Long-term outcomes of HLA-matched sibling compared with mismatched related and unrelated donor hematopoietic stem cell transplantation for chronic phase chronic myelogenous leukemia: a single institution experience in China

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) remains the only curative therapy for chronic myelogenous leukemia (CML). In this study, the long-term outcomes of HLA-matched sibling donor (MSD) with mismatched related donor (MRD) and unrelated donor (URD) transplantation for CML in the first chronic phase (CML-CP1) using different graft vs. host disease (GVHD) prophylaxis regimens according to donor source and the degree of HLA matching were compared. The data of 91 patients with CML-CP1 were analyzed with respect to GVHD, overall survival (OS), and transplant-related mortality (TRM). The incidence of grade II?CIV acute GVHD was 25.5% in the MSD and 40.5% in the MRD/URD group (P?=?0.133). The 1-year cumulative incidence of chronic GVHD was not different between the MSD and the MRD/URD groups, while extensive chronic GVHD was different between the two groups (31.9% vs. 10.8%, P?=?0.023). The 5-year cumulative relapse rate was not different between the MSD and the MRD/URD groups, while TRM was different between the two groups (6.6% vs. 26.3%, P?=?0.010). The 5-year cumulative OS was 90.9%, 71.5%, and 85.4% in the MSD, the MRD/URD, and the HLA allele-matched URD transplantation, respectively (MSD vs. MRD/URD, P?=?0.013; MSD vs. HLA allele-matched URD, P?=?0.437). In conclusion, survival in HLA allele-matched URD is equivalent to MSD, but in MRD and mismatched URD is inferior to MSD in patients with CML-CP1 undergoing allo-HSCT using different GVHD prophylaxis regimens according to donor source and degree of HLA matching. Patients undergoing MRD/URD transplantation have an equal quality of life as patients undergoing MSD transplantation.     

Hematopoietic transplantation from adult unrelated donors as treatment for acute myeloid leukemia

Transplantation from unrelated donors (URD) is increasingly being used as treatment for hematological malignancies, including acute myeloid leukemia (AML). This increase is the consequence of the availability of more than 11 million URD volunteers and the more efficient donor search process in the recent years. Median time to identify a suitable URD is now 2 months. More than 50% of Caucasian patients have an human leukocyte antigen (HLA)-allele donor match and a one-antigen or allele HLA-mismatched donor may also be acceptable. Complications of URD transplants are particularly frequent and severe, with long-term OS in the registries being 10-20% inferior to HLA-identical sibling transplantation. High resolution DNA techniques for donor and recipient HLA matching have contributed to the survival in experienced centres after unrelated donor SCT approaching that achieved with sibling donors. The introduction of reduced intensity conditioning (RIC) has extended URD transplants to elderly and/or debilitated patients with AML. With this approach, TRM decreases, although graft-versus-host disease-related morbidity and mortality remain a problem. Despite this complication, results after URD transplantation in this age group seem better than those achieved with chemotherapy and/or autologous transplantation. To confirm this possibility, prospective multicenter comparisons of URD transplants after RIC with other treatment options for elderly AML patients have recently been started.     

Unrelated donor transplants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 x 10⁹/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 x 10⁹/L. Factors associated with poorer survival included WBC more than 100 x 10⁹/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.     

Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program

Over a period of 8.5 years (February 1988 to October 1996), 1423 patients with chronic myelogenous leukemia (CML) underwent unrelated donor (URD) bone marrow transplants (BMTs) facilitated by the National Marrow Donor Program (NMDP) at 85 transplant centers. One hundred thirty-seven evaluable (9.9%) patients failed to engraft, and an additional 83 (6.6%) evaluable patients experienced late graft failure. Grade III/IV acute graft-versus-host disease (GVHD) developed in 33% of patients (95% confidence interval [CI], 30%-36%). The incidence of extensive chronic GVHD was 60% (95% CI, 56%-63%) at 2 years. Only 5.7% of patients (95% CI, 3.6%-7.8%) transplanted in chronic phase developed hematologic relapse at 3 years. Several factors were independently associated with improved disease-free survival (DFS), including transplant in chronic phase, transplant within 1 year of diagnosis, younger recipient age, a cytomegalovirus seronegative recipient, and development of no or mild acute GVHD. The combined effect of these factors on outcome is manifest in a subset (n = 157) of young (less than 35 years), chronic phase patients transplanted within 1 year of diagnosis using HLA-matched donors who had 63% (95% CI, 53%-73%) DFS at 3 years. URD BMT therapy for CML is both feasible and effective with more frequent and more rapid identification of suitable donors. Early URD transplant during chronic phase yields good results and should be considered in CML patients otherwise eligible for transplant but without a suitable related donor.     

