Agathe Rosenmayr

Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation.

We assessed long-term outcome in 155 patients who had undergone an allogeneic/syngeneic stem cell transplant (SCT) and were in complete remission for more than 2 years after transplant. Probability of late transplant-related mortality was 6%, and affected only patients with chronic graft-versus-host disease (cGVHD). Thirteen percent of patients experienced relapse. Overall survival projected at 10 and 15 years was 83% and 76%, respectively. Secondary malignancies occurred in two patients, 7.5 and 11 years after SCT. Three female and four male patients parented children 19 to 84 months after SCT. Quality of life (QoL) was assessed in a cross-sectional study by the means of a 30-item questionnaire (QLQ-C30) of the EORTC. The questionnaire was sent to 127 patients remaining alive and answered by 106 patients. Seventy-three percent reported a good to very good QoL within 5 years after SCT and 78% after this time point. However, patients with cGVHD had significant impairment of physical, role and social functioning and only 60% of them were fit for work. These results from long-term survivors show that high cure rates with good to very good QoL can be achieved by allogeneic or syngeneic SCT.

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

Summary: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.

Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry.

Summary. Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft‐versus‐host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post‐transplant follow‐up was 5·6 years (range, 0·2‐‐16·7). Multivariate analysis of transplant‐related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia‐free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.

KIR genes and KIR ligands affect occurrence of acute GVHD after unrelated, 12/12 HLA matched, hematopoietic stem cell transplantation

Interactions of polymorphic killer Ig-like receptor (KIR) receptors with KIR ligands have been shown to modify the outcome of hematopoietic SCT (HSCT). The association of these genetic factors with different transplantation endpoints, however, varies substantially, depending on clinical and study setup variables. We aimed to assess whether KIR ligands, KIR genes and KIR haplotypes are associated with HSCT outcome of 124 patients with various hematological malignancies, transplanted with 12/12 HLA matched grafts from unrelated donors. For this purpose, patient and donor KIR gene and KIR ligand polymorphisms were determined and correlated with clinical data in simple and multiple models. We found that a missing HLA-C2 ligand for donor inhibitory KIR2DL1 was significantly associated with an increased risk of acute GVHD (aGVHD) (II–IV) (hazard ratio (HR)=2.23, 95% confidence interval (95% CI): 1.21–4.10, P=0.010), as were the AA KIR haplotypes in patients and donors in HLA-C1CX (HR=2.37, 95% CI: 1.16–4.84, P=0.018) and in HLA-Bw4− (HR=3.20, 95% CI: 1.35–7.60, P=0.008) patients. On the contrary, transplantation of HLA-C1C2 patients with KIR2DS2 positive grafts were associated with a decreased risk of aGVHD (II–IV) (HR=0.24, 95% CI: 0.07–0.85, P=0.027). Thus, our single center study provides evidence for the modification of aGVHD risk by KIRs and their ligands.

Antithymocyte Globulin Pharmacokinetics in Pediatric Patients After Hematopoietic Stem Cell Transplantation

To analyze the dose effects of rabbit-derived antithymocyte globulin (ATG) in children after allogeneic hematopoietic stem cell transplantation (HSCT), ATG serum levels were monitored in 32 children and adolescents (median age 3.42 years, range 0.34-18.67 years) and the incidence of acute and chronic graft-versus-host disease, rejection, viral infections, EBV-lymphoproliferative disease, and survival was correlated with the ATG dose used. Cumulative doses from 7.5 to 20 mg/kg showed a constant half-life and linear correlation between dose and Cmax, whereas higher doses (30-40 mg/kg) accumulated in the body. High-dose ATG is of no benefit for preventing graft-versus-host disease but is associated with a significant increase in EBV-linked disease, and it appears to enhance the susceptibility to fatal viral infections and rejection. These data strongly support the use of a low-dose ATG regimen in pediatric HSCT.

Prophylactic red blood cell exchange for prevention of severe immune hemolysis in minor ABO‐mismatched allogeneic peripheral blood progenitor cell transplantation after reduced‐intensity conditioning

BACKGROUND: Delayed severe immune hemolysis due to donor‐derived passenger lymphocytes is observed in minor and/or bidirectional ABO‐mismatched transplants, especially after reduced‐intensity conditioning (RIC). The incidence is reported in up to 30 percent of patients and can result in multiorgan failure (MOF) and death.

