partners.org.

References

References
1
Ballen
 
KK
King
 
RJ
Chitphakdithai
 
P
, et al. 
The national marrow donor program 20 years of unrelated donor hematopoietic cell transplantation.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
9 Suppl
(pg. 
2
-
7
)
2
Ferrara
 
GB
Bacigalupo
 
A
Lamparelli
 
T
, et al. 
Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain.
Blood
2001
, vol. 
98
 
10
(pg. 
3150
-
3155
)
3
Kawase
 
T
Morishima
 
Y
Matsuo
 
K
, et al. 
Japan Marrow Donor Program
High-risk HLA allele mismatch combinations responsible for severe acute graft-versus-host disease and implication for its molecular mechanism.
Blood
2007
, vol. 
110
 
7
(pg. 
2235
-
2241
)
4
Bacigalupo
 
A
A closer look at permissive HLA mismatch.
Blood
2013
, vol. 
122
 
22
(pg. 
3555
-
3556
)
5
Pidala
 
J
Wang
 
T
Haagenson
 
M
, et al. 
Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality.
Blood
2013
, vol. 
122
 
22
(pg. 
3651
-
3658
)
6
Fleischhauer
 
K
Locatelli
 
F
Zecca
 
M
, et al. 
Graft rejection after unrelated donor hematopoietic stem cell transplantation for thalassemia is associated with nonpermissive HLA-DPB1 disparity in host-versus-graft direction.
Blood
2006
, vol. 
107
 
7
(pg. 
2984
-
2992
)
7
Stern
 
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
, vol. 
112
 
7
(pg. 
2990
-
2995
)
8
van Rood
 
JJ
Loberiza
 
FR
Zhang
 
MJ
, et al. 
Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or an HLA-haploidentical sibling.
Blood
2002
, vol. 
99
 
5
(pg. 
1572
-
1577
)
9
Barker
 
JN
Krepski
 
TP
DeFor
 
TE
Davies
 
SM
Wagner
 
JE
Weisdorf
 
DJ
Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow.
Biol Blood Marrow Transplant
2002
, vol. 
8
 
5
(pg. 
257
-
260
)
10
Cho
 
BS
Yoon
 
JH
Shin
 
SH
, et al. 
Comparison of allogeneic stem cell transplantation from familial-mismatched/haploidentical donors and from unrelated donors in adults with high-risk acute myelogenous leukemia.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
10
(pg. 
1552
-
1563
)
11
Drobyski
 
WR
Klein
 
J
Flomenberg
 
N
, et al. 
Superior survival associated with transplantation of matched unrelated versus one-antigen-mismatched unrelated or highly human leukocyte antigen-disparate haploidentical family donor marrow grafts for the treatment of hematologic malignancies: establishing a treatment algorithm for recipients of alternative donor grafts.
Blood
2002
, vol. 
99
 
3
(pg. 
806
-
814
)
12
Wang
 
Y
Liu
 
DH
Xu
 
LP
, et al. 
Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
6
(pg. 
821
-
830
)
13
Laughlin
 
MJ
Eapen
 
M
Rubinstein
 
P
, et al. 
Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia.
N Engl J Med
2004
, vol. 
351
 
22
(pg. 
2265
-
2275
)
14
Ooi
 
J
Takahashi
 
S
Tomonari
 
A
, et al. 
Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
12
(pg. 
1341
-
1347
)
15
Oran
 
B
Wagner
 
JE
DeFor
 
TE
Weisdorf
 
DJ
Brunstein
 
CG
Effect of conditioning regimen intensity on acute myeloid leukemia outcomes after umbilical cord blood transplantation.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
9
(pg. 
1327
-
1334
)
16
Rocha
 
V
Labopin
 
M
Sanz
 
G
, et al. 
Acute Leukemia Working Party of European Blood and Marrow Transplant Group; Eurocord-Netcord Registry
Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia.
N Engl J Med
2004
, vol. 
351
 
22
(pg. 
2276
-
2285
)
17
Sanz
 
J
Sanz
 
MA
Saavedra
 
S
, et al. 
Cord blood transplantation from unrelated donors in adults with high-risk acute myeloid leukemia.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
1
(pg. 
86
-
94
)
18
van Heeckeren
 
WJ
Fanning
 
LR
Meyerson
 
HJ
, et al. 
Influence of human leucocyte antigen disparity and graft lymphocytes on allogeneic engraftment and survival after umbilical cord blood transplant in adults.
Br J Haematol
2007
, vol. 
139
 
