Bone marrow transplantation using unrelated donors for patients with advanced leukemia or bone marrow failure

Thirty-four patients received bone marrow transplants from unrelated donors. Donors and recipients were phenotypically matched for 6 of 6 HLA-A, B, and DR antigens in 27 cases and at 5 of 6 antigens in 7 cases. Twenty-three patients had leukemia, six had myelodysplasia, and five had aplastic anemia. Twenty-four patients had durable engraftment. Five died of sepsis prior to engraftment. Five patients failed to engraft; 2 of these patients had autologous bone marrow recovery. Seventeen patients developed grade greater than or equal to II acute graft-versus-host disease for an actuarial probability of 67 +/- 20%. The severity of acute graft-versus-host disease and its mortality appeared increased for recipients matched for 5 of 6 HLA-A, B, and DR antigens. Of the 34 patients, 13 (38%) are alive; actuarial survival beyond 6 months is 44 +/- 17%. None of the 25 leukemia and myelodysplasia patients achieving engraftment have relapsed. For leukemia and myelodysplasia recipients of 6 of 6 HLA-matched grafts, actuarial survival at 6 months was 55 +/- 21% compared with 14 +/- 26% for recipients matched for 5 of 6 HLA loci (P = 0.19). Infection and acute graft-versus-host disease were the primary causes of death in the engrafted patients. Survival for aplastic anemia patients was 20%. Late deaths due to pneumonia and bronchiolitis obliterans occurred after one year in 2 patients. Closely matched unrelated donor bone marrow transplants are associated with a higher incidence of graft failure and graft-versus-host disease than typically reported for transplants from HLA-identical siblings, but these preliminary data suggest a lower rate of relapse.     

Association of HLA-E polymorphism with severe bacterial infection and early transplant-related mortality in matched unrelated bone marrow transplantation

Despite prophylactic measures, susceptibility to severe infections in patients who had undergone bone marrow transplantation (BMT) is quite variable. To evaluate the potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections, we analyzed 77 unrelated-donor (UD) BMT pairs identically matched for classical HLA class I and class II alleles. Multivariate analysis taking into account the patient-, donor- and transplant-related factors showed that bacterial infections and transplant-related mortality (TRM) at day 180 were high when the donor genotype was HLA-E*0101/E*0101 (hazard ratio [HR]=2.20; P=0.03 and HR=2.12, P=0.048, respectively), suggesting that homozygous state for HLA-E*0101 allele is a risk factor for early severe bacterial infections and TRM in UD-BMT.     

Effect of antithymocyte globulin on quantitative immune recovery and graft-versus-host disease after partially T-cell-depleted bone marrow transplantation: a comparison between recipients of matched related and matched unrelated donor grafts

The effect of antithymocyte globulin (ATG) on quantitative immune recovery and graft-versus-host disease (GVHD) after partially T-cell-depleted bone marrow transplantation was analyzed in 59 and 32 recipients of grafts from matched related donors and matched unrelated donors (MUDs), respectively. The conditioning regimen was similar in all patients, except for ATG which was given only to MUD recipients. Thirteen MUD patients were treated with high-dose (20 mg/kg) ATG and 19 with low-dose (8 mg/kg) ATG. During the posttransplant period, CD3+, CD4+, and CD8+ T-cell numbers and the incidence of acute and chronic GVHD were significantly lower in MUD recipients compared with matched related donor recipients. MUD recipients treated with high-dose ATG showed the worst T-cell and subsets recovery. These data indicate that ATG, often used as part of conditioning regimens in recipients of T-cell-depleted grafts from MUDs, contributes to the severe and prolonged T-cell deficiency that is typical of these patients. On the other hand, it effectively reduces the incidence and severity of GVHD.     

Selection of unrelated bone marrow donors by serology,molecular typing and cellular assays

As compared to hematopoietic stem cell transplantation (HSCT) with HLA genotypically identical donors, phenotypically matched unrelated HSCT is associated with lower survival. Serologically undisclosed HLA disparities account for the increased rate of post-transplant complications. With more than 1300 alleles currently identified, high-resolution molecular typing techniques have to be applied to distinguish the extensive degree of allelic polymorphism of the HLA system. Whereas a HLA-ABDR-serologically identical donor can be identified in the International Registry for >90% of the patients, only half of them can benefit of a highly compatible donor if donor selection is based on allele level matching for HLA-A/B/Cw/DRB1/B3/B5/DQB1 loci. During the last 10 years, we identified only approximately 20% of all known HLA alleles in the searches for our mainly Caucasoid patients. Rare alleles (i.e. alleles that represent <1% of a given serotype) do not have a major impact in patient/donor matching. Most of the incompatibilities are clustered in a limited number of serotypes that can be targeted first during the searches. However, due to linkage disequilibrium (e.g. B-Cw or DRB1-DQB1), incompatibilities at a given locus are often associated with disparities at adjacent loci. In vitro cellular assays such as the cytotoxic T-lymphocyte precursor frequency (CTLpf) analysis may contribute in discriminating functionally relevant HLA class I disparities, as well as minor antigen mismatches in case of sensitized donors. When a rare variant or an uncommon association in the patient's HLA haplotype has been found, the tissue typing laboratory may recommend considering a mismatched donor early in the search procedure instead of continuing a search with a low probability of success.     