Outcomes of transplantation with partial T-cell depletion of matched or mismatched unrelated or partially matched related donor bone marrow in children and adolescents with leukemias

Graft-versus-host disease (GVHD) remains a major barrier to successful hematopoietic stem cell transplant for patients who lack a matched related donor. Partial T-cell depletion (TCD) of the graft may decrease the risk of severe GVHD with unrelated donors (URD) and partially matched related donors (PMRD) while retaining an antileukemic effect. We analyzed our experience using URD and PMRD for pediatric patients with leukemias from 1990 to 2001. A subgroup of 'matched' URD donor pairs was retrospectively analyzed for high-resolution class I. Partial TCD was accomplished with monoclonal antibody T10B9 or OKT3 and complement. There were 76 URD (45% matched) and 28 PMRD recipients. Event-free survival (EFS) was 38.3%, and overall survival (OS) 45.1% at 3 years. On multivariate analysis, there was no difference in survival based upon marrow source, but nonrelapse mortality was higher with the use of PMRD. Relapse occurred in 6% of ALL patients, and 22.8% of AML/MDS patients. Grades III-IV GVHD was observed in only 6.7% of patients. Partial TCD allows use of matched or mismatched URD, or PMRD with little mortality from GVHD, durable engraftment, and no increase in relapse risk.     

Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value

We analyzed 112 patients with high-risk acute myeloid leukemia (61 in complete remission [CR]; 51 in relapse), who received human leukocyte-antigen (HLA)-haploidentical transplants from natural killer (NK) alloreactive (n = 51) or non-NK alloreactive donors (n = 61). NK alloreactive donors possessed HLA class I, killer-cell immunoglobulin-like receptor (KIR) ligand(s) which were missing in the recipients, KIR gene(s) for missing self recognition on recipient targets, and alloreactive NK clones against recipient targets. Transplantation from NK-alloreactive donors was associated with a significantly lower relapse rate in patients transplanted in CR (3% versus 47%) (P > .003), better event-free survival in patients transplanted in relapse (34% versus 6%, P = .04) and in remission (67% versus 18%, P = .02), and reduced risk of relapse or death (relative risk versus non-NK-alloreactive donor, 0.48; 95% CI, 0.29-0.78; P > .001). In all patients we tested the "missing ligand" model which pools KIR ligand mismatched transplants and KIR ligand-matched transplants from donors possessing KIR(s) for which neither donor nor recipient have HLA ligand(s). Only transplantation from NK-alloreactive donors is associated with a survival advantage.     

Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes

Inhibitory killer immunoglobulin (Ig)-like receptors (KIRs) recognize HLA-C and -B epitopes on target cells, thereby regulating natural killer (NK) cell activity. In 178 patients receiving T-cell-depleted HLA-identical sibling transplants for acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS), analysis of donor KIR genotype with HLA genotype demonstrated that 62.9% of the patients lacked an HLA ligand for donor-inhibitory KIR. Lack of HLA ligand for donor-inhibitory KIR (missing KIR ligand) had no effect on disease-free survival (DFS), overall survival (OS), or relapse in patients receiving transplants for CML and ALL. In patients with AML and MDS, however, there was a significant missing KIR ligand effect on DFS (P = .014; hazard ratio [HR], 0.53; 95% confidence interval [95% CI], 0.28-0.88) and OS (P = .03; HR, 0.53; 95% CI, 0.3-0.93). Incidence of relapse was also lower in patients with AML and MDS who lacked the HLA ligand for donor-inhibitory KIR (P = .04; HR, 0.41; 95% CI, 0.18-0.97). AML and MDS patients lacking 2 HLA ligands for donor-inhibitory KIR had the highest DFS (P = .002) and OS (P = .003). There was no significant contribution of donor-activating KIR to transplantation outcome in these patients. These data indicate that the absence of class I ligand in the recipient for donor-inhibitory KIR can be a prognostic factor for transplantation outcome in HLA-identical sibling transplantation and that the lack of HLA-C or -B ligands for donor-inhibitory KIR can contribute to improved outcomes for patients with AML and MDS.     

