Nuclear factor-κB1 and MicroRNA-146a polymorphisms and risk of acute graft versus host disease post allogeneic stem cell transplantation

Acute graft-versus-host disease (aGVHD) is a severe inflammatory complication of haematopoeitic stem cell transplantation. The nuclear factor- Kappa Beta (NF-κB) signaling pathway regulates T cell activation. The NF-κB controls the expression of microRNA-146a (miR-146a) that in turn regulates NF-κB activation through a negative feedback loop. We aim to analyze the association between NF-κB1 encoding p50 (rs28362491, −94 in.ertion/deletion ATTG) and miR-146a (rs2910164, G > C) polymorphisms and risk of aGVHD. Genotyping was performed for 135 HLA-matched donors using polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).The incidence of aGVHD grades II-IV was 24/135 (17.8 %). NF-κB1 genotype and cytomegalovirus infection were significantly associated with risk of aGVHD II-IV (p = 0.022, HR = 3.17, 95 % CI:1.18-8.51 and p = 0.048, HR = 2.56, 95 % CI:1.01–6.52, respectively). In multivariate analysis, NF-κB1homozygous deletion/deletion genotype was the only independent risk factor associated with aGVHD II-IV (p = 0.013, HR = 3.50, 95 % CI:1.30–9.44). No significant association could be observed between miR-146a polymorphism and aGVHD. Combined NF-κB1 and miR146a genotype analysis warrants investigation in a larger cohort. Our preliminary data do not support the association between miR146a and aGVHD, but suggest an association between NF-κB1 and risk of aGVHD that may pave the way for the development of a novel targeted therapy if proved in a larger cohort.     

Incidence of invasive fungal disease after unmanipulated haploidentical stem cell transplantation was significantly higher than that after HLA-matched sibling transplantation

The aim of this study was to determine the incidence, clinical features and outcome of invasive fungal disease (IFD) after either unmanipulated haploidentical haematopoietic stem cell transplantation (HSCT) or human leukocyte antigen (HLA)-matched sibling HSCT. This was a head-to-head comparative study performed at a single centre. Patients were admitted between 2007 and 2010, and IFD was evaluated according to the revised EORTC/MSG criteria, with only proven and probable cases included. Of the 1042 consecutive patients enrolled, 390 received the HLA-matched HSCT and 652 received unmanipulated haploidentical HSCT. A total of 61 (5.8%) patients had IFD, including 15 proven cases and 46 probable cases. The incidence of IFD after unmanipulated haploidentical HSCT was significantly higher than that after HLA-matched transplantation (7.1% vs. 3.3%, respectively; p 0.007). IFD occurred later in patients receiving HLA-matched transplantation compared with patients receiving unmanipulated haploidentical HSCT (141.5 vs. 23 days, respectively; p 0.04). In multivariate analysis, acute graft-versus-host disease (GVHD) grades III to IV (HR = 2.214, 95% CI, 1.139–4.304; p 0.019), extensive chronic GVHD (HR = 2.413, 95% CI, 1.377–4.228; p 0.002) and haploidentical transplantation (HR = 2.648, 95% CI, 1.111–6.310; p 0.028) were identified as significant risk factors associated with IFD. The response to antifungal therapy and the IFD-attributable mortality were similar between the two types of transplantation. In conclusion, patients who received unmanipulated haploidentical HSCT had a higher risk of IFD than those patients who received HLA-matched HSCT, but the prognosis of IFD was not associated with the HLA type.     

