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1.  Hematopoietic stem cell transplantation in children with acute leukemia: similar outcomes in recipients of umbilical cord blood versus marrow or peripheral blood stem cells from related or unrelated donors 
Korean Journal of Pediatrics  2012;55(3):93-99.
This study compared outcomes in children with acute leukemia who underwent transplantations with umbilical cord blood (UCB), bone marrow, or peripheral blood stem cells from a human leukocyte antigen (HLA)-matched related donor (MRD) or an unrelated donor (URD).
This retrospective study included consecutive acute leukemia patients who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) at Samsung Medical Center between 2005 and 2010. Patients received stem cells from MRD (n=33), URD (n=46), or UCB (n=41).
Neutrophil and platelet recovery were significantly longer after HSCT with UCB than with MRD or URD (P<0.01 for both). In multivariate analysis using the MRD group as a reference, the URD group had a significantly higher risk of grade III to IV acute graft-versus-host disease (GVHD; relative risk [RR], 15.2; 95% confidence interval [CI], 1.2 to 186.2; P=0.03) and extensive chronic GVHD (RR, 6.9; 95% CI, 1.9 to 25.2; P<0.01). For all 3 donor types, 5-year event-free survival (EFS) and overall survival were similar. Extensive chronic GVHD was associated with fewer relapses (RR, 0.1; 95% CI, 0.04 to 0.6; P<0.01). Multivariate analysis showed that lower EFS was associated with advanced disease at transplantation (RR, 3.2; 95% CI, 1.3 to 7.8; P<0.01) and total body irradiation (RR, 2.1; 95% CI, 1.0 to 4.3; P=0.04).
Survival after UCB transplantation was similar to survival after MRD and URD transplantation. For patients lacking an HLA matched donor, the use of UCB is a suitable alternative.
PMCID: PMC3315625  PMID: 22474464
Umbilical cord blood; Hematopoietic stem cell transplantation; Stem cell donor
2.  HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia 
Journal of Clinical Oncology  2009;27(10):1644-1652.
Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined.
Patients and Methods
We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1.
Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD.
In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible.
PMCID: PMC2668970  PMID: 19224849
3.  Use of Matched Unrelated Donors Compared with Matched Related Donors is Associated with Lower Relapse and Superior Progression Free Survival after Reduced Intensity Conditioning Hematopoietic Stem Cell Transplantation 
As success of reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n= 246) and MRD (n=187) RIC HSCT for hematologic malignancies at our institution. Diseases included: AML(127), NHL(71), CLL (68), MDS (64), HD(40), CML (25), MM(23), MPD (12), ALL(7), other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-MTX or tacrolimus/sirolimus +/− mini-MTX. Unrelated donors were younger compared to MRD (median age: 33 yrs vs. 52 yrs, p<0.0001), and provided larger CD34+ products (median CD34+ cells infused: 8.7 × 106/kg vs. 7.5 × 106/kg, p=0.002). Distribution of diseases, disease risk, prior transplant, and CMV status was similar in both cohorts. Cumulative incidence of grade II–IV acute GVHD (at day+180), 2 year-chronic GVHD, and 2-year non-relapse mortality (NRM) were 20% vs. 16%, 55% vs. 50%, and 8% vs. 6% in URD and MRD, respectively (p=NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% vs. 65% (p=0.005). With median follow-up of 26.5 and 35.8 months, 2-yr progression free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD and 29% for MRD (p= 0.01). Overall survival at 2 years were 56% for URD vs. 50% for MRD (p=0.53). In multivariable analysis, URD was associated with a lower risk of relapse (HR 0.67, p =0.002) and superior PFS (HR 0.69, p=0.002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.