Impact of HLA-DPB1 allelic and single amino acid mismatches on HSCT

The interpretation of the role of HLA‐DPB1 in unrelated haematopoietic stem cell transplantation (HSCT) is subject to discussion. We have investigated the role of HLA‐DPB1 allele matching in HSCT outcomes in 161 recipients who were HLA‐A, ‐B, ‐C, ‐DRB1 and ‐DQB1‐matched with their unrelated donors at the allelic level (10/10). In addition, we analysed the association of polymorphic amino acid mismatches of DPB1 molecule with HSCT end‐points, and a previously published permissiveness concept. HLA‐DPB1 allele mismatches were significantly associated with an increased incidence of acute graft‐versus‐host disease (aGvHD) and worse overall survival (OS). The mismatch at amino acid position 69 significantly increased the risk for transplant‐related mortality (TRM). Risk factors for aGvHD also included mismatches at positions 8, 9, 35, 76 and 84. This is to our knowledge, the first report of an in vivo effect of single amino acid mismatches on HSCT outcomes. In this study, grouping of allelic mismatches into permissive and non‐permissive categories and their association with transplantation end‐points was relevant for TRM but not for other clinical end‐points.

Association of HLA-E polymorphism with the outcome of hematopoietic stem-cell transplantation with unrelated donors.

HLA-E is a nonclassical human leukocyte antigen (HLA) class I gene with two antithetical products HLAE*0101 and HLA-E*0103. They are found on most tissues (1), HLA-E*0103 being expressed at considerably higher levels than HLA-E*0101. These differences depend on the affinity for available peptides and on the stability of refolded complexes (2). We correlated the HLA-E polymorphism with the outcome of hematopoietic stem-cell transplantation (HSCT) with unrelated donors. The median follow-up time of 124 patients transplanted at the University Hospital in Vienna between September 1995 and December 2005 was 80 months (range 35–158 months). Clinical endpoints were acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD), transplant-related mortality (TRM), relapse, and overall survival. Finally, 121 patients were evaluated for aGvHD and 102 for cGvHD. All patient donor pairs were matched for HLA-A, -B, -C, -DRB1, -DRB3/4/5, and -DQB1 alleles at four digit resolution. Patient and donor characteristics used in the statistical models are summarized in Table 1. Donor selection criteria, assessment of aGvHD and cGvHD, and supportive care during HSCT have been previously described (3). Statistical analyses comprised simple and multiple Cox regression models and competing risk analyses (4). HLA-E typing was performed by sequencing based typing of axon 3. The distribution of HLA-E alleles was similar in patients (HLA-E*0101: n 45, 37%; HLA-E*0101, *0103: n 53, 43%; HLA-E*0103: n 24, 20%) and donors (HLA-E*0101: n 38, 31%; HLA-E*0101, *0103: n 56, 46%; HLAE*0103: n 28, 23%). Two patients and two donors could not be typed due to missing DNA samples. Simple and competing risk analyses did not show evidence of an association of either of the analyzed genetic factors with clinical endpoints. Multiple regression analyses, however, showed associations with aGvHD (II–IV) (cumulative incidence at 80 days 41%, 95% confidence interval[CI]30–49), overall cGvHD (cumulative incidence at 3 years 39%, 95% CI 28–48), relapse (cumulative incidence at 3 years, 39% 95% CI 29– 48), and TRM (cumulative incidence at 180 days 17%, 95% CI 10–23). As to GvHD, HLA-E*0103, *0103 in donors was associated with a decreased risk of aGvHD (II–IV) (hazards ratio [HR] 0.39, 95% CI 0.16 – 0.99, P 0.047), whereas HLA-E*0101, *0103 in donors was associated with a decreased risk of overall cGvHD (HR 0.36, 95% CI 0.14 – 0.90, P 0.030). Regarding relapse, HLA-E*0103 alleles were associated with a higher risk (HR 2.24, 95% CI 1.03– 4.88, P 0.042). Concerning TRM, HLA-E*0103, *0103 in donors was a risk factor (HR 3.94, 95% CI 1.03– 15.02, P 0.045), whereas the presence of HLA-E*0101 alleles was protective (HR 0.32, 95% CI 0.11– 0.94, P 0.037). In summary, the presence of HLA-E*0103 in donors is associated with decreased risks of aGvHD (II–IV) and cGvHD and an increased risk of relapse. Regarding early posttransplant effects, HLA-E*0103 is associated with an increased risk of TRM. In addition to the genetic factors, multiple analyses showed significantly increasedriskofTRMinpatientswithaGvHD (I–IV), in patients at high-risk disease stage at transplantation, and in patients with donors older than 27 years (data not shown). Tamouza et al. (5) were the first to describe an association of HLA-E polymorphism with TRM in HSCT with unrelated donors. In their study, however, they found an association of HLA-E*0101, *0101 with increased TRM. This discrepancy might be due to differences between study populations (Tamouza et al. included also pediatric patients) and clinical protocols used. Especially, patients with bone marrow failure syndromes were more frequent in the Tamouza et al. study (27% vs. 0.8% in our patients). Patients suffering from bone marrow failure syndromes have high mortality rates after unrelated donor HSCT (6). The source of stem cells represents another difference (7). Although in our study, 56.5% of patients received peripheral blood stem cells, all patients in the study of Tamouza et al. had been transplanted with bone marrow-derived cells, known to prolong the time to hematologic and immunologic reconstitution and, therefore, prolong susceptibility to infections. Even though HLA-E*0103 allele cell surface expression exceeds that of HLAE*0101 (8), a similar correlation in the effectiveness of viral or bacterial antigen presentation has not been shown. Moreover, an impaired efficiency of HLA-E*0103 alleles in minor histocompatibility antigen presentation and T-lymphocyte stimulation hasbeenpostulated(9). Inefficientpresentation of minor histocompatibility antigens by HLA-E*0103 would be consistent with less aGvHD, an increased relapse rate, and increased TRM due to infections, as observed in our patients. Although our donor selection was based on a 12 of 12 allelic match, 47% of the pairs were mismatched for HLA-E alleles indicating different haplotypes. Therefore, it is possible that HLA-E serves as a surrogate marker for adjacent polymorphic loci that confer the effects we have observed. Katarina Ludajic Agathe Rosenmayr Ingrid Faé Gottfried F. Fischer Division of Blood Group Serology Medical University of Vienna Vienna, Austria

