HLA-matched Sibling Hematopoietic Stem Cell Research Articles

Impact of donor and recipient characteristics on graft-versus-host disease and survival in HLA-matched sibling hematopoietic stem cell transplantation

ObjectiveTo analyze the impact of donor- and recipient-related factors on Graft-versus-host disease (GVHD) and overall survival of transplantation from matched sibling donors. Methodwe retrospectively analyzed the clinical features of 68 consecutive hematological patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) from matched sibling from 2011 and 2017. ResultsThe incidence of Ⅱ- Ⅳacute GVHD (aGVHD) and chronic GVHD (cGVHD) after transplantation was 13.6 % and 19.7 %, respectively. We also noted the donor and recipient characteristics had no impact on Ⅱ- Ⅳ aGVHD incidence.We found sex mismatch (F-M) did not increase the risk of cGVHD in the model if a female donor was younger than 30 years (P = 1.000), but cGVHD increased if the female donor was ≥30 years (P = 0.002). Recipients≥40 years undergoing HCT from donors ≥30 years were at higher risk for cGVHD (P = 0.021). Development of Ⅱ- Ⅳ aGVHD and cGVHD had no effect on overall survival (P = 0.159, 0.081). Non-remission status at allo-HCT was linked to lower overall survival (P = 0.001). ConclusionThe incidence of cGVHD was higher when male recipients received hematopoietic progenitor cells from female ≥30 years donors, and when older than 40 years recipients received hematopoietic progenitor cells from ≥30 years donors. Patients in non-remission status at allo-HCT was inclined to have lower overall survival.

Young Female Donors Do Not Increase the Risk of Graft-versus-Host Disease or Impact Overall Outcomes in Pediatric HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

Optimal donor selection is critical in hematopoietic stem cell transplantation (HSCT). Donor–recipient sex mismatch, donor age, and female donor–donor parity are known to impact graft-versus-host disease (GVHD) and outcomes in adults. Minor histocompatibility antigens encoded by the human Y chromosome can result in specific antibody formation in some female donors, may increase in frequency with increasing donor age, and may be contributory to the increased incidence of GVHD. To better understand the role of donor age/sex and sex matching in HSCT outcomes, we conducted a retrospective study of pediatric patients receiving their first myeloablative sibling donor HSCT (n = 244) from 1998 to 2012. Observed rates of GVHD were low: 17% of patients surviving past engraftment (n = 243) developed grades II to IV acute GVHD (aGVHD) and 14% surviving ≥ 100 days (n = 229) developed chronic GVHD (cGVHD). On multivariate analysis the risk of aGVHD, cGVHD, and death increased with patient age as expected. Female donor sex and sex mismatch (female donor–male recipient) had no impact on the development of aGVHD. cGVHD was increased with female donors only if the donor was ≥12 years old. No cGVHD was observed among 109 patients aged < 10 years who received a 6/6 HLA-matched marrow HSCT, regardless of donor age or sex. Survival was mostly driven by diagnosis. Results suggest that in pediatric HSCT, young HLA-matched siblings are equivalently good donors regardless of sex or donor–recipient sex mismatch.

Neurocognitive Functioning in Adults Who Underwent Nonmyeloablative HLA-Matched Sibling Hematopoietic Stem Cell Transplant (SCT) for Sickle Cell Disease (SCD)

Individuals with SCD are at risk for neurocognitive impairments. While potentially curative, SCTs come with their own risk of neurotoxicities, particularly from radiation and high-dose ablative chemotherapies. Newer, nonmyeloablative regimens may prevent some of these toxicities. This study examines the long-term cognitive impact of nonmyeloablative transplants in adults with SCD. Seventeen adults (11 males; mean age = 32.2 years, SD=9.0, range 17–52) participated in neuropsychological evaluations before transplant and 12 months post-transplant, as part of a research protocol at the National Heart Lung and Blood Institute. Donors were HLA-matched siblings; the conditioning regimen consisted of alemtuzumab and 300cGy total body irradiation, and they received sirolimus for graft-versus-host disease prophylaxis. Evaluations assessed global cognition, processing speed, memory, attention, and executive functions. Patients completed the PROMIS Physical Functioning questionnaire. Global cognition was within normal limits. Mean Verbal and Performance IQ scores were average at baseline and follow-up, with no significant changes noted. Mean processing speed scores were average, and increased significantly from baseline (M=92.1, SD=10.1) to 12 months (M=99.2, SD=11.6, t=2.1, p=.013). Mean scores on memory, attention and executive tests were average and stable across time points. No group declines in mean cognitive scores were noted. Mean t-scores on the physical functioning questionnaire increased from 41.6 (SD=4.7) to 49.0 (SD=10.0; t=3.4, p=.01), indicating significant improvement from baseline to 12 months post-transplant. Hemoglobin levels increased significantly from pre-transplant (M=9.1, SD=0.9) to post-transplant (M=13.1, SD=2.2; t=8.9, p<.0001). In this small sample, a comparison of neurocognitive scores from baseline to 12 months post-nonmyeloablative SCT does not indicate any deleterious effects from transplant. In fact, a significant improvement emerged in mental processing speed. Physical functioning also improved per patient questionnaires. As suggested by some prior research, the significant increase in hemoglobin levels may underlie improvements in processing speed.