3
(pg. 
464
-
474
)
19
Cutler
 
C
Stevenson
 
K
Kim
 
HT
, et al. 
Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis.
Bone Marrow Transplant
2011
, vol. 
46
 
5
(pg. 
659
-
667
)
20
Barker
 
JN
Weisdorf
 
DJ
DeFor
 
TE
, et al. 
Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy.
Blood
2005
, vol. 
105
 
3
(pg. 
1343
-
1347
)
21
Ballen
 
KK
Spitzer
 
TR
Yeap
 
BY
, et al. 
Double unrelated reduced-intensity umbilical cord blood transplantation in adults.
Biol Blood Marrow Transplant
2007
, vol. 
13
 
1
(pg. 
82
-
89
)
22
Chen
 
YB
Aldridge
 
J
Kim
 
HT
, et al. 
Reduced-intensity conditioning stem cell transplantation: comparison of double umbilical cord blood and unrelated donor grafts.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
5
(pg. 
805
-
812
)
23
de Lima
 
M
McNiece
 
I
Robinson
 
SN
, et al. 
Cord-blood engraftment with ex vivo mesenchymal-cell coculture.
N Engl J Med
2012
, vol. 
367
 
24
(pg. 
2305
-
2315
)
24
Delaney
 
C
Heimfeld
 
S
Brashem-Stein
 
C
Voorhies
 
H
Manger
 
RL
Bernstein
 
ID
Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution.
Nat Med
2010
, vol. 
16
 
2
(pg. 
232
-
236
)
25
Cutler
 
C
Kim
 
HT
Sun
 
L
, et al. 
Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation.
Blood
2011
, vol. 
118
 
25
(pg. 
6691
-
6697
)
26
Anasetti
 
C
Amos
 
D
Beatty
 
PG
, et al. 
Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.
N Engl J Med
1989
, vol. 
320
 
4
(pg. 
197
-
204
)
27
Yoshihara
 
S
Maruya
 
E
Taniguchi
 
K
, et al. 
Risk and prevention of graft failure in patients with preexisting donor-specific HLA antibodies undergoing unmanipulated haploidentical SCT.
Bone Marrow Transplant
2012
, vol. 
47
 
4
(pg. 
508
-
515
)
28
Ciurea
 
SO
Saliba
 
RM
Rondon
 
G
, et al. 
Outcomes of patients with myeloid malignancies treated with allogeneic hematopoietic stem cell transplantation from matched unrelated donors compared with one human leukocyte antigen mismatched related donors using HLA typing at 10 loci.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
6
(pg. 
923
-
929
)
29
Crocchiolo
 
R
Ciceri
 
F
Fleischhauer
 
K
, et al. 
HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: a study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry.
Bone Marrow Transplant
2009
, vol. 
44
 
9
(pg. 
571
-
577
)
30
Hasegawa
 
W
Lipton
 
JH
Messner
 
HA
, et al. 
Influence of one human leukocyte antigen mismatch on outcome of allogeneic bone marrow transplantation from related donors.
Hematology
2003
, vol. 
8
 
1
(pg. 
27
-
33
)
31
Hauzenberger
 
D
Schaffer
 
M
Ringdén
 
O
, et al. 
Outcome of haematopoietic stem cell transplantation in patients transplanted with matched unrelated donors vs allele-mismatched donors: a single centre study.
Tissue Antigens
2008
, vol. 
72
 
6
(pg. 
549
-
558
)
32
Anasetti
 
C
Logan
 
BR
Confer
 
DL
Blood and Marrow Transplant Clinical Trials Network
Peripheral-blood versus bone marrow stem cells.
N Engl J Med
2013
, vol. 
368
 
3
pg. 
288
 
33
Anasetti
 
C
Logan
 
BR
Lee
 
SJ
, et al. 
Blood and Marrow Transplant Clinical Trials Network
Peripheral-blood stem cells versus bone marrow from unrelated donors.
N Engl J Med
2012
, vol. 
367
 
16
(pg. 
1487
-
1496
)
34
Aversa
 
F
Terenzi
 
A
Tabilio
 
A
, et al. 
Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse.
J Clin Oncol
2005
, vol. 
23
 
15
(pg. 
3447
-
3454
)
35
Rizzieri
 
DA
Koh
 
LP
Long
 
GD
, et al. 
Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.
J Clin Oncol
2007
, vol. 
25
 
6
(pg. 
690
-
697
)
36
Huang
 
XJ
Liu
 
DH
Liu
 
KY
, et al. 
Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation.
Biol Blood Marrow Transplant
2009
, vol. 
15
 