Prognosis after unmanipulated HLA-haploidentical blood and marrow transplantation is correlated to the numbers of KIR ligands in recipients

OBJECTIVES: The goal of this study was to explore the role of NK cell alloreaction in predicting prognosis under unmanipulated HLA-haploidentical blood and marrow transplantation and examine whether the presence of any individual donor-activating KIR gene had an influence on the clinical outcome. METHODS: We studied the HLA and KIR genotype of 64 donor-recipient pairs, who underwent transplantation. RESULTS: In contrast to Perugia's KIR ligand-ligand mismatch model or Handgretinger's KIR receptor-ligand mismatch model or Bignon's KIR gene-gene mismatch model between donor-recipient pairs, we found that the cumulative incidence of 3-yr disease-free survival (DFS), overall survival (OS), and transplantation-related mortality (TRM) were best predicted by the number of KIR ligands carried by patients (HR 0.355, 95% CI 0.186-0.678, P = 0.002 for DFS; HR 0.445, 95% CI 0.233-0.848, P = 0.014 for OS; HR 0.450, 95% CI 0.219-0.926, P = 0.030 for TRM). Moreover, an analysis of KIR ligand numbers was found to be correlative in patients with lymphoid malignancy. The KIR ligand-ligand mismatch model is a good predictor of acute graft vs. host disease (aGVHD; HR 3.812, 95% CI 1.667-8.720, P = 0.002). Meanwhile, the presence of donor-activating KIR2DS3 also contributed significantly to acute (HR 2.967, 95% CI 1.265-6.958, P = 0.012) and chronic GVHD (HR 2.541, 95% CI 1.127-5.730, P = 0.025). CONCLUSIONS: These data indicate that prognosis after transplantation is associated with the numbers of KIR ligands in recipients and T-cell alloreaction may play a predominant role in this model.     

Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT

Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell-mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia.     

Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.     

Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study

We report results in 41 consecutive patients with chronic lymphocytic leukemia (CLL) who underwent allogeneic hematopoietic cell transplantation (HCT) after fludarabine, melphalan, and alemtuzumab conditioning. Donors were 24 HLA-matched siblings and 17 unrelated volunteers, 4 of them mismatched with recipients. All but 3 patients had initial hematologic recovery, but 5 more patients had secondary graft failure. Median intervals to neutrophil (greater than 0.5 x 10(9)/L) and platelet (greater than 20 x 10(9)/L) recovery were 14 days (range, 9-30 days) and 11 days (range, 8-45 days), respectively. Eleven (27%) patients had relapses and received escalated donor lymphocyte infusions, but only 3 of them had sustained responses. Acute and chronic graft-versus-host disease (GVHD) was observed in 17 (41%) and 13 (33%) patients, respectively. Seventeen (41%) patients have died, 5 of progressive disease. The 2-year overall survival and transplantation-related mortality (TRM) rates were 51% (95% confidence interval [CI], 33%-69%) and 26% (95% CI, 14%-46%), respectively. The alemtuzumabbased regimen was feasible and effective in patients with CLL with a relatively low rate of GVHD. However, TRM remains relatively high as a result of a variety of viral and fungal infections. Studies are ongoing to address the efficacy of reduced doses of alemtuzumab in this group of immunosuppressed patients.     

Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors

OBJECTIVE: About one third of patients requiring allogeneic hematopoetic stem cell transplantation (HSCT) would not find a matched sibling or alternative donor. Allogeneic HSCT from matched unrelated and mismatched donors carries an increased risk of graft-vs-host disease (GVHD) and transplant-related mortality (TRM). MATERIALS AND METHODS: We used anti-thymocyte globulin (ATG-Fresenius) at a median dose of 90 mg/kg body weight as part of a total body irradiation or busulfan-based conditioning regimen for prevention of serious GVHD. All patients received cyclosporine A and short-course methotrexate. We compared outcomes of 65 recipients of human leukocyte antigen (HLA)-mismatched unrelated grafts and 194 recipients of HLA-matched unrelated grafts. Mismatches involved one or two loci. Both groups were comparable in age, graft source, diagnosis, stage of disease, and conditioning regimen, and differed only in dose of ATG administered. RESULTS: For matched and mismatched transplants, respectively, there was no significant difference in graft failure (0.5% vs 3%; p = 0.16), in the cumulative incidence of grade II to IV acute GVHD (45% vs 35%; p = 0.14) and no difference in overall chronic GVHD (42% vs 40%; p = 0.68). Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 55% vs 50% (p = 0.99) and 47% vs 47% (p = 1.0), respectively. The cumulative incidence of relapse and TRM at 5 years were 24% vs 25% (p = 0.63), and 29% vs 27% (p = 0.59), respectively. CONCLUSION: Inclusion of ATG-Fresenius in the conditioning regimen permits HSCT from mismatched unrelated donors without excess TRM and GVHD, resulting in identical OS and DFS of recipients of HLA-matched and HLA-mismatched grafts.     

Impact of HLA matching on outcome of hematopoietic stem cell transplantation in children with inherited diseases: a single-center comparative analysis of genoidentical, haploidentical or unrelated donors

Summary:Hematological inherited diseases can be cured by hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling donor (MSD), but the outcome of unrelated donors (URD) or haploidentical donors (HMD) has been a cause of concern. In all, 94 children affected with inherited diseases underwent HSCT at a single center using MSD (group A, n=31), URD (group B, n=23) or HMD (group C, n=40). There was no difference in the rate of engraftment or in the incidence of grades III-IV acute graft-versus-host disease (GVHD) between the groups. Survival rate was 80.6% in group A, 62.5% in group B and 47.5% in group C (P=0.023). In group B, survival rate was 73.7% in the subgroup with zero or one class I mismatch, and 25% in the subgroup with two or more class I mismatches (P=0.04). In group C, survival rate was 83.3% in the 9/10-identical subgroup, 64.3% in the seven or 8/10 subgroup, and 25% in the five or 6/10 subgroup (P=0.0007). Thus, engraftment, incidence of GVHD and survival are similar in recipients of grafts from MSD, URD with 0-1 class I-mismatch, or HMD with at least 7/10 HLA matches. The low success of HSCT using more disparate donors suggests reserving them for patients with very poor prognosis.     

Allo-SCT in children with high-risk leukemia using unmanipulated grafts from alternative donors

Allogeneic HSCT is a curative treatment for high-risk leukemia. In Europe, approximately 15% of children have an HLA-matched sibling, but in 65-70% HLA allele-matched (9-10/10) unrelated donors (UD) can be identified. Transplantation using an HLA partially mismatched donor, unrelated cord blood or haploidentical family donor with graft manipulation is then considered with preference on the basis of local experience and/or availability. Here we evaluate the outcomes of 87 consecutive patients with leukemia transplanted with unmanipulated graft from matched or partially mismatched UD or cord blood (CB) at our institution between January 2001 and December 2007. Within the median follow-up of 30 months, the acute GVHD grade II was diagnosed in 70.9% patients; grades III-IV only in 4.6%. The overall incidence of chronic GVHD was 43.3% (extensive in 34.9%). The probability of 3-year EFS was 59.5% and that of 3-year overall survival was 66.9%. TRM at day +100 was 4.5%, and overall it was 13.8%. Fourteen patients (16.1%) died as a consequence of post-transplant leukemia relapse. We conclude that the prognosis of patients transplanted for leukemia using unmanipulated grafts from HLA-matched or partially mismatched UD or CB is comparable and satisfactory. TRM and relapse rate are lower than in the earlier period.     