Minor ABO-Mismatches are Risk Factors for Acute Graft-versus-Host Disease in Hematopoietic Stem Cell Transplant Patients

We investigated the impact of ABO and Rhesus (Rh) blood group matching on the outcome of hematopoietic stem cell transplantation (HSCT) of 154 patients matched at 10/10 HLA loci with unrelated donors. ABO and Rh, as potential risk factors, were modeled with the clinical outcome--acute and chronic graft-versus-host disease (aGVHD, cGVHD), relapse, treatment-related mortality (TRM), and overall survival (OS)--by simple, multiple, and competing risk analyses. We found that minor ABO-mismatches represent a significant risk factor for aGVHD (II-IV) with an estimated risk increase of almost 3-fold (hazard ratio [HR]=2.92, 95% confidence interval [CI]: 1.43-5.95, P=.003), and even 4-fold for aGVHD (III-IV) (HR=4.24, 95% CI: 1.70-10.56, P=.002), but not for other transplant endpoints. No significant association of the Rh matching status with any of the HSCT endpoints was seen. These results suggest that ABO minor mismatches may play a role in aGvHD pathophysiology, possibly by providing the setting for T cell activation and antibody mediated damage. To decrease the risk of aGVHD, ABO matching should be considered in HSCT.

Improved Outcome in Patients with Chronic Myelogenous Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation Over the Past 25 Years: A Single-Center Experience

Although imatinib has become standard first-line therapy in chronic myelogenous leukemia (CML), allogeneic hematopoietic stem cell transplantation (HSCT) is still considered to be an important treatment alternative for patients with drug resistance or advanced disease. We retrospectively analyzed 175 adult CML patients who underwent HSCT at our institution between 1983 and 2007, with the aim to compare outcomes in patient subgroups and to identify prognostic variables. The median follow-up was 65 months. The probability of overall survival (OS) for all patients was 62%, with a significant improvement seen in the imatinib-era (2001-2007) compared to previous time periods (P <.05). Furthermore, a significantly better outcome for patients with chronic phase CML compared to patients with accelerated or blast phase could be observed (P < .05). Cumulative incidence (CI) of treatment-related mortality (TRM) was 9.7% at 100 days and 1 year after HSCT. CI of relapse was 5% at 1 year and 7.5% at 3 years after HSCT. Post-HSCT outcome was not influenced by pretreatment therapy with imatinib, donor type, or a conditioning regimen with total body irradiation (TBI). These data confirm earlier observations and suggest that allogeneic HSCT is still an important treatment option for high-risk patients with CML, and should thus remain an integral component in current and future treatment algorithms.