2
(pg. 
257
-
265
)
37
Raiola
 
AM
Dominietto
 
A
Ghiso
 
A
, et al. 
Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning.
Biol Blood Marrow Transplant
2013
, vol. 
19
 
1
(pg. 
117
-
122
)
38
Luznik
 
L
O’Donnell
 
PV
Symons
 
HJ
, et al. 
HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
6
(pg. 
641
-
650
)
39
Brunstein
 
CG
Barker
 
JN
Weisdorf
 
DJ
, et al. 
Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease.
Blood
2007
, vol. 
110
 
8
(pg. 
3064
-
3070
)
40
Brunstein
 
CG
Fuchs
 
EJ
Carter
 
SL
, et al. 
Blood and Marrow Transplant Clinical Trials Network
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
, vol. 
118
 
2
(pg. 
282
-
288
)
41
Majhail
 
NS
Brunstein
 
CG
Tomblyn
 
M
, et al. 
Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
3
(pg. 
282
-
289
)
42
Yoshihara
 
S
Ikegame
 
K
Taniguchi
 
K
, et al. 
Salvage haploidentical transplantation for graft failure using reduced-intensity conditioning.
Bone Marrow Transplant
2012
, vol. 
47
 
3
(pg. 
369
-
373
)
43
Liu
 
H
Wang
 
X
Geng
 
L
, et al. 
Successful second transplantation with non-myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.
Pediatr Transplant
2010
, vol. 
14
 
4
(pg. 
465
-
470
)
44
Macmillan
 
ML
Blazar
 
BR
DeFor
 
TE
Wagner
 
JE
Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a phase I-II clinical trial.
Bone Marrow Transplant
2009
, vol. 
43
 
6
(pg. 
447
-
454
)
45
Mehta
 
J
Singhal
 
S
Gee
 
AP
, et al. 
Bone marrow transplantation from partially HLA-mismatched family donors for acute leukemia: single-center experience of 201 patients.
Bone Marrow Transplant
2004
, vol. 
33
 
4
(pg. 
389
-
396
)
46
Di Bartolomeo
 
P
Santarone
 
S
De Angelis
 
G
, et al. 
Haploidentical, unmanipulated, G-CSF-primed bone marrow transplantation for patients with high-risk hematologic malignancies.
Blood
2013
, vol. 
121
 
5
(pg. 
849
-
857
)
47
Grosso
 
D
Carabasi
 
M
Filicko-O’Hara
 
J
, et al. 
A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing.
Blood
2011
, vol. 
118
 
17
(pg. 
4732
-
4739
)
48
Lu
 
DP
Dong
 
L
Wu
 
T
, et al. 
Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation.
Blood
2006
, vol. 
107
 
8
(pg. 
3065
-
3073
)
49
Solomon
 
SR
Sizemore
 
CA
Sanacore
 
M
, et al. 
Haploidentical transplantation using T cell replete peripheral blood stem cells and myeloablative conditioning in patients with high-risk 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
, vol. 
18
 
12
(pg. 
1859
-
1866
)
50
Nakamae
 
H
Storer
 
BE
Storb
 
R
, et al. 
Low-dose total body irradiation and fludarabine conditioning for HLA class I-mismatched donor stem cell transplantation and immunologic recovery in patients with hematologic malignancies: a multicenter trial.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
3
(pg. 
384
-
394
)
51
Koreth
 
J
Stevenson
 
KE
Kim
 
HT
, et al. 
Bortezomib-based graft-versus-host disease prophylaxis in HLA-mismatched unrelated donor transplantation.
J Clin Oncol
2012
, vol. 
30
 
26
(pg. 
3202
-
3208
)
52
Ogawa
 
H
Ikegame
 
K
Yoshihara
 
S
, et al. 
Unmanipulated HLA 2-3 antigen-mismatched (haploidentical) stem cell transplantation using nonmyeloablative conditioning.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
10
(pg. 
1073
-
1084
)
53
Federmann
 
B
Bornhauser
 
M
Meisner
 
C
, et al. 
Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: a phase II study.
Haematologica
2012
, vol. 
97
 
10
(pg. 
1523
-
1531
)
54
Kurokawa
 
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
, vol. 
91
 
4
(pg. 
661
-
669
)
55
Guo
 
M
Sun
 
Z
Sun
 
QY
, 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
, vol. 
15
 
8
(pg. 
930
-
937
)
56
Bashey
 
A
Zhang
 
X
Sizemore
 
CA
, 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
, vol. 
31
 
10
(pg. 
1310
-
1316
)
57
Rodrigues
 
CA
Sanz
 
G
Brunstein
 
CG
, et al. 
Analysis of risk factors for outcomes after unrelated cord blood transplantation in adults with lymphoid malignancies: a study by the Eurocord-Netcord and lymphoma working party of the European group for blood and marrow transplantation.
J Clin Oncol
2009
, vol. 
27
 