HLA-C polymorphisms in two cohorts of donors for bone marrow transplantation

The typing for HLA-C in transplantation was rather neglected in the past. However, several recent studies have emphasized its role in transplantation and its association with the outcome. Serological typing of HLA-C could identify only a limited number of HLA-C antigens, resulting in a number of HLA-C blanks. This was mainly due to the low expression of surface HLA-C and the small number of available specific anti-sera. Performing molecular methods has identified new HLA-C alleles and filled the blank of most serological typed antigens. In this study, we compared serological and molecular typing of HLA-C in two cohorts of healthy Saudis. Our serological typing method identified HLA-C1-7 with different frequencies, 23.5% of the alleles were not identified and thus defined as blank. Using the SSP molecular method, all samples were typed and all alleles were defined. Both methods showed that C?07 and C?06 have the highest frequency in the Saudi population. Our study emphasizes the importance of molecular methods in identifying all possible HLA-C alleles.     

无关供者脐带血和骨髓移植治疗不同亚型急性白血病的疗效

除同胞供者骨髓移植之外,无关供者脐带血移植（cordbloodtransplantation,CBT）与无关供者骨髓移植（bonemallowtrans—plantation,BMT）也是治疗成年急性白血病患者的重要方法。急性白血病分为急性淋巴细胞白血病（ALL）和急性髓细胞白血病（AML）两类。既往比较CBT和BMT治疗效果的研究由于受样本量的限制,未比较两种方法分别对AML与ALL的疗效。最近,13本脐带血库和骨髓库对CBT和BMT治疗急性白血病的结果进行分析,弥补了这个不足。     

Factors associated with ambivalence about bone marrow donation among newly recruited unrelated potential donors

BACKGROUND: Previous research has indicated that feelings of ambivalence about donation are associated with donors' decisions not to donate and with less positive physical and psychosocial outcomes among donors who donated despite feeling ambivalent. The current study examines the prevalence of ambivalence among newly recruited potential bone marrow donors and identifies factors associated with greater ambivalence. METHODS: Using a cross-sectional design, questionnaires were mailed to a stratified random sample of individuals newly recruited to the National Marrow Donor Program registry at 71 local donor centers. A total of 426 new recruits (63%) completed and returned the questionnaire. RESULTS: Bivariate analyses indicated that multiple recruitment experience and donor perception variables were significantly associated with ambivalence. Multivariate analysis revealed that the following eight variables were uniquely associated with higher levels of ambivalence after adjusting for the effects of other key indicators: participating in other volunteer activities, joining at a drive for a specific patient, perceiving the recruitment staff as less informative, being discouraged from joining by others, not having an intrinsic commitment to donate, being encouraged by one's culture or religion to join, believing there are risks to donation, and having a greater number of medical, work, and family concerns about donation. CONCLUSIONS: Potential donors who are motivated by an intrinsic commitment to donate, rather than extrinsic pressure, are less ambivalent about donating. In addition, recruitment staff have a potentially critical role in reducing ambivalence among new recruits by providing information that may allay any unrealistic concerns recruits may have about the medical risks and impact of donation on work and family.     

HLA-DR, DQ, and/or DP genotypic mismatches between recipient-donor pairs in unrelated bone marrow transplantation and transplant clinical outcome

Sixteen recipient-donor pairs who underwent unrelated BMT were analyzed for their HLA-class II identity by DNA-RFLP, in order to evaluate the importance of the genotypic HLA-DR, DQ, DP identity in the clinical outcome of unrelated bone marrow transplantation. From our study, a clear correlation between the HLA-DR, DQ, and DP genetic identity and acute GVHD (aGVHD) is not obvious since the number of studied cases is still limited. Nevertheless, it seems that the genetic identity influence the clinical outcome and patient survival. Six patients out of the ten who experienced severe aGVHD (greater than grade II) differed from their respective donors by HLA-DP mismatch in the GVH direction. Two patients rejected their grafts, and both presented HLA-DP incompatibilities in both GVH and HVG directions. Hence, HLA-DP may function as a transplantation antigen like the other HLA-class II molecules (DR, DQ) in unrelated BMT. Accordingly, we propose considering it in the pretransplantation histocompatibility testing. Nevertheless, further studies with larger numbers of cases should be done in order to confirm the role of HLA-DP. No correlation was observed between the mixed lymphocyte reaction (MLR) reactivity and the incidence of aGVHD. Accordingly, MLR response seems to be an incomplete indicator of GVHD, and a functional test is still to be found.     

The clinical impact of early gram-positive bacteremia and the use of vancomycin after allogeneic bone marrow transplantation

BACKGROUND: Gram-positive bacteremia (GPB) is an increasing infection after allogeneic bone marrow transplantation (BMT). Our purpose was to identify risk factors for GPB, to evaluate its impact on early mortality and morbidity, and to compare prophylactic with empirical intravenous vancomycin. METHODS AND RESULTS: We studied 89 consecutive BMTs in adult patients. Early GPB occurred in 29% of posttransplantation episodes. T-cell depletion (odds ratio [OR]: 0.18) and vancomycin-prophylaxis (OR: 0.28) reduced the risk of GPB. Mortality at 6 weeks was not significantly different in patients with GPB (15% vs. 9.5%, P = 0.669). GPB was associated with the development of major complications, the use of amphotericin B, and prolonged neutropenia. Vancomycin prophylaxis led to an increased risk of early renal dysfunction (OR: 18.7). CONCLUSION: GPB contributes to overall morbidity during the early post-BMT episode but has no impact on mortality. Vancomycin prophylaxis is effective to reduce GPB but has a negative effect on renal function.