Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells.

Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti-viral adaptive responses. However, the viral ligand that drives the activation and differentiation of adaptive NKG2C+ NK cells has remained unclear. Here we found that adaptive NKG2C+ NK cells differentially recognized distinct HCMV strains encoding variable UL40 peptides that, in combination with pro-inflammatory signals, controlled the population expansion and differentiation of adaptive NKG2C+ NK cells. Thus, we propose that polymorphic HCMV peptides contribute to shaping of the heterogeneity of adaptive NKG2C+ NK cell populations among HCMV-seropositive people.

Comparison of Dynamic International Prognostic Scoring System and MYelofibrosis SECondary to PV and ET Prognostic Model for Prediction of Outcome in Polycythemia Vera and Essential Thrombocythemia Myelofibrosis after Allogeneic Stem Cell Transplantation.

We aimed to validate the MYelofibrosis SECondary to PV and ET prognostic model (MYSEC-PM) in 159 patients with myelofibrosis secondary to polycythemia vera (PV) and essential thrombocythemia (ET) from the European Society for Blood and Marrow Transplantation registry undergoing transplantation from matched siblings or unrelated donors. Furthermore, we aimed to test its prognostic performance in comparison with the Dynamic International Prognostic Scoring System (DIPSS). Score performance was analyzed using the concordance index (C): the probability that a patient who experienced an event had a higher risk score than a patient who did not (C > .5 suggesting predictive ability). Median follow-up of the total cohort was 41 months (range, 34 to 54), 45 months in post-PV and 38 months in post-ET myelofibrosis. Survival at 1, 2, and 4 years was 70% (95% CI, 63% to 77%), 61% (95% CI, 53% to 69%), and 52% (95% CI, 43% to 61%) for the total cohort; 70% (95% CI, 59% to 80%), 61% (95% CI, 49% to 73%), and 51% (95% CI, 38% to 64%) for post-PV; and 71% (95% CI, 61% to 81%), 61% (95% CI, 50% to 72%), and 54% (95% CI, 42% to 66%) for post-ET myelofibrosis (P = .78). Overall, the DIPSS was not significantly predictive of outcome (P = .28). With respect to the MYSEC-PM, overall survival at 4 years was 69% for the low-risk, 55% for the intermediate 1-risk, 47% for the intermediate 2-risk, and 22% (0% to 45%) for the high-risk groups. The prognostic model was predictive of survival overall (P = .05), whereas groups with intermediate 2 and high risk showed no significant difference (P = .44). Assessment of prognostic utility yielded a C-index of .575 (95% CI, .502 to .648) for the DIPSS, whereas assessment of the MYSEC-PM resulted in a C-statistics of .636 (95% CI, .563 to .708), indicating improvement in prediction of post-transplant survival using the new MYSEC-PM. In addition, transplantations from an unrelated donor in comparison with an HLA-identical sibling showed worse outcome (P = .04), and transplant recipients seropositive for cytomegalovirus in comparison with seronegative recipients (P = .01) showed worse survival. In conclusion, incorporating transplant-specific and clinical and mutational information together with the MYSEC-PM may enhance risk stratification.

Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events occur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged ≥65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors.

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy.

The adult cerebral form of X-linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event-free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre-transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event-free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan-based conditioning.

Matching for the MICA-129 polymorphism is beneficial in unrelated hematopoietic stem cell transplantation.

Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a highly polymorphic ligand of the activating NKG2D receptor on natural killer (NK) cells, γδ-T cells, and NKT cells. MICA incompatibilities have been associated with an increased graft-versus-host disease (GVHD) incidence, and the MICA-129 (met/val) dimorphism has been shown to influence NKG2D signaling in unrelated hematopoietic stem cell transplantation (uHSCT). We investigated the effect of MICA matching on survival after uHSCT. We sequenced 2172 patients and their respective donors for MICA. All patients and donors were high-resolution HLA-typed and matched for 10/10 (n = 1379), 9/10 (n = 636), or 8/10 (n = 157) HLA alleles. Within each HLA match group, cases matched and mismatched for MICA and MICA-129 were analyzed for the end points overall survival (OS), disease-free survival (DFS), nonrelapse mortality (NRM), relapse-incidence (RI), and GVHD. Mismatches at the MICA locus as well as MICA-129 increased with the number of HLA mismatches (MICA mismatched 10/10, 9.2% [n = 127]; 9/10, 22.3% [n = 142]; 8/10, 38.2% [n = 60]; MICA-129 mismatched 10/10, 3.9% [n = 54]; 9/10, 10.2% [n = 65]; 8/10, 17.2% [n = 27]). Adverse OS was observed in the 10/10 match group if MICA-129 was mismatched (10/10, hazard ratio [HR], 1.77; confidence interval [CI], 1.22-2.57; P = .003). MICA-129 mismatches correlated with a significantly worse outcome for DFS in the 10/10 HLA match group (HR, 1.77; CI, 1.26-2.50; P = .001). Higher rates of aGVHD were seen in MICA-129 mismatched cases. Our results indicate that MICA-129 matching is relevant in uHSCT. Prospective typing of patients and donors in unrelated donor search may identify mismatches for MICA-129, and compatible donor selection may improve outcome for this small but high-risk subgroup.

Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis on 698 patients by the Chronic Malignancies Working Party of the European Society of Blood and Marrow Transplantation.