PMCID: PMC3080446  PMID: 21193054
4.  Classification of HLA-Matching for Retrospective Analysis of Unrelated Donor Transplantation: Revised Definitions to Predict Survival 
The best unrelated donor (URD) for hematopoietic cell transplantation (HCT) is allele-matched at HLA-A,B,C and DRB1. Earlier studies mostly used incomplete or lower resolution HLA typing for analysis of transplant outcome. To understand the impact of incomplete HLA characterization, we analyzed 14,797 URD HCT (1995-2006) using multivariable regression modeling adjusting for factors affecting survival. Of 21 matching cohorts, we identified 3 groups with significantly different outcomes. Well-matched cases had either no identified HLA mismatch and informative data at 4 loci or allele matching at HLA-A,B & DRB1 (n=7,477, 50% of the population). Partially matched pairs had a defined, single locus mismatch and/or missing HLA data (n=4,962, 34%). Mismatched cases had ≥2 allele or antigen mismatches (n=2,358, 16%). Multivariate adjusted five-year survival estimates were: Well-matched: 54.1 (95% confidence interval), 52.9-55.4); Partially matched: 43.7 (42.3-45.2) and Mismatched: 33.4 (32.5-36.5), p<0.001. A better matched donor yielded 10-11% better 5 year survival. Importantly, intermediate resolution A,B and DRB1 allele matched “6/6 antigen matched” HCT had survival outcomes within the partially matched cohort. We suggest that these proposed HLA subgroupings be used when complete HLA typing is not available. This improved categorization of HLA matching status allows adjustment for donor-recipient HLA compatibility and can standardize interpretations of prior URD HCT experience.
PMCID: PMC2668157  PMID: 18541193
5.  Scoring HLA Class I Mismatches by HistoCheck Does Not Predict Clinical Outcome in Unrelated Hematopoietic Stem Cell Transplantation 
Currently, there is no well-accepted rating system to reliably predict which human leukocyte antigen (HLA)-mismatched (MM) unrelated donor (URD) should be selected for patients who do not have an HLA allele-matched donor. We evaluated the ability of an MM ranking system, HistoCheck, to predict the risk associated with HLA class I disparity in a population of 744 single allele or antigen HLA-A, B, or C MM myeloablative URD hematopoietic stem cell transplant (HCT) recipients with AML, ALL, CML or MDS, facilitated through the NMDP from 1988–2003. Multivariate models were used to adjust for other significant clinical risk factors. HLA MMs were scored using the HistoCheck web-based tool and the patients divided into 4 quartiles: Dissimilarity Score (DSS) 1.04–2.84 (allele MM), >2.84–13.75 (allele and antigen MM), >13.75–19.39 (antigen MM) and >19.39–36.62 (antigen MM). Using the lowest scoring quartile as the reference, the DSS groups were evaluated for associations with relapse, treatment-related mortality (TRM), acute and chronic graft-versus-host disease (GVHD), leukemia-free survival (LFS), and overall survival (OS) in the entire cohort, and in subset analyses by disease and disease stage. No significant associations were found between DSS and any outcomes in the overall cohort using the quartile categories or treating DSS as a continuous variable. Higher DSS scores were associated with decreased engraftment in early stage disease (p=0.0003) but not in other disease stages. In summary, DSS does not correlate with transplantation outcomes, and the HistoCheck scoring system does not provide an effective strategy to rank HLA class I MM. The data set used in this study is available to evaluate new algorithms proposed for donor selection.
PMCID: PMC3270214  PMID: 21963622
6.  Long-term Outcomes of Adults with Acute Lymphoblastic Leukemia after Autologous or Unrelated Donor Bone Marrow Transplantation 
Bone marrow transplantation  2007;41(7):635-642.
For adults with high-risk or recurrent acute lymphoblastic leukemia (ALL) who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analyzed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) complete remission. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post-transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five year leukemia-free (37% vs. 39%) and overall (38% vs. 39%) survival rates were similar for Auto HSCT vs. URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long follow-up in this analysis demonstrated that either Auto or URD HSCT can result in long-term leukemia free and overall survival for adult ALL patients. The optimal time (CR1 vs. CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.
PMCID: PMC2587442  PMID: 18084335
acute lymphoblastic leukemia (ALL); adult; autologous HSCT; unrelated donor HSCT
7.  Unrelated Donor Hematopoietic Cell Transplantation: Factors Associated with a Better HLA Match 
The impact of non-HLA patient factors on the match of the selected unrelated donor (URD) for hematopoietic cell transplantation (HCT) has not been fully evaluated. National Marrow Donor Program (NMDP) data for 7486 transplants using peripheral blood stem cells (PBSC) or bone marrow from years 2000–2005 were evaluated using multivariate logistic regression to identify independent non-HLA patient factors associated with completing a more closely matched URD transplant.