The diversity of KIR gene in Chinese Northern Han population and the impact of donor KIR and patient HLA genotypes on outcome following HLA-identical sibling allogeneic hematopoietic stem cell transplantation for hematological malignancy in Chinese people

Killer cell immunoglobulin-like receptors (KIRs) are members of a group of molecules that specifically recognize HLA class I ligands and are found on subsets of human lymphopoetic cells. The number of KIR loci can vary between individuals, resulting in a heterogeneous array of possible KIR genes. The range of observed profiles has been explained by the occurrence of two haplotype families termed A and B, which can be distinguished on the basis of certain KIR sequences. Immunogenetic analysis of different ethnic populations shows significant differences in terms of the distribution for group A and group B haplotypes. Recently, attention has been focused on the role of killer cell immunoglobulin-like receptor (KIR)-ligand incompatibility in the graft-versus-host direction between donor and recipient in allogeneic hematopoietic stem-cell transplantation (ASCT). The goal of this study was to study the frequency of specific KIR genes in Chinese Northern Han population and evaluate the role of KIR-ligand mismatch in Chinese HLA-identical sibling hematopoietic stem cell transplantation patients with hematological malignancy. Here genomic DNA from 150 Northern Chinese Han individuals was typed for the presence or absence of KIR genes. Seventy-four allogeneic stem cell transplantation donor/recipient pairs were typed for HLA-A, B, C and KIR. Sixteen KIR genes were observed in the population, and framework genes 3DL3, 3DP1, 2DL4, and 3DL2 were present in all individuals. Twenty-two different genotypes were found. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 51.9% (78/150). We observed that 57 out of 74 (77.3%) donor–recipient pairs could be characterized by lack of recipient HLA ligand for donor KIR. We observed that 36 out of 45 (80%) donor–recipient HLA-identical sibling transplant pairs could be characterized by lack of recipient HLA ligand for donor KIR. Cumulative incidence analysis of aGVHD in patients undergoing HLA-identical sibling hematopoietic stem cell transplantation in this study demonstrated a decreased incidence of severe aGVHD in patients lacking HLA ligand for donor-inhibitory KIR2DL1 (31.4 vs. 70%, P = 0.029). And also in AML (acute myeloid leukemia) patients lacking HLA ligand for donor-inhibitory KIR and KIR2DL1 (17.6 vs. 75%, P = 0.03). Our data demonstrated that the Chinese Han population is distinct in KIR gene frequencies and putative KIR haplotypes in comparison to some other populations. Almost all allogeneic donors could be characterized as having an inhibitory KIR for each of the three known class I ligands. KIR and KIR2DL1 mismatch is associated with lower aGVHD in Chinese after HLA-identical sibling hematopoietic stem cell transplantation. L. P. Dou and D. H. Zheng contribute equally to this article.     

Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.     

Unrelated cord blood and mismatched unrelated volunteer donor transplants, two alternatives in patients who lack an HLA-identical donor

The aim was to evaluate two transplant strategies for patients who lack HLA-identical donors, namely HLA-A, HLA-B or -DR beta 1 mismatched unrelated donor (MM URD) transplants (n=14) and umbilical cord blood transplants (UCB, n=27). Diagnosis, disease stage and age were similar in the two groups. Cell dose was lower in the UCB group (P<0.001). Median time to ANC of >0.5 x 10(9)/l was 30 days in the UCB group and 17 days in the MM URD group (P=0.002). Engraftment of plt was delayed in the UCB group (P=0.03). The UCB patients required fewer erythrocyte transfusions (P=0.001). At 100 days, complete donor chimerism for CD3 was 63 and 44% in the UCB and MM URD groups, respectively. Acute GVHD of grades II-IV were 30% in the UCB group and 21% in the MM URD group. The corresponding figures for chronic GVHD were 9 and 20%, respectively. TRM was 30% in the UCB patients and 50% in the MM URD patients. Three-year survival was 66% in the UCB group and 14% in the MM URD group (P=0.006). Although the material is small and heterogeneous, engraftment was delayed, leukocyte chimerism was not significantly different and survival was superior using UCB rather than MM URD transplants.     