The Association of KIR2DS4 and Its Variant KIR1D with CMV Infection after HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

Objective To expolore the association of KIR2DS4 and its variant KIR1D with cytomegalovirus(CMV) infection after HLA-matched sibling hematopoietic stem cell transplantation.Methods Polymerase chain reaction with sequence-specific primers (PCR-SSP) method was used to genotype KIR genes in 267 donor-recipient pairs from Oct 2005 to Apr 2014. Posttransplant monitoring for CMV infection was performed by immune histochemically assays .165 donor-recipient pairs who belong to KIR gene haplotype AA were analyzed for the presence of KIR2DS4 and its variant KIR1D and then further subdivided into the following groups: 2DS4-/1D+ (homozygous for the deletion variant KIR1D), 2DS4+/1D+ (heterozygous), 2DS4+/1D- (two intact KIR2DS4 alleles). Furthermore, we investigated the influence of the KIR2DS4 variants on CMV infection of 165 patients receiving Sibling related HLA matched transplantation.Results There were no significant differences in frequency of KIR2DS4 or KIR1D between donors and recipients in the haplotype AA group. The ratio of 2DS4+ and KIR1D in haplotype AA group was 2:1.There was no difference on neutrophil engraftment and platelet recovery among the three groups after hematopoietic stem cell transplantation. The CMV infection rate was significantly higher in 2DS4+/1D- group compared with 2DS4+/1D+ group (44.0% vs 19.0%，P=0.002)．In 2DS4-/1D+ group ，the CMV infection rate was higer than that in 2DS4+KIR1D+ group (50.0% vs 19%，P=0.028). However，there was no difference in CMV infection rate between 2DS4+/1D-group and 2DS4-/1D+ group.Conclusion KIR2DS4 and its variant KIR1D are associated with CMV infection after HLA-matched sibling hematopoietic stem cell transplantation DisclosuresNo relevant conflicts of interest to declare.

Comparative analysis of unrelated cord blood transplantation and HLA-matched sibling hematopoietic stem cell transplantation in children with high-risk or advanced acute leukemia

The aim of this report was to present a clinical comparison of unrelated cord blood transplantation (CBT) and human leukocyte antigen (HLA)-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) in children with high-risk or advanced acute leukemia. A total of 115 consecutive pediatric patients received unrelated CBT (n = 90) or sibling allo-PBSCT/BMT (n = 25) between 2000 and 2012. Neutrophil and platelet recovery were significantly delayed after CBT compared to allo-PBSCT/BMT. There was no difference in the incidence of acute graft-versus-host disease (GVHD) or chronic GVHD between the two groups. The cumulative incidence of transplant-related mortality (TRM) was higher in the CBT group than in the allo-PBSCT/BMT group (32.5 vs 12.8 %) (p = 0.03). The cumulative incidence of relapse was 13.1 % after CBT, which was significantly lower than that of after allo-PBSCT/BMT (45.3 %) (p = 0.015). The overall survival (OS) and leukemia-free survival (LFS) in the CBT group were similar to those of the allo-PBSCT/BMT group; however, for acute myeloid leukemia (AML) patients, the 5-year LFS in the CBT group was slightly better than the allo-PBSCT/BMT group (55.7 % for CBT and 32.7 % for allo-PBSCT/BMT) (p = 0.08). Our comparisons suggest that for high-risk or advanced childhood acute leukemia, unrelated CBT has a higher TRM and similar long-term survival, but better antileukemia effect than HLA-matched sibling PBSCT/BMT. New strategies and better supportive care are required to decrease the TRM of CBT.