Advanced (intermediate and late stage) disease was significantly associated with an increased likelihood of transplant using a less-matched (partially-matched or mismatched) donor. Additionally, Black patients were 2.83 times, Asian 2.05 times, and Hispanic 1.73 times more likely to have a less-matched HCT donor than Caucasian patients. Younger patients, HCT at lower volume centers and in earlier years had significantly higher likelihood of having a less HLA matched URD transplant.
Our analysis provides encouraging evidence of HLA matching improvement in recent years. Initiating a patient’s URD search early in the disease process, especially for patients from non-Caucasian racial and ethnic groups, will provide the best likelihood for identifying the best available donor and making informed transplant decisions.
PMCID: PMC3319684  PMID: 19041054
Unrelated Donor; HLA match; Hematopoietic Cell Transplantation
8.  Sibling versus Unrelated Donor Allogeneic Hematopoietic Cell Transplantation for CML: Refined HLA-matching shows more GVHD but not less relapse 
Unrelated donor (URD) hematopoietic cell transplantation (HCT) can eradicate chronic myelogenous leukemia (CML). It has been postulated that greater donor:recipient-histoincompatibility can augment the graft vs. leukemia (GvL) effect. We previously reported similar, but not equivalent outcomes of URD vs. sibling donor HCT for CML using an older, less precise classification of HLA-matching.
Our recently refined HLA-matching classification, suitable for interpretation when complete allele-level typing is unavailable was used to reanalyze outcomes of previous HCT for CML.
We observed that new matching criteria identifies substantially more frequent mismatch than older, less precise “6 of 6 antigen” matched URD-HCT. Only 37% of those previously called “HLA-matched” were HLA-well-matched in new classification and 44% were partially-matched. The refined matching classification confirmed that partially matched or mismatched URD:recipient pairs have significantly greater risks of graft failure compared to either sibling or well-matched URD-HCT. Acute and chronic GVHD are significantly more frequent with all levels of recategorized URD HLA-matching. Importantly, survival and leukemia-free survival remain significantly worse following URD-HCT at any matching level. No augmented GvL effect accompanied URD HLA-mismatch. Compared to sibling donor transplants, we observed marginally increased, but not significantly different risks of relapse in either well-matched, partially-matched or mismatched URD-HCT.
These data confirm the utility of our revised HLA-matching schema as applicable for analysis of retrospective data sets when fully informative, allele level-typing is unavailable. In this analysis, greater histoincompatibility can augment GVHD but does not improve protection against relapse thus the best donor is still the most closely matched.
PMCID: PMC2929002  PMID: 19822308
CML; HLA matching; Unrelated donor allotransplantation; Graft vs. Leukemia; Graft vs. Host disease
9.  Effects of mismatching for Minor Histocompatibility Antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants 
Several studies in HLA-matched sibling hematopoietic stem cell transplantation (HSCT) have reported an association between mismatches in minor histocompatibility antigens (mHAg) and outcomes. We assessed whether single and multiple minor mHAg mismatches are associated with outcomes in 730 unrelated donor, HLA-A, B, C, DRB1, and DQB1 allele-matched hematopoietic stem cell transplants (HSCT) facilitated by the National Marrow Donor Program (NMDP) between 1996 and 2003. Patients had acute and chronic leukemia or myelodysplastic syndrome, received myeloablative conditioning regimens and calcineurin inhibitor-based graft-versus-host-disease (GvHD) prophylaxis, and most received bone marrow (85%). Donor and recipient DNA samples were genotyped for mHAg including: HA-1, HA-2, HA-3, HA-8, HB-1, CD31125/563. Primary outcomes included grades III–IV acute GvHD and survival; secondary outcomes included chronic GvHD, engraftment, and relapse. Single disparities at HA-1, HA-2, HA-3, HA-8, and HB-1 were not significantly associated with any of the outcomes analyzed. In HLA-A2 positive individuals, single CD31563 or multiple mHAg mismatches in the HvG vector were associated with lower risk of grades III–IV acute GVHD. Based on these data, we conclude that mHAg incompatibility at HA-1, HA-2, HA-3, HA-8, HB-1 and CD31 has no detectable effect on the outcome of HLA matched unrelated donor HSCT.