Comparison of HLA Allele Mismatch and Antigen Mismatch in Unrelated Bone Marrow Transplantation in Patients with Leukemia

We compared the effect of HLA single-antigen and single-allele mismatched unrelated bone marrow transplantation (UBMT) without in vivo/ex vivo T cell depletion. Becasue a single DRB1 mismatch is preferred among 1-allele or 1-antigen mismatched donors, we performed mismatched allele- or antigen-specific analyses with a single DRB1 mismatch as the reference. In adjusted comparison by multivariate analyses, an HLA-DRB1 single-allele mismatch resulted in a decreased risk of nonrelapse mortality (NRM; relative risk [RR], 1.33; 95% confidence interval [CI], 1.08 to 1.63, P?=?.006) compared with an HLA-DR single-antigen mismatch and conferred a decreased risk of NRM (RR, 1.25; 95% CI, 1.01 to 1.57; P?=?.025) and overall mortality (RR, 1.16; 95% CI, 1.00 to 1.37; P?=?.046) compared with an HLA-C single-antigen mismatch. Relative to an HLA-DRB1 single-allele mismatch, 2-mismatch transplants, including those with 1 or more antigen mismatches, resulted in a significantly increased risk of NRM (1-antigen/1-allele mismatch: RR, 1.68; 95% CI, 1.03 to 2.05; P < .001; 2-antigen mismatch: RR, 1.58; 95% CI, 1.04 to 2.02; P?=?.001) and overall mortality (1-antigen/1-allele mismatch: RR, 1.27; 95% CI, 1.09 to 1.47; P?=?.002; 2-antigen mismatch: RR, 1.27; 95% CI, 1.03 to 1.57; P?=?.02). NRM correlated with the combined number of mismatches and allele or antigen mismatches, with rates of 22%, 27%, 32%, 31%, and 38% at 4years for full match, single-allele mismatch, single-antigen mismatch, 2-allele mismatch, and 2 mismatches that included an antigen mismatch, respectively. Our results support the preference for an allele mismatch rather than an antigen mismatch in unrelated bone marrow donors with 1 DR mismatch or 2 mismatches for T cell–replete UBMT.     

Does matching for SNPs in the MHC gamma block in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic stem cell transplant improve outcomes?

Background

Matching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes.

Refinement of the Definition of Permissible HLA-DPB1 Mismatches with Predicted Indirectly ReCognizable HLA-DPB1 Epitopes

Hematopoietic stem cell transplantation with HLA-DPB1–mismatched donors leads to an increased risk of acute graft-versus-host disease (GVHD). Studies have indicated a prognostic value for classifying HLA-DPB1 mismatches based on T cell–epitope (TCE) groups. The aim of this study was to determine the contribution of indirect recognition of HLA-DP–derived epitopes, as determined with the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) method. We therefore conducted a retrospective single-center analysis on 80 patients transplanted with a 10/10 matched unrelated donor that was HLA-DPB1 mismatched. HLA-DPB1 mismatches that were classified as GVH nonpermissive by the TCE algorithm correlated to higher numbers of HLA class I as well as HLA class II presented PIRCHE (PIRCHE-I and -II) compared with permissive or host-versus-graft nonpermissive mismatches. Patients with acute GVHD grades II to IV presented significantly higher numbers of PIRCHE-I compared with patients without acute GVHD (P < .05). Patients were divided into 2 groups based on the presence or absence of PIRCHE. Patients with PIRCHE-I or -II have an increased hazard of acute GVHD when compared with patients without PIRCHE-I or -II (hazard ratio [HR], 3.19; 95% confidence interval [CI], 1.10 to 9.19; P < .05; and HR, 4.07; 95% CI, .97 to 17.19; P = .06, respectively). Patients classified as having an HLA-DPB1 permissive mismatch by the TCE model had an increased risk of acute GVHD when comparing presence of PIRCHE-I with absence of PIRCHE-I (HR, 2.96; 95% CI, .84 to 10.39; P = .09). We therefore conclude that the data presented in this study describe an attractive and feasible possibility to better select permissible HLA-DPB1 mismatches by including both a direct and an indirect recognition model.     