供受者KIR配体表达对单倍体相合造血干细胞移植预后的影响

目的:探讨供受者杀伤细胞免疫球蛋白样受体(KIR)配体表达在单倍体相合造血干细胞移植(HSCT)预后中的意义.方法:接受单倍体相合HSCT患者31例,均未进行体外T细胞去除(TCD).采用序列特异性引物聚合酶链式反应(PCR-SSP)分型技术对供受者人类白细胞抗原(HLA)及供者KIR基因型进行检测.分别分析供受者表达不同的KIR配体(是否表达HLA-A3或A11、-Bw4以及C1纯合和C1/C2杂合)对造血重建、移植物抗宿主病(GVHD)、无病生存(DFS)、移植后感染及移植相关死亡(TRM)等方面的影响.结果:患者HLA-Bw4和C1/C2共表达组血小板植入较非共表达组延迟(P＜0.05).供者表达HLA-Bw4组与不表达组相比,DFS显著延长,TRM降低(均P<0.05).供者HLA-Bw4与C1/C2共表达组DFS亦显著高于非共表达组(P＜0.05).供者表达HLA-A3或A11组的巨细胞病毒血症发生率显著低于不表达组(P＜0.05).结论:在非体外TCD的单倍体相合HSCT中,患者HLA-Bw4和C1/C2共表达组血小板植入延迟;供者表达HLA-Bw4可以改善患者的DFS,降低TRM,尤其与C1/C2共表达时改善DFS作用更为显著.     

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

There is consensus that matching of unrelated donors (URD) and patients for HLA class II alleles improves the outcome of hematopoietic stem cell transplantation (HSCT). However, the significance of HLA class I allelic mismatches for transplant outcome is under discussion and reports on long-term effects like chronic graft-versus-host disease (GVHD) are rare. Thus, we investigated the association of human leukocyte antigen (HLA) class I allele mismatches and outcome in 144 patients given HSCT from URD who were matched for HLA-DRB1, DRB3/4/5, and DQB1 alleles. The risk of chronic GVHD was significantly increased in patients with class I mismatched donors, the mismatch either detected by low- or high-resolution typing. A single HLA class I allele mismatch significantly increased the risk of chronic GVHD in multivariate analysis. Overall survival was significantly reduced in patient/donor pairs with more than one-allele class I mismatch. Thus, selection of unrelated donors for transplantation should be based on high-resolution HLA class I typing.     

Unrelated donor bone marrow transplantation: influence of HLA A and B incompatibility on outcome

We have studied the outcome of 211 consecutive unrelated donor (URD) bone marrow transplants (BMT) performed at the University of Minnesota (Minneapolis, MN) between May 1985 and December 1992. Ninety patients (43%) received marrow matched serologically at HLA A, B, and DR loci; 86 (41%) received marrow with a major and 32 (15%) marrow with a minor serologic mismatch at the HLA A or B locus. Multivariate analysis revealed that older age had an adverse effect on survival. In younger (age less than 18 years) recipients, survival after fully matched (A, B, and DR sub-type) or major mismatched (A or B locus), DR subtype- matched donor BMT was not significantly different (P = .4; survival: 53% v 41%, respectively, at 3 years). For adults, survival after matched donor BMT was significantly better than that with mismatched donors (P < .01; survival: 30% v 10%, respectively, at 3 years). Formal quality of life assessment by telephone interview demonstrated similar functional status in survivors of URD and related donor (RD) BMT at least 2 years post-BMT. URD BMT provides effective therapy for a variety of lethal hematopoietic diseases that rivals outcome of RD transplant in some cases. Use of URD marrow with a major mismatch at one HLA A or B locus is well tolerated in young, but not in older, recipients. These observations should be used to improve donor selection and counseling for URD BMT candidates.