PMCID: PMC2721718  PMID: 19539218
10.  Availability of Cord Blood Extends Allogeneic Hematopoietic Stem Cell Transplant Access to Racial and Ethnic Minorities 
Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access due to the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ≥ 4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (p < 0.001). However, the majority of both groups had 5–6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (p < 0.001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (p < 0.001). Their median weight was significantly higher than CB transplant recipients (p < 0.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.
PMCID: PMC3685152  PMID: 20800103
11.  Donor and Recipient CMV Serostatus and Outcome of Pediatric Allogeneic HSCT for Acute Leukemia in the Era of CMV-Preemptive Therapy 
In the era of cytomegalovirus(CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients age 0–8 who underwent primary HSCT for acute leukemia in 1997–007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and non-relapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D−/R−). On univariate analysis, D−/R− grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, p<0.05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D−/R− graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46–6.76) and treatment failure (2.45, 1.46–4.12) but not significantly with NRM (2.00, 0.44–9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors.
PMCID: PMC2803021  PMID: 19135943
12.  Role of HLA in Hematopoietic Stem Cell Transplantation 
Bone Marrow Research  2012;2012:680841.
The selection of hematopoietic stem cell transplantation (HSCT) donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA) match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR) genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.
PMCID: PMC3467756  PMID: 23082252
13.  Role of the inhibitory KIR ligand HLA-Bw4 and HLA-C expression levels in the recognition of leukemic cells by Natural Killer cells 
Transplantation of acute myeloid leukemia (AML) patients with grafts from related haploidentical donors has been shown to result in a potent graft-versus-leukemia effect. This effect is mediated by NK cells because of the lack of activation of inhibitory killer cell immunoglobulin-like receptors (KIRs) which recognize HLA-Bw4 and HLA-C alleles. However, conflicting results have been reported about the impact of KIR ligand mismatching on the outcome of unrelated HLA-mismatched hematopoietic stem cells transplants (HSCT) to leukemic patients. The interpretation of these conflicting results is hampered by the scant information about the level of expression of HLA class I alleles on leukemic cells, although this variable may affect the activation of inhibitory KIRs. Therefore in the present study, utilizing a large panel of human monoclonal antibodies we have measured the level of expression of HLA-A, -B and -C alleles on 20 B-chronic lymphoid leukemic (B-CLL) cell preparations, on 16 B-acute lymphoid leukemic (B-ALL) cell preparations and on 19 AML cell preparations. Comparison of the level of HLA class I antigen expression on leukemic cells and autologous normal T cells identified selective downregulation of HLA-A and HLA-B alleles on 15 and 14 of the 20 B-CLL, on 2 and 5 of the 16 B-ALL and on 7 and 11 of the 19 AML patients tested, respectively. Most interestingly HLA-C alleles were markedly downregulated on all three types of leukemic cells; the downregulation was most pronounced on AML cells. The potential functional relevance of these abnormalities is suggested by the dose-dependent enhancement of NK cell activation caused by coating the HLA-HLA-Bw4 epitope with monoclonal antibodies on leukemic cells which express NK cell activating ligands. Our results suggest that besides the HLA and KIR genotype, expression levels of KIR ligands on leukemic cells should be included among the criteria used to select the donor-recipient combinations for HSCT.
PMCID: PMC3426282  PMID: 18841361
NK cells; HLA class I molecules; Killer cell immunoglobulin-like receptors; Leukemia; Flow cytometry; Hematopoietic stem cell transplantation
14.  HLA-C–Dependent Prevention of Leukemia Relapse by Donor Activating KIR2DS1 
The New England journal of medicine  2012;367(9):805-816.
Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)–cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT.
We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes.
Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P = 0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P = 0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P = 0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P = 0.01).
Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C–dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.)
PMCID: PMC3767478  PMID: 22931314
15.  Association of HLA-G Low Expressor Genotype with Severe Acute Graft-Versus-Host Disease after Sibling Bone Marrow Transplantation 
Background: Human leukocyte antigen-G (HLA-G) molecules play a prominent role in immune tolerance. Structurally similar to their classical HLA homologs, they are distinct by having high rate of polymorphism in the non-coding regions including a functionally relevant 14-base pair (bp) insertion/deletion (Ins/Del) allele in the 3′ untranslated region (3′UTR), rarely examined in a hematopoietic stem cell transplantation (HSCT) setting. Here, we analyzed the potential impact of HLA-G Ins/Del dimorphism on the incidence of acute graft-versus-host disease (aGvHD), transplant-related mortality (TRM), overall survival (OS), and incidence of relapse after HSCT using bone marrow (BM) as stem cell source from HLA-matched donors. Methods: One hundred fifty-seven sibling pairs, who had undergone HSCT, were studied for the distribution of the HLA-G 14 bp Ins/Del polymorphism using a polymerase chain reaction (PCR)-based technique. Potential genetic association with the incidence of aGvHD, TRM, and OS was analyzed by monovariate and multivariate analyses. Results: Monovariate analysis showed that the homozygous state for the 14-bp Ins allele is a risk factor for severe aGvHD (grade III and IV; P = 0.008), confirmed subsequently by multivariate analysis [hazard ratio (HR) = 3.5; 95% confidence interval (95%CI) = 1.3–9.5; P = 0.012]. We did not find any association between HLA-G polymorphism and the other studied complications. Conclusion: Our data suggest that the HLA-G low expressor 14 bp Ins allele constitutes a risk factor for the incidence of severe aGvHD in patients who received BM as stem cell source.
PMCID: PMC3342264  PMID: 22566863
hematopoietic stem cell transplantation; HLA-G polymorphism; acute GvHD
16.  HLA-C Antigen mismatches are associated with worse outcomes in unrelated donor peripheral blood stem cell transplantation 
The association between human leukocyte antigen (HLA) matching and outcome in unrelated donor, peripheral blood stem cell (PBSC) transplantation has not been established.
Patients and Methods
1933 unrelated donor-recipient pairs transplanted between 1999-2006 for AML, ALL, MDS or CML and who had high resolution HLA typing for HLA-A, B, C, DRB1, DQA1 and DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics.
Matching for HLA-A, -B, -C and DRB1 alleles [8/8 match] was associated with better survival at one year compared with 7/8 HLA-matched pairs (56% vs. 47%). Using 8/8 HLA-matched patients as the baseline (n=1243), HLA-C antigen mismatches (n=189) were statistically significantly associated with lower LFS (RR 1.36 [95% CI 1.13-1.64] p=0.0010), and increased risk for mortality (RR=1.41 [1.16-1.70], p=0.0005), treatment-related mortality (RR=1.61 [1.25-2.08], p=0.0002), and grades III-IV graft-versus-host disease (RR=1.98 [1.50-2.62], p<0.0001). HLA-B antigen or allele mismatching was associated with a higher risk for acute GVHD grades III-IV. No statistically significant differences in outcome were observed for HLA-C allele mismatch (n=61), nor for mismatches at HLA-A antigen/allele (n=136), HLA-DRB1 allele (n=39) or HLA-DQ antigen/allele (n=114) compared to 8/8 HLA-matched pairs. HLA mismatching was not associated with relapse or chronic GVHD.
HLA-C antigen mismatched unrelated PBSC donors are associated with worse outcomes compared with 8/8 HLA-matched donors. Limited power due to small sample sized prevents comment about other mismatches.
PMCID: PMC3071866  PMID: 20870028
17.  Unrelated donor umbilical cord blood transplantation for the treatment of hematologic malignancies 
Current opinion in hematology  2008;15(6):568-575.
Purpose of review
This review summarizes the state of the art of unrelated donor (URD) umbilical cord blood transplantation (UCBT) for the treatment of hematologic malignancies and discusses the current issues associated with the use of this hematopoietic stem cell (HSC) source.