Single Antigen–Mismatched Unrelated Hematopoietic Stem Cell Transplantation Using High-Dose Post-Transplantation Cyclophosphamide Is a Suitable Alternative for Patients Lacking HLA-Matched Donors

The optimal prophylaxis regimen for graft-versus-host disease (GVHD) in the setting of mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation (alloHSCT) is not defined. The use of high-dose post-transplant cyclophosphamide (PTCy) in haploidentical transplantation has proven feasible and effective in overcoming the negative impact of HLA disparity on survival. We hypothesized that PTCy could also be effective in the setting of MMUD transplantation. We retrospectively analyzed 86 consecutive adult recipients of alloHSCT in our institution, comparing 2 contemporaneous groups: PTCy MMUD (n?=?26) versus matched unrelated donor (MUD) (n?=?60). Graft source was primarily peripheral blood (92%). All PTCy MMUD were HLA 7/8 (differences in HLA class I loci in 92% of patients) and received PTCy plus tacrolimus ± mofetil mycophenolate as GVHD prophylaxis. No differences were observed between PTCy MMUD and MUD in the 100-day cumulative incidence of acute GVHD grades II to IV (31% versus 22%, respectively; P?=?.59) and III to IV (8% versus 10%, P?=?.67). There was a trend for a lower incidence of moderate to severe chronic GVHD at 1 year after PTCy MMUD in comparison with MUD (22% versus 41%, P?=?.098). No differences between PTCy MMUD and MUD were found regarding nonrelapse mortality (25% versus 18%, P?=?.52) or relapse rate (11% versus 19%, P?=?.18). Progression-free survival and overall survival at 2 years were similar in both cohorts (67% versus 54% [HR, .84; 95% CI, .38 to 1.88; P?=?.68] and 72% versus 57% [HR, .71; 95% CI, .31 to 1.67; P?=?.44], respectively). The 2-year cumulative incidence of survival free of moderate to severe chronic GVHD and relapse tended to be higher in the PTCy MMUD group (47% versus 24%; HR, .60; 95% CI, .31 to 1.14; P?=?.12). We conclude that HLA 7/8 MMUD transplantation using PTCy plus tacrolimus is a suitable alternative for those patients who lack a MUD.     

Prognostic Impact of Donor Source on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Adults with Chronic Myelomonocytic Leukemia: A Nationwide Retrospective Analysis in Japan

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for patients with chronic myelomonocytic leukemia (CMML). We retrospectively compared the post-transplantation outcomes of 159 patients with CMML who underwent allo-HSCT using 4 types of donor sources: HLA-matched related donor graft, unrelated bone marrow (U-BM), unrelated cord blood (U-CB), and HLA-mismatched related donor graft. The median patient age at allo-HSCT was 54 years (range, 16 to 75 years). In multivariate analyses, the use of HLA-matched related donor grafts correlated with better overall survival than U-BM (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.21 to 3.48; P?=?.008), U-CB (HR, 3.80; 95% CI, 2.07 to 6.95; P?<?.001), or HLA-mismatched related donor grafts (HR, 6.18; 95% CI, 2.70 to 14.15; P?<?.001). Mortality after the relapse or progression of CMML did not significantly differ among the 4 types of donor source. Transplantation-related mortality was highest in recipients of U-CB (HR, 3.32; 95% CI, 1.33 to 8.26; P?=?.010). In patients with CMML, allo-HSCT using an alternative donor may contribute to durable remission; however, further improvements in transplantation-related mortality are required for this type of transplantation.     

Synergistic Effect of Major Histocompatibility Complex Class I–Related Chain A and Human Leukocyte Antigen–DPB1 Mismatches in Association with Acute Graft-versus-Host Disease after Unrelated Donor Hematopoietic Stem Cell Transplantation