Comparison of Unrelated Cord Blood Transplantation and HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Patients with Chronic Myeloid Leukemia in Advanced Stage

This is the first report to present a clinical comparison of unrelated cord blood transplantation (CBT) and HLA-matched sibling allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in advanced stage (accelerated phase or blast crisis). A total of 32 consecutive patients with advanced CML received unrelated CBT (n = 16) or HLA-matched sibling allogeneic peripheral blood stem cell or bone marrow transplantation (allo-PBSCT/BMT) (n = 16) between 2002 and 2011. The median day to neutrophil engraftment and the median day to platelet engraftment were longer in the unrelated CBT group. The cumulative incidence of grades 1 to 2 acute graft-versus-host disease (aGVHD), grades 3 to 4 aGVHD, and chronic graft-versus-host disease did not differ significantly between the 2 cohorts. The cumulative incidence of transplantation-related mortality (TRM) at day +180 was higher in CBT group (37.5% versus 12.5%, P = .013). The risk of relapse was lower in CBT patients compared with that of allo-PBSCT/BMT patients (14.2% versus 42.7%, P = .03). The long-term survival in CBT group patients was slightly better than that of allo-PBSCT/BMT group, although the difference did not reach statistical significance: the 5-year overall survival for CBT patients and allo-PBSCT/BMT patients was 62.5% and 48.6%, respectively (P = .10), whereas the 5-year leukemia-free-survival rate was 50% and 40.5%, respectively (P = .12). Our comparisons suggest that patients with advanced CML receiving unrelated CBT had a lower relapse rate, a slightly better long-term survival, but a higher early TRM than those receiving HLA-matched related allo-PBSCT/BMT.

Impact of vitamin D receptor gene polymorphisms on clinical outcomes of HLA‐matched sibling hematopoietic stem cell transplantation

We hypothesized that polymorphisms of the vitamin D receptor (VDR) gene might affect clinical outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). Three VDR gene polymorphisms (BsmI G>A, ApaI G>T, and TaqI T>C) were genotyped in 147 patients who underwent HLA-matched sibling allogeneic HSCT. Frequencies of infection, graft-vs.-host disease (GVHD), overall survival (OS), and disease-free survival (DFS) were compared according to genotypes and haplotypes. Infection and acute GVHD had trends to be less frequent in patients with ApaI TT genotype than non-TT genotypes (p = 0.061 and p = 0.059, respectively). For TaqI genotypes, there were no statistical differences in frequency of infection and acute GVHD (p = 0.84 and p = 0.30, respectively), but TC genotype was associated with longer OS and DFS than TT genotype (p = 0.022 and p = 0.038, respectively). In the ApaI-TaqI haplotype analysis, patients with TC haplotype had significantly longer OS and DFS than those without TC haplotype (p = 0.022 and p = 0.038, respectively). In multivariable analysis, TaqI genotype and ApaI-TaqI haplotype of recipients were independent prognostic factors for both OS and DFS. This study suggests that the genotype and haplotype of VDR in recipient might be associated with clinical outcome of sibling HLA-matched HSCT.

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 (MDS), received myeloablative conditioning regimens and calcineurin inhibitor-based graft-versus-host-disease (GVHD) prophylaxis, and most received bone marrow (BM; 85%). Donor and recipient DNA samples were genotyped for mHAg including: HA-1, HA-2, HA-3, HA-8, HB-1 and CD31(125/563). Primary outcomes included grades III-IV acute GVHD (aGVHD) and survival; secondary outcomes included chronic GVHD (cGVHD), 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 CD31(563) or multiple mHAg mismatches in the HVG vector were associated with lower risk of grades III-IV aGVHD. 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.

HLA-Matched Sibling Hematopoietic Stem Cell Transplantation for Fanconi Anemia: Comparison of Irradiation and Nonirradiation Containing Conditioning Regimens

Related to the underlying DNA repair defect that is the hallmark of Fanconi anemia (FA), preparatory regimen-related toxicities have been obstacles to hematopoietic cell transplantation (HCT). In an attempt to decrease the risk and severity of regimen-related toxicities, nonirradiation regimens have been explored. The aim of this study is to compare outcomes after irradiation and nonirradiation regimens in 148 FA patients and identify risk factors impacting upon HCT outcomes. Hematopoietic recovery, acute and chronic graft-versus-host disease (aGVHD, GVHD), and mortality were similar after irradiation and nonirradiation regimens. In both groups of recipients aged >10 years, prior use of androgens and cytomegalovirus seropositivity in either the donor or recipient were associated with higher mortality. With median follow-ups >5 years, the 5-year probability of overall survival, adjusted for factors impacting overall mortality was 78% and 81% after irradiation and nonirradiation regimens, P = .61. In view of the high risk of cancer and other radiation-related effects on growth and development, these results support the use of nonirradiation preparatory regimens. As the peak time for developing solid tumors after HCT is 8 to 9 years, longer follow-up is required before definitive statements can be made regarding the impact of nonirradiation regimens on cancer risk.