Recent findings
In contrast to the very high transplant-related mortality associated with the early experience of UCBT, recent series have been associated with comparable survival to that of human leucocyte antigen-matched URD transplantation in children with similarly promising results in adults with the use of double-unit grafts. In addition, utilization of reduced-intensity conditioning regimens has been successful extending access to patients unsuitable for myeloablation. Consequently, the use of umbilical cord blood as a HSC source and the global inventory of units in public banks is rapidly increasing although challenges associated with engraftment, unit quality, and infectious complications remain and will be discussed in this review.
URD umbilical cord blood is an alternative HSC source offering a unique set of advantages and disadvantages as compared with the transplantation of HSC from unrelated volunteers. Improved transplant outcomes are now making UCBT a rival to URD transplantation for the treatment of hematologic malignancies.
PMCID: PMC3705957  PMID: 18832927
allogeneic transplantation; cord blood; hematologic malignancy
18.  High Risk Pediatric Acute Lymphoblastic Leukemia: To Transplant or Not to Transplant? 
Because survival with both chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) approaches to high risk pediatric acute lymphoblastic leukemia (ALL) generally improves through the years, regular comparisons of outcomes with either approach for a given indication are needed to decide when HSCT is indicated. Improvements in risk classification are allowing clinicians to identify patients at high risk for relapse early in their course of therapy. Whether patients defined as high risk by new methods will benefit from HSCT requires careful testing. Standardization and improvement of transplant approaches has led to equivalent survival outcomes with matched sibling and well-matched unrelated donors, however, survival using mismatched and haploidentical donors is generally worse. Trials comparing chemotherapy and HSCT must obtain sufficient data about therapy and stratify the analysis to assess the outcomes of best-chemotherapy with best-HSCT approaches.
PMCID: PMC3053056  PMID: 21195303
19.  The Presence of Anti-HLA Antibodies before and after Allogeneic Hematopoietic Stem Cells Transplantation from HLA-Mismatched Unrelated Donors 
Bone Marrow Research  2012;2012:539825.
Although anti-human leukocyte antigen antibodies (anti-HLA Abs) are important factors responsible for graft rejection in solid organ transplantation and play a role in post-transfusion complications, their role in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has not been finally defined. Enormous polymorphism of HLA-genes, their immunogenicity and heterogeneity of antibodies, as well as the growing number of allo-HSCTs from partially HLA-mismatched donors, increase the probability that anti-HLA antibodies could be important factors responsible for the treatment outcomes. We have examined the incidence of anti-HLA antibodies in a group of 30 allo-HSCT recipients from HLA-mismatched unrelated donors. Anti-HLA Abs were identified in sera collected before and after allo-HSCT. We have used automated DynaChip assay utilizing microchips bearing purified class I and II HLA antigens for detection of anti-HLA Abs. We have detected anit-HLA antibodies against HLA-A, B, C, DR, DQ and DP, but no donor or recipient-specific anti-HLA Abs were detected in the studied group. The preliminary results indicate that anti-HLA antibodies are present before and after allo-HSCT in HLA-mismatched recipients.
PMCID: PMC3488384  PMID: 23150827
20.  Outcomes of allogeneic hematopoietic cell transplantation for adolescent and young adults compared to children and older adults with acute myeloid leukemia 
Adolescents and young adults (AYAs) with cancer have not experienced improvements in survival to the same extent as children and older adults. We compared outcomes among children (<15 years), AYAs (15-40 years) and older adults (>40 years) receiving allogeneic hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML).
Patients and Methods
Our cohort consisted of 900 children, 2708 AYA and 2728 older adult recipients of HLA-identical sibling or unrelated donor (URD) transplant using myeloablative or reduced-intensity/non-myeloablative conditioning. Outcomes were assessed over three time periods (1980-1988, 1989-1997, 1998-2005) for sibling and two time periods (1989-1997, 1998-2005) for URD HCT. Analyses were stratified by donor type.