2
(pg. 
256
-
263
)
58
Woolfrey
 
A
Klein
 
JP
Haagenson
 
M
, et al. 
HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
6
(pg. 
885
-
892
)
59
Lee
 
SJ
Klein
 
J
Haagenson
 
M
, et al. 
High-resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation.
Blood
2007
, vol. 
110
 
13
(pg. 
4576
-
4583
)
60
Koreth
 
J
Ahn
 
KW
Pidala
 
J
, et al. 
HLA-mismatch is associated with worse outcomes after unrelated donor reduced intensity conditioning hematopoietic cell transplantation: A CIBMTR analysis [abstract].
Blood
2013
, vol. 
122
 
21
 
Abstract 547
61
Weisdorf
 
D
Cooley
 
S
Devine
 
S
, et al. 
T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
6
(pg. 
937
-
943
)
62
Weisdorf
 
D
Spellman
 
S
Haagenson
 
M
, et al. 
Classification of HLA-matching for retrospective analysis of unrelated donor transplantation: revised definitions to predict survival.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
7
(pg. 
748
-
758
)
63
Loiseau
 
P
Busson
 
M
Balere
 
ML
, et al. 
HLA Association with hematopoietic stem cell transplantation outcome: the number of mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 is strongly associated with overall survival.
Biol Blood Marrow Transplant
2007
, vol. 
13
 
8
(pg. 
965
-
974
)
64
Morishima
 
Y
Sasazuki
 
T
Inoko
 
H
, et al. 
The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors.
Blood
2002
, vol. 
99
 
11
(pg. 
4200
-
4206
)
65
Brunstein
 
CG
Gutman
 
JA
Weisdorf
 
DJ
, et al. 
Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood.
Blood
2010
, vol. 
116
 
22
(pg. 
4693
-
4699
)
66
Sasazuki
 
T
Juji
 
T
Morishima
 
Y
, et al. 
Effect of matching of class I HLA alleles on clinical outcome after transplantation of hematopoietic stem cells from an unrelated donor. Japan Marrow Donor Program.
N Engl J Med
1998
, vol. 
339
 
17
(pg. 
1177
-
1185
)
67
Arora
 
M
Weisdorf
 
DJ
Spellman
 
SR
, et al. 
HLA-identical sibling compared with 8/8 matched and mismatched unrelated donor bone marrow transplant for chronic phase chronic myeloid leukemia.
J Clin Oncol
2009
, vol. 
27
 
10
(pg. 
1644
-
1652
)
68
Greinix
 
HT
Faé
 
I
Schneider
 
B
, et al. 
Impact of HLA class I high-resolution mismatches on chronic graft-versus-host disease and survival of patients given hematopoietic stem cell grafts from unrelated donors.
Bone Marrow Transplant
2005
, vol. 
35
 
1
(pg. 
57
-
62
)
69
Crocchiolo
 
R
Zino
 
E
Vago
 
L
, et al. 
Gruppo Italiano Trapianto di Midollo Osseo, Cellule Staminale Ematopoietiche (CSE) e Terapia Cellulare; Italian Bone Marrow Donor Registry
Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation.
Blood
2009
, vol. 
114
 
7
(pg. 
1437
-
1444
)
70
Ludajic
 
K
Balavarca
 
Y
Bickeböller
 
H
, et al. 
Impact of HLA-DPB1 allelic and single amino acid mismatches on HSCT.
Br J Haematol
2008
, vol. 
142
 
3
(pg. 
436
-
443
)
71
Shaw
 
BE
Gooley
 
TA
Malkki
 
M
, et al. 
The importance of HLA-DPB1 in unrelated donor hematopoietic cell transplantation.
Blood
2007
, vol. 
110
 
13
(pg. 
4560
-
4566
)
72
Ho
 
VT
Kim
 
HT
Liney
 
D
, et al. 
HLA-C mismatch is associated with inferior survival after unrelated donor non-myeloablative hematopoietic stem cell transplantation.
Bone Marrow Transplant
2006
, vol. 
37
 
9
(pg. 
845
-
850
)
73
Wang
 
Y
Liu
 
DH
Liu
 
KY
, et al. 
Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center.
Cancer
2013
, vol. 
119
 