The clinical relevance of mismatches at the MHC class I–related chain A (MICA) in hematopoietic stem cell transplantation (HSCT) remains unclear. We investigated the association of MICA donor/recipient mismatch and whether there is an interaction between these and HLA-DPB1 mismatch on clinical outcomes after unrelated donor HSCT. Our study included 227 patients who underwent unrelated donor allogeneic HSCT at our institution between 2000 and 2010. Among these, 177 (78%) received HSCT from a 10/10 HLA-matched donor. MICA genotyping was performed using commercially available kits. In univariable analysis, the risk of grade II to IV acute graft-versus-host disease (GVHD) was greater for patients with MICA mismatch (hazard ratio [HR], 1.73; P = .02) than for those with HLA-DPB1 mismatch (HR, 1.62; P = .07). When MICA and HLA-DPB1 were assessed simultaneously, patients mismatched at both loci had the greatest risk (HR, 2.51; P < .01) and those mismatched at only 1 locus had somewhat greater risk (HR, 1.53; P = .12) than patients matched at both loci; this remained significant in multivariable analysis. The 100-day incidence was 66%, 45%, and 31%, respectively (P = .03). Results were similar for grade III and IV acute GVHD, with 100-day incidence 34%, 16%, and 8% (P = .01). These results are clinically pertinent to donor selection strategies and indicate that patients with mismatch at both MICA and HLA-DPB1 are at increased risk for acute GVHD.     

Allogeneic Stem Cell Transplantation versus Tyrosine Kinase Inhibitors Combined with Chemotherapy in Patients with Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia

Here we compare outcomes between the tyrosine kinase inhibitors (TKIs) plus chemotherapy regimen and allogeneic hematopoietic stem cell transplantation (transplantation cohort) in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+?ALL) and explore factors associated with prognosis. Data from 145 Ph+?ALL patients were analyzed retrospectively. Patients were treated with imatinib plus chemotherapy and then transplantation or continuous TKIs with chemotherapy based on patient preference. A total of 145 Ph+?ALL patients were recruited for this study (median age, 37 years; range, 14 to 65). Among these patients, 81 were men (55.9%) and 86 underwent IKZF1 detection, which identified 59 patients (68.6%) with IKZF1 deletions. After treatment 136 patients (95.8%) achieved complete remission (CR) eventually. With a median follow-up of 33 months (range, 4 to 114) for CR patients, 77 patients (57.9%) underwent transplantation and 56 (42.1%) received continuous TKIs with chemotherapy. At the 4-year follow-up the cumulative incidence of relapse (CIR), disease-free survival (DFS), and overall survival (OS) were 29.4% (95% confidence interval [CI], 24.9% to 34.4%), 60.9% (95% CI, 56.5% to 65.3%), and 69.2% (95% CI, 65.1% to 73.3%), respectively. Multivariate analysis showed that WBC?counts <?30?×?10⁹/L at diagnosis (hazard ratio [HR], 4.2; 95% CI, 1.9 to 9.2; P??<?.001; HR, 2.6; 95% CI, 1.4 to 4.9; P?=?.003; HR, 2.7; 95% CI, 1.4 to 5.4; P?=?.003), 3-log reduction of BCR-ABL levels from baseline after 2 consolidation cycles (HR, 4.4; 95% CI, 1.9 to 9.9; P?<?.001; HR, 3.1; 95% CI, 1.7 to 5.9; P? <?.001; HR, 3.5; 95% CI, 1.9 to 8.7; P?=?.001; defined as “minimal residual disease low level”), and transplantation (HR, 5.0; 95% CI, 2.2 to 11.2; P??<?.001; HR, 3.3; 95% CI, 1.7 to 6.4; P???<?.001; HR, 4.1; 95% CI, 1.9 to 8.7; P???<?.001) were the favorable factors of CIR, DFS, and OS. According to the first 2 risk factors, CR patients were divided into 3 groups: low risk (no factor, n?=?42, 31.6%), intermediate risk (1 factor, n?=?73, 54.9%), and high risk (2 factors, n?=?18, 13.5%). In the low-risk group at the 4-year follow up no significant difference existed between the transplant and nontransplant arms for the probabilities of CIR (8.5% versus 7.7%, P?=?.671), DFS (88.2% versus 83.9%, P?=?.426), and OS (96.6% versus 83.3%, P?=?.128). In the intermediate- and high-risk groups at the 4-year follow-up, CIR (23.6% versus 36.9%, P?=?.017; 37.5% versus 100.0%, P???<.001), DFS (62.4% versus 43.8%, P?=?.048; 56.2% versus 0%, P???<.001), and OS (76.1% versus 47.7%, P?=?.037; 51.4% versus 6.3%, P?=?.001) rates were significantly better in the transplant arm than in the nontransplant arm. In surviving patients of the low-risk group, no difference in complete molecular response (CMR) rates (85.7% versus 72.7%, P?=?.379) between the transplant and nontransplant arms was found. However, in the intermediate-risk group the proportion of CMR was significantly higher in the transplant arm than in the nontransplant arm (82.8% versus 42.9%, P?=?.006). In the high-risk group 4 of 7 transplant patients (57.1%) were in CMR, and no patients survived in the nontransplant arm. Allogeneic hematopoietic stem cell transplantation confers significant survival advantages for Ph+?ALL patients compared with TKIs plus chemotherapy, especially in intermediate- and high-risk patients.     