Overall survival for AYAs using either siblings or URD improved over time. Although children had better and older adults had worse survival compared to AYAs, improvements in survival for AYAs did not lag behind those for children and older adults. After sibling donor HCT, five-year adjusted survival for the three time periods was 40%, 48% and 53% for children, 35%, 41% and 42% for AYAs and 22%, 30% and 34% for older adults. Among URD HCT recipients, five-year adjusted survival for the two time periods was 38% and 37% for children, 24% and 28% for AYAs and 19% and 23% for older adults. Improvements in survival occurred due to a reduction in risk of treatment-related mortality. The risk of relapse did not change over time.
Improvements in survival among AYAs undergoing allogeneic HCT for AML have paralleled those among children and older adults.
PMCID: PMC3288160  PMID: 22040843
Bone marrow transplantation  2011;47(6):810-816.
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment, albeit in a minority of patients with accelerated (AP) or blast phase (BP) chronic myeloid leukemia (CML). Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic HSCT performed between 1999–2004 in advanced phase CML using data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185), and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or bone marrow (53%) HSCT after myeloablative (78%) or non-myeloablative (22%) conditioning. 52% in CP2, 49% in AP, and 46% in BP received IM pre-HSCT. Disease-free survival was 35–40% for CP2, 26–27% for AP and 8–11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by stages of CML or pre-HSCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of outcomes of allogeneic HSCT for advanced phase CML in the IM era.
PMCID: PMC3896981  PMID: 21986636
Imatinib; allogeneic transplantation; chronic myeloid leukemia; accelerated phase; blast phase; outcomes
22.  Comparison of Matched Unrelated and Matched Related Donor Myeloablative Hematopoietic Cell Transplantation for Adults with Acute Myeloid Leukemia in First Remission 
Hematopoietic cell transplantation (HCT) from a matched related donor (MRD) benefits many adults with acute myeloid leukemia (AML) in first complete remission (CR1). The majority of patients do not have such a donor, however, requiring use of an alternative donor if HCT is undertaken. We retrospectively analyzed 226 adult AML CR1 patients undergoing myeloablative unrelated donor (URD) (10/10 match, n=62; ≤9/10, n=29) or MRD (n=135) HCT from 1996–2007. Five-year estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) were 57.9%, 29.7%, and 16.0%, respectively. Failure for each of these outcomes was slightly higher for 10/10 URD than MRD HCT, although statistical significance was not reached for any endpoint. The adjusted hazard ratios (HR) were 1.43 (0.89–2.30, p=0.14) for overall mortality, 1.17 (0.66–2.08, p=0.60) for relapse, and 1.79 (0.86–3.74, p=0.12) for NRM, respectively, and the adjusted odds ratio (OR) for grades 2–4 acute graft-versus-host disease was 1.50 (0.70–3.24, p=0.30). Overall mortality among 9/10 and 10/10 URD recipients was similar (adjusted HR=1.16 [0.52–2.61], p=0.71). These data indicate that URD HCT can provide long-term survival for CR1 AML; outcomes for 10/10 URD HCT, and possibly 9/10 URD HCT, suggest that this modality should be considered in the absence of a suitable MRD.
PMCID: PMC3001162  PMID: 20485378
acute myeloid leukemia (AML); first complete remission; hematopoietic stem cell transplantation; unrelated donor; matched related donor
23.  Bortezomib-Based Graft-Versus-Host Disease Prophylaxis in HLA-Mismatched Unrelated Donor Transplantation 
Journal of Clinical Oncology  2012;30(26):3202-3208.
HLA-mismatched unrelated donor (MMUD) hematopoietic stem-cell transplantation (HSCT) is associated with increased graft-versus-host disease (GVHD) and impaired survival. In reduced-intensity conditioning (RIC), neither ex vivo nor in vivo T-cell depletion (eg, antithymocyte globulin) convincingly improved outcomes. The proteasome inhibitor bortezomib has immunomodulatory properties potentially beneficial for control of GVHD in T-cell-replete HLA-mismatched transplantation.