Human Leukocyte Antigens of A33, B58 or DR7 Decrease the Treatment-Related Mortality in HLA-Matched Sibling Hematopoietic Stem Cell Transplantation in Association with Heat Shock Protein 70-Hom Polymorphisms.

Human leukocyte antigens(HLA) are expected to influence outcomes or adverse effects in allogeneic hematopoietic stem cell transplantation through its immunologic function. However, the types of HLA and its mechanism to affect clinical outcomes are not well defined. In the other hand, heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses and was reported to influence the incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. And it was also reported that HLA types were associated with polymorphisms of HSP70-hom in several diseases. So, we evaluated the association between HLA types and HSP70-hom polymorphisms and identified the specific HLA types to affect clinical outcomes in allogeneic hematopoietic stem cell transplantation. We analyzed the DNA of patients and donors who underwent allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donors at single institute between 1998 and 2005 for malignancy or aplastic anemia. The HSP70-hom polymorphisms, rs2227956 and rs2075800, were genotyped and HLA typing was conducted in 141 patients and their donors. Individual haplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. The HSP70-hom polymorphisms of patients were completely identical to those of their donors. Patients(101) with TG haplotype (TG/TA, TG/TG or TG/CG) did not only show less treatment-related mortality but also had longer overall survival compared with those(40) with non-TG haplotype (TA/TA or TA/CG). (P=0.011, P=0.013,respectively) TG haplotype was associated with HLA types of A33, B58 and DR7.(P<0.001, P=0.002, P=0.039, respectively) Patients with HLA types of A33, B58 or DR7 showed less treatment-related mortality compared with patients without the these HLA types in multivariate analyses with age, sex, transplant method, stem cell source and risk group.(P=0.034, HR=0.397, 95% CI: 0.169–0.931) In conclusion, HLA types of A33, B58 or DR7 in HLA-matched sibling hematopoietic stem cell transplantation were protective for treatment-related mortality in association with HSP70-hom polymorphisms. [Display omitted]

Homozygous Status for HLA-E*0103 Confers Protection from Acute Graft-Versus-Host Disease and Transplant-Related Mortality in HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

The posttransplant period following hematopoietic stem cell transplantation (HSCT) is potentially high risk for developing survival-compromising complications, many of which are known to be under the control of immunogenetic factors. Given the dual role of human leukocyte antigen (HLA)-E molecules in innate and adaptive immune processes, we analyzed the impact of HLA-E polymorphism in genoidentical HSCT setting. We analyzed 187 HLA-genoidentical sibling pairs for HLA-E polymorphism. To explore its potential association with the incidence of acute and chronic graft versus host disease (aGVHD, cGVHD), severe infections, risk for transplant-related mortality (TRM), and overall survival, HLA-E locus was genotyped by a polymerase chain-reaction-sequence-specific primer (PCR-SSP) strategy. Multivariate analysis, taking into account the patient-, donor- and transplant-related factors, showed that the incidence of aGVHD and TRM at day 180 were low when the genotype was HLA-E*0103/E*0103, either in the donor or in the recipient, the pairs being identical for HLA-E alleles (hazard ratio [HR]=0.71, P=0.009; and HR=0.42, P=0.04, respectively). We also found a trend towards association between E*0103 homozygosity and improved survival (P=0.05). There was no association between HLA-E polymorphism and incidence of severe infections. These data suggest that the homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against aGVHD and TRM and likely contributes to improved survival in HLA-genoidentical bone marrow transplantation.

Hematopoietic stem cell transplantation for Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry

The Diamond Blackfan Anemia (DBA) Registry of North America is a detailed database of patients with DBA from the United States and Canada. To date, 354 patients have been registered. From this database an analysis of the outcome of hematopoietic stem cell transplantation for DBA was undertaken. Of the 20 transplanted patients who met criteria for the diagnosis of DBA, eight underwent an allogeneic HLA-matched sibling hematopoietic stem cell transplant (SCT) and 12 an alternative donor SCT. The median age at transplant for all patients was 6 years 2 months; 3 years 10 months vs 9 years 1 month for HLA-matched sibling and alternative donor SCT, respectively. All of the HLA-matched sibling transplants were done using a non-irradiation-containing regimen, whereas the majority of alternative donor transplants were performed using total body irradiation. The survival for HLA-matched sibling vsalternative donor transplant was 87.5% +/- 11.7% vs 14.1% +/- 12.1% at greater than 5 years from SCT (P = 0.015). The use of HLA-matched sibling SCT should be considered for all patients with suitable donors. However, alternative donor SCT in DBA must be approached cautiously, the potential for severe aplastic anemia (SAA) or hematopoietic malignancy not withstanding.