Predicted indirectly recognizable HLA epitopes are not associated with clinical outcomes after haploidentical hematopoietic stem cell transplantation

Haploidentical stem cell transplantation (haplo-SCT) provides an alternative method to cure patients with malignant and nonmalignant hematologic diseases who lack a human leukocyte antigen (HLA) matched related or unrelated donor. HLA disparity between donor and patient was the main reason causing lots of clinical immune response. The aim of this study was to investigate whether indirect recognition of mismatched HLA could predict the clinical outcomes in haplo-SCT. The probability of indirect recognition was predicted by the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model. 577 patients with acute leukemia or myelodysplastic syndrome receiving haplo-SCT were enrolled in the study. Patients were divided into 4 quartiles according to PIRCHE-Ⅰ or PIRCHE-Ⅱ. Although the cumulative incidences of chronic graft-versus-host disease (GVHD) were significantly different among the 4 PIRCHE-Ⅰgroups, with 20.4% for group 0–6, 40.5% for group >6–11, 26.1% for group >11–19 and 23.9% for group >19 (P?=?.007), PIRCHE-Ⅰ was not significantly associated with chronic GVHD in multivariate models (RR, 0.993; 95% CI, 0.858–1.149; P?=?.926). And no significant associations were observed between PIRCHE-Ⅰ or PIRCHE-Ⅱ and other clinical outcomes. In summary, PIRCHE did not correlate with clinical outcomes and could not predict haplo-SCT outcomes.     

Delayed onset of graft‐versus‐host disease in immunodeficent human leucocyte antigen‐DQ8 transgenic,murine major histocompatibility complex class II‐deficient mice repopulated by human peripheral blood mononuclear cells

Haematopoietic humanization of mice is used frequently to study the human immune system and its reaction upon experimental intervention. Immunocompromised non‐obese diabetic (NOD)‐Rag1^–/– mice, additionally deficient for the common gamma chain of cytokine receptors (γc) (NOD‐Rag1^–/– γc^–/– mice), lack B, T and natural killer (NK) cells and allow for efficient human peripheral mononuclear cell (PBMC) engraftment. However, a major experimental drawback for studies using these mice is the rapid onset of graft‐versus‐host disease (GVHD). In order to elucidate the contribution of the xenogenic murine major histocompatibility complex (MHC) class II in this context, we generated immunodeficient mice expressing human MHC class II [human leucocyte antigen (HLA)‐DQ8] on a mouse class II‐deficient background (Aβ^–/–). We studied repopulation and onset of GVHD in these mouse strains following transplantation of DQ8 haplotype‐matched human PBMCs. The presence of HLA class II promoted the repopulation rates significantly in these mice. Virtually all the engrafted cells were CD3⁺ T cells. The presence of HLA class II did not advance B cell engraftment, such that humoral immune responses were undetectable. However, the overall survival of DQ8‐expressing mice was prolonged significantly compared to mice expressing mouse MHC class II molecules, and correlated with an increased time span until onset of GVHD. Our data thus demonstrate that this new mouse strain is useful to study GVHD, and the prolonged animal survival and engraftment rates make it superior for experimental intervention following PBMC engraftment.     