Patients and Methods
We conducted a prospective phase I/II trial of a GVHD prophylaxis regimen of short-course bortezomib, administered once per day on days +1, +4, and +7 after peripheral blood stem-cell infusion plus standard tacrolimus and methotrexate in patients with hematologic malignancies undergoing MMUD RIC HSCT. We report outcomes for 45 study patients: 40 (89%) 1-locus and five (11%) 2-loci mismatches (HLA-A, -B, -C, -DRB1, or -DQB1), with a median of 36.5 months (range, 17.4 to 59.6 months) follow-up.
The 180-day cumulative incidence of grade 2 to 4 acute GVHD was 22% (95% CI, 11% to 35%). One-year cumulative incidence of chronic GVHD was 29% (95% CI, 16% to 43%). Two-year cumulative incidences of nonrelapse mortality (NRM) and relapse were 11% (95% CI, 4% to 22%) and 38% (95% CI, 24% to 52%), respectively. Two-year progression-free survival and overall survival were 51% (95% CI, 36% to 64%) and 64% (95% CI, 49% to 76%), respectively. Bortezomib-treated HLA-mismatched patients experienced rates of NRM, acute and chronic GVHD, and survival similar to those of contemporaneous HLA-matched RIC HSCT at our institution. Immune recovery, including CD8+ T-cell and natural killer cell reconstitution, was enhanced with bortezomib.
A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.
PMCID: PMC3434979  PMID: 22869883
24.  Outcomes of Severe Combined Immunodeficiency Patients Treated with Hematopoietic Stem Cell Transplantation with and without Pre-conditioning 
The effect of pre-transplant conditioning upon the long-term outcomes of patients receiving hematopoietic stem cell transplantation (HSCT) for severe combined immunodeficiency (SCID) has not been completely determined.
To assess the outcomes of 23 mostly conditioned SCID patients and compare their outcomes to 25 nonconditioned SCID transplanted patients previously reported.
In the present study, we reviewed the medical records of these 23 consecutive mostly conditioned SCID patients transplanted between 1998 and 2007.
Eighteen patients (median age at transplant 10 [range 0.8–108] mo) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplant conditioning and one was not conditioned, 13 (72%) engrafted and survive a median of 3.8 [1.8–9.8] yr, 5 of 13 (38%) require IVIG, and 6 of 6 age-eligible children attend school. Of five recipients (median age at transplant 7 [range 2–23] mo) of matched related donor transplants, all 5 engrafted and survive a median of 7.5 [range 1.5–9.5] yr, 1 requires IVIG, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: IL2γR in 7 patients, IL7αR in 4 patients, RAG1 in 2 patients, ADA in 2 patients, and AK2 in 1 patient. Early outcomes and quality of life of the previous non-conditioned vs. the present conditioned cohorts were not statistically different but longer-term follow-up is necessary for confirmation.
HSCT in SCID patients results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pre-transplant conditioning.
PMCID: PMC3271026  PMID: 19895994
Hematopoietic stem cell transplantation; graft-versus-host disease; severe combined immunodeficiency; immune reconstitution; primary immunodeficiency; conditioning
25.  HLAMatchmaker-Defined Triplet Matching Is Not Associated with Better Survival Rates of Patients with Class I HLA Allele Mismatched Hematopoietic Cell Transplants from Unrelated Donors 
This report addresses the concept that permissible HLA mismatching, i.e. mismatches that do not generate an allogeneic response, in hematopoietic stem cell transplantation (HCT) can be determined with structural similarity of polymorphic regions. We have applied the triplet version of a structural algorithm called HLAMatchmaker that considers short sequences involving polymorphic amino acid residues on the molecular surface as key elements of immunogenic epitopes. The triplet matching effect was analyzed in a National Marrow Donor Program dataset consisting of 744 unrelated hematopoietic cell transplantation cases with one HLA-A,-B or -C mismatch and 1690 fully HLA-A,-B,-C,-DR,-DQ allele matched cases. In multivariate models adjusting for other significant clinical risk factors, the degree of triplet mismatching did not significantly correlate with patient survival, engraftment or acute graft versus host disease. Other structurally based strategies should be pursued to identify permissible HLA mismatches in HCT.
PMCID: PMC2572684  PMID: 18721770

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