5
(pg. 
978
-
985
)
74
Martelli
 
MF
Di Ianni
 
M
Ruggeri
 
L
, et al. 
“Designed” grafts for HLA-haploidentical stem cell transplantation.
Blood
2014
, vol. 
123
 
7
(pg. 
967
-
973
)
75
Ringdén
 
O
Okas
 
M
Uhlin
 
M
Uzunel
 
M
Remberger
 
M
Mattsson
 
J
Unrelated cord blood and mismatched unrelated volunteer donor transplants, two alternatives in patients who lack an HLA-identical donor.
Bone Marrow Transplant
2008
, vol. 
42
 
10
(pg. 
643
-
648
)
76
Kumar
 
P
Defor
 
TE
Brunstein
 
C
, et al. 
Allogeneic hematopoietic stem cell transplantation in adult acute lymphocytic leukemia: impact of donor source on survival.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
12
(pg. 
1394
-
1400
)
77
Ciurea
 
SO
Mulanovich
 
V
Saliba
 
RM
, et al. 
Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
12
(pg. 
1835
-
1844
)
78
Burroughs
 
LM
O’Donnell
 
PV
Sandmaier
 
BM
, et al. 
Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
11
(pg. 
1279
-
1287
)
79
Takahashi
 
S
Ooi
 
J
Tomonari
 
A
, et al. 
Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen.
Blood
2007
, vol. 
109
 
3
(pg. 
1322
-
1330
)
80
Eapen
 
M
Rocha
 
V
Sanz
 
G
, et al. 
Center for International Blood and Marrow Transplant Research; Acute Leukemia Working Party Eurocord (the European Group for Blood Marrow Transplantation)
National Cord Blood Program of the New York Blood Center
Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis.
Lancet Oncol
2010
, vol. 
11
 
7
(pg. 
653
-
660
)
81
Marks
 
DI
Woo
 
KA
Zhong
 
X
, et al. 
Unrelated umbilical cord blood transplant for adult acute lymphoblastic leukemia in first and second complete remission: a comparison with allografts from adult unrelated donors.
Haematologica
2014
, vol. 
99
 
2
(pg. 
322
-
328
)
82
Wagner
 
JE
Barker
 
JN
DeFor
 
TE
, et al. 
Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.
Blood
2002
, vol. 
100
 
5
(pg. 
1611
-
1618
)
83
Miyakoshi
 
S
Yuji
 
K
Kami
 
M
, et al. 
Successful engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with advanced hematological diseases.
Clin Cancer Res
2004
, vol. 
10
 
11
(pg. 
3586
-
3592
)
84
Fernandez-Viña
 
MA
Wang
 
T
Lee
 
SJ
, et al. 
Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation.
Blood
2014
, vol. 
123
 
8
(pg. 
1270
-
1278
)
85
Hale
 
GA
Shrestha
 
S
Le-Rademacher
 
J
, et al. 
Alternate donor hematopoietic cell transplantation (HCT) in non-Hodgkin lymphoma using lower intensity conditioning: a report from the CIBMTR.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
7
(pg. 
1036
-
1043
)
86
Huang
 
XJ
Zhu
 
HH
Chang
 
YJ
, 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
, vol. 
119
 
23
(pg. 
5584
-
5590
)
87
Lee
 
KH
Lee
 
JH
Lee
 
JH
, et al. 
Reduced-intensity conditioning therapy with busulfan, fludarabine, and antithymocyte globulin for HLA-haploidentical hematopoietic cell transplantation in acute leukemia and myelodysplastic syndrome.
Blood
2011
, vol. 
118
 
9
(pg. 
2609
-
2617
)
88
Cohen
 
YC
Scaradavou
 
A
Stevens
 
CE
, et al. 
Factors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries.
Bone Marrow Transplant
2011
, vol. 
46
 
1
(pg. 
70
-
76
)
89
Stevens
 
CE
Carrier
 
C
Carpenter
 
C
Sung
 
D
Scaradavou
 
A
HLA mismatch direction in cord blood transplantation: impact on outcome and implications for cord blood unit selection.
Blood
2011
, vol. 
118
 
14
(pg. 
3969
-
3978
)
90
Narimatsu
 
H
Miyakoshi
 
S
Yamaguchi
 
T
, et al. 
Japan Cord Blood Bank Network
Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1072 patients in Japan.
Blood
2008
, vol. 
112
 
6
(pg. 
2579
-
2582
)
91
Brunstein
 
CG
Cantero
 
S
Cao
 
Q
, et al. 
Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation.
Biol Blood Marrow Transplant
2009
, vol. 
15
 
2
(pg. 
214
-
222
)