Level of Vascular Endothelial Growth Factor Predicts Both Relapse and Nonrelapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation

Although the prognostic significance of vascular endothelial growth factor (VEGF) has been researched extensively in patients with hematologic malignancies undergoing chemotherapy, its role in allogeneic hematopoietic stem cell transplantation (HSCT) requires further investigation. The present study evaluated the associations between VEGF level and relapse rate and early complications after HSCT. VEGF levels were analyzed in 91 consecutive patients before the start of conditioning, on day 0, on the day of engraftment, and on the day of diagnosis of veno-occlusive disease (VOD). Compared with a normal level, an elevated high VEGF-A level before conditioning was associated with an increased 2-year relapse rate (55% versus 24%, P = .003; hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.49 to 7.08) and decreased event-free survival (20% versus 44%; P = .022; HR, 2.03; 95% CI, 1.11 to 3.72). No association was found between VEGF level and the incidence of acute GVHD (P > .05). In patients with VOD, VEGF-A level was elevated on day 0 and on the day of VOD diagnosis (P < .05). A low VEGF-A level on day 0 was associated with reduced nonrelapse mortality (14% versus 35%; P = .048; HR, 0.32; 95% CI, 0.10 to 0.99). Our results indicate that a high VEGF-A level before HSCT increases the risk of relapse, and a high level after conditioning is associated with increased risks of early complications and nonrelapse mortality.     

Relative Impact of HLA Matching and Non-HLA Donor Characteristics on Outcomes of Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndrome

Increasing donor–recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n?=?872) or unrelated (10/10 MUD, n?=?1553) or HLA-mismatched unrelated (<10/10 MMUD, n?=?790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient–female donor), and cytomegalovirus (CMV) mismatching (positive recipient–negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P?=?.25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P?=?.46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity.     

The prognostic value of polycomb group protein B‐cell‐specific moloney murine leukemia virus insertion site 1 in stage II colon cancer patients

The aim of this study was to investigate the prognostic value of B‐cell‐specific moloney murine leukemia virus insertion site 1 (BMI1) protein expression in primary tumors of stage II colon cancer patients. BMI1 protein expression was assessed by immunohistochemistry in a retrospective patient cohort consisting of 144 stage II colon cancer patients. BMI1 expression at the invasive front of the primary tumors correlated with mismatch repair status of the tumors. Furthermore, BMI1 expression at the luminal surface correlated with T‐stage, tumor location, and the histological subtypes of the tumors. In a univariate Cox proportional hazard analysis, no statistical significant association between risk of relapse and BMI1 protein expression at the invasive front (HR: 1.12; 95% CI 0.78–1.60; p = 0.53) or at the luminal surface of the tumor (HR: 1.06; 95% CI 0.75–1.48; p = 0.70) was found. Likewise, there was no association between 5‐year overall survival and BMI1 expression at the invasive front (HR: 1.12; 95% CI 0.80–1.56; p = 0.46) or at the luminal surface of the tumor (HR: 1.16; 95% CI 0.86–1.60; p = 0.33). In conclusion, BMI1 expression in primary tumors of stage II colon cancer patients could not predict relapse or overall survival of the patients, thus having a limited prognostic value in stage II colon cancer patients.     

Biomarkery choroby przeszczep-przeciw-gospodarzowi – współczesny stan wiedzy i nadzieje na przyszłość

Despite the progress that has been made in the diagnosis and treatment of graft versus host disease (GvHD) this complication remains a major limitation of allogeneic haematopoietic stem cell transplantation (alloHSCT). The goal of searching for GvHD biomarkers is the individualization of immunosuppressive propylaxis in patients undergoing alloHSCT and personalized therapy of patients with diagnosed GvHD. The approaches for biomarker discovery may be based on the knowledge of the pathophysiology of acute and chronic GvHD, or carried out with the use of modern proteomics. This paper presents the results of prospective studies aimed at the discovery and validation of GvHD biomarkers. The predictive, diagnostic and prognostic value of the biomarkers, such as interleukin 8, tumor necrosis factor α (TNF-α), soluble TNF receptor type 1, soluble receptor for interleukin 2, hepatocyte growth factor, cytokeratin-18 fragments, regenerating islet-derived 3-α and elafin are discussed, along with the consideration on the usefulness of monitoring of immune cells subpopulations, such as regulatory T cells, NKT cells, naive B cells and memory B cells. The potential impact of biomarkers on GvHD prophylaxis and treatment is presented.     

Does minor histocompatibility antigen HA-1 disparity affect the occurrence of graft-versus-host disease in tunisian recipients of hematopoietic stem cells?

INTRODUCTION:

Minor histocompatibility antigen HA‐1 (MiHAg‐HA‐1) disparity between a patient and his or her human leukocyte antigen (HLA) genoidentical donor has been widely associated with an increased risk of graft‐versus‐host disease following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE:

To examine the effect of HA‐1 disparity on the incidence of both acute and chronic graft‐versus‐host disease in Tunisian recipients of hematopoietic stem cells.

METHODS:

A total of 60 patients and their 60 respective sibling hematopoietic stem cell donors were enrolled in this study. All patients prophylactically received cyclosporine A and/or methotrexate for graft‐versus‐host disease. An HA‐1 genotyping assay was performed with the SSP‐PCR method, and HLA‐A*0201‐ and/or HLA‐A*0206‐positive samples were identified using the Luminex HLA typing method.

RESULTS:

The Luminex HLA typing assay showed that 54 patients were positive for either the HLA‐A*0201 or HLA‐A*0206 alleles. Among these cases, six pairs were mismatched for MiHAg‐HA‐1. Both acute and chronic graft‐versus‐host disease occurred in four mismatched patients (Fisher''s p‐values were 0.044 and 0.170, respectively). A univariate logistic regression model analysis showed that only acute graft‐versus‐host disease may be affected by recipient MiHAg‐HA‐1 disparity (p: 0.041, OR: 6.727), while chronic graft‐versus‐host disease correlates with both age and recipient/donor sex mismatch (p: 0.014, OR: 8.556 and p: 0.033, OR: 8.664, respectively).

CONCLUSION:

Our findings support previously reported data suggesting a significant association between HA‐1 disparity and the risk of acute graft‐versus‐host disease following hematopoietic stem cell transplantation.     

Risk factors of Ganciclovir-related neutropenia after allogeneic stem cell transplantation: a retrospective monocentre study on 547 patients

Cytomegalovirus (CMV) infection is a serious complication that may occur in the weeks or months following bone marrow transplantation. However, both Ganciclovir and the CMV infection itself can cause marrow toxicity, notably neutropenia, that may consequently expose these immunosuppressed patients to life-threatening bacterial and/or fungal infections. The aim of this retrospective study was to identify factors associated with the occurrence of grade III–IV neutropenia among patients receiving pre-emptive Ganciclovir therapy after allogeneic stem cell transplantation at our Institution. We identified 547 consecutive patients transplanted from January 2005 to June 2011 at our Institution. In all, 190 patients (35%) presented with CMV reactivation of whom 30 patients (5%) were excluded from the analysis because they already had neutropenia at the time of reactivation. Finally, 160 (29%) patients were analysed. According to multivariate analysis, at the time of treatment initiation, the risk factors significantly associated with a grade III–IV Ganciclovir-related neutropenia included a high viral load (hazard ratio (HR) = 2.68, 95% CI 1.25–5.737, p 0.01); an absolute neutrophil count >3000 was a protective factor (HR = 0.26, 95% CI 0.125–0.545, p <0001) whereas serum creatinine >2 mg/dL was associated with higher Ganciclovir-related neutropenia (HR = 2.4, 95% CI 1.11–5.17, p 0.002). This large analysis revealed three risk factors for Ganciclovir-related neutropenia among patients with CMV reactivation after allogeneic stem cell transplantation; prompt identification of patients at risk when antiviral therapy is started may allow clinicians to adopt adequate preventive measures, so reducing the morbidity and mortality associated with CMV reactivation.     

Domestic and foreign donor candidates result in differential probability of matching minor histocompatibility antigens – relevance of selection for hematopoietic stem cell transplantation

Mismatches between patient and donor at minor histocompatibility antigens (minor H antigens) account for most of the genetic component of histocompatibility problems in human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantations (HSCTs). There are usually more genetic differences outside the matched HLA region between unrelated donors and patients than in transplantations between related individuals. Also, foreign unrelated donors may differ from domestic donors at several loci as allele frequencies vary between populations. To unravel differences in minor H antigen matching when using unrelated donors from various registries worldwide, we genotyped 10 minor H antigen loci for 143 consecutive Finnish patients and 424 unrelated donor candidates. We observed that probability of matching specific minor H antigens was different for domestic and foreign donor candidates. HA-2 and HA-3 minor H antigens were significantly more often mismatched with Finnish donor candidates ( P  = 0.0003 for HA-2 and P = 0.004 for HA-3), whereas ACC1 and ACC2 minor H antigens were significantly more often mismatched with foreign donor candidates ( P  = 0.04 for ACC1 and P  = 0.03 for ACC2). This observation is of clinical importance when specific minor H antigens are intended to match or mismatch in the future to minimize the risk for graft- vs -host disease or to maximize the graft- vs -malignancy effect in HLA-matched HSCT from an unrelated donor.     

Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). We characterized the incidence, risk factors, and long-term outcomes associated with TA-TMA by performing a comprehensive review of all adult patients (n?=?1990) undergoing allogeneic HSCT at the Dana Farber Cancer Institute/Brigham and Women's Hospital between 2005 and 2013. Using the City of Hope criteria, we identified 258 patients (13%) with “definite” TMA and 508 patients (26%) with “probable” TMA. Mismatched donor transplantation (subdistribution hazard ratio [sHR], 1.79; 95% confidence interval [CI], 1.17 to 2.75; P?=?.007), sirolimus-containing graft-versus-host disease prophylaxis (sHR, 1.73; 95% CI, 1.29 to 2.34; P?<?.001), myeloablative conditioning (sHR, 1.93, 95% CI, 1.38 to 2.68; P?<?.001), and high baseline lactate dehydrogenase (LDH) level (sHR, 1.64; 95% CI, 1.26 to 2.13; P?<?.001) were associated with definite TMA. Moreover, positive cytomegalovirus serostatus (sHR, 1.41; 95% CI, 1.16 to 1.71; P?<?.001), high and very high disease risk index (sHR, 1.48; 95% CI, 1.12 to 1.96, P?=?.007), and high baseline LDH level (sHR, 1.25; 95% CI, 1.05 to 1.49; P?=?.011) were associated with probable TMA. In multivariable analyses, definite and probable TMA were each independently associated with higher mortality (HR, 5.24; 95% CI, 4.43 to 6.20 and HR, 2.12; 95% CI, 1.84 to 2.44, respectively), and long-term kidney dysfunction (HR, 5.43; 95% CI, 4.61 to 6.40 and HR, 2.20; 95% CI, 1.92 to 2.51, respectively). Definite and probable TMA were also independently associated with an increased risk of nonrelapse mortality and shorter progression-free survival. Our findings indicate that TA-TMA is common following HSCT and is independently associated with increased risk of death and kidney dysfunction.