No standard exists for the treatment of myelodysplastic syndrome relapsing after allogeneic stem cell transplantation. We performed a retrospective registry analysis of outcomes and risk factors in 698 patients, treated with different strategies. The median overall survival from relapse was 4.7 months (95% confidence interval: 4.1-5.3) and the 2-year survival rate was 17.7% (95% confidence interval: 14.8-21.2%). Shorter remission after transplantation (P<0.001), advanced disease (P=0.001), older age (P=0.007), unrelated donor (P=0.008) and acute graft-versus-host disease before relapse (P<0.001) adversely influenced survival. At 6 months from relapse, patients had received no cellular treatment, (i.e. palliative chemotherapy or best supportive care, n=375), donor lymphocyte infusion (n=213), or a second transplant (n=110). Treatment groups were analyzed separately because of imbalanced characteristics and difficulties in retrospectively evaluating the reason for individual treatments. Of the patients who did not receive any cellular therapy, 109 were alive at 6 months after relapse, achieving a median overall survival from this landmark of 8.9 months (95% confidence interval: 5.1-12.6). Their 2-year survival rate was 29.7%. Recipients of donor lymphocytes achieved a median survival from first infusion of 6.0 months (95% confidence interval: 3.7-8.3) with a 2-year survival rate of 27.6%. Longer remission after first transplantation (P<0.001) and younger age (P=0.009) predicted better outcome. Among recipients of a second transplant, the median survival from second transplantation was 4.2 months (95% confidence interval: 2.5-5.9), and their 2-year survival rate was 17.0%. Longer remission after first transplantation (P<0.001), complete remission at second transplant (P=0.008), no prior chronic graft-versus-host disease (P<0.001) and change to a new donor (P=0.04) predicted better outcome. The data enabled identification of patients benefiting from donor lymphocyte infusion and second transplantation, and may serve as a baseline for prospective trials.

Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy.

The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21-48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.

Human leukocyte antigen-E mismatch is associated with better hematopoietic stem cell transplantation outcome in acute leukemia patients.

The immunomodulatory role of human leukocyte antigen (HLA)-E in hematopoietic stem cell transplantation (HSCT) has not been extensively investigated. To this end, we genotyped 509 10/10 HLA unrelated transplant pairs for HLA-E, in order to study the effect of HLA-E as a natural killer (NK)-alloreactivity mediator on HSCT outcome in an acute leukemia (AL) setting. Overall survival (OS), disease free survival (DFS), relapse incidence (RI) and non-relapse mortality (NRM) were set as endpoints. Analysis of our data revealed a significant correlation between HLA-E mismatch and improved HSCT outcome, as shown by both univariate (53% vs 38%, P=0.002, 5-year OS) and multivariate (hazard ratio (HR)=0.63, confidence interval (CI) 95%=0.48-0.83, P=0.001) analyses. Further subgroup analysis demonstrated that the positive effect of HLA-E mismatch was significant and pronounced in advanced disease patients (n=120) (5-year OS: 50% vs 18%, P=0.005; HR=0.40, CI 95%=0.22-0.72, P=0.002; results from univariate and multivariate analyses, respectively). The study herein is the first to report an association between HLA-E incompatibility and improved post-transplant prognosis in AL patients who have undergone matched unrelated HSCT. Combined NK and T cell HLA-E-mediated mechanisms may account for the better outcomes observed. Notwithstanding the necessity for in vitro and confirmational studies, our findings highlight the clinical relevance of HLA-E matching and strongly support prospective HLA-E screening upon donor selection for matched AL unrelated HSCTs.

Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic hematopoietic cell transplantation is widely used to treat adults with high-risk acute lymphoblastic leukemia. The aim of this study was to analyze whether the results changed over time and to identify prognostic factors. Adult patients treated between 1993 and 2012 with myeloablative allogeneic hematopoietic cell transplantation from HLA matched sibling (n=2681) or unrelated (n=2178) donors in first complete remission were included. For transplantations from sibling donors performed between 2008 and 2012, 2-year probabilities of overall survival were: 76% (18-25 years old), 69% (26-35 and 36-45 years old) and 60% (46-55 years old). Among recipients of transplantations from unrelated donors, the respective survival rates were 66%, 70%, 61%, and 62%. In comparison with the 1993-2007 period, significant improvements were observed for all age groups except for the 26-35-year old patients. In a multivariate model, transplantations performed between 2008 and 2012, when compared to 1993-2007, were associated with significantly reduced risks of non-relapse mortality (Hazard Ratio 0.77, P=0.00006), relapse (Hazard Ratio 0.85, P=0.007), treatment failure (Hazard Ratio 0.81, P<0.00001), and overall mortality (Hazard Ratio 0.79, P<0.00001). In the analysis restricted to transplantations performed between 2008 and 2012, the use of total body irradiation-based conditioning was associated with reduced risk of relapse (Hazard Ratio 0.48, P=0.004) and treatment failure (Hazard Ratio 0.63, P=0.02). We conclude that results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia improved significantly over time. Total body irradiation should be considered as the preferable type of myeloablative conditioning.

Residual thymic tissue and lymph node involvement by acute myeloid leukaemia presenting as mediastinal, strongly 18 FDG-PET-positive masses.

We report on a multidisciplinary management of a 68-year-old AML patient presenting with a PET-positive mediastinal tumour typical for lymph node metastasis. It was removed via minimally invasive thoracoscopic intervention and was identified as a thymus residual infiltrated by AML. Follow-up PET-CT scan after resection and remission induction chemotherapy was completely normal. To our knowledge, this is the first documented case report of AML presenting with PET-positive infiltrates of thymic and lymph node tissue along the aortic bow mimicking a second intrathoracic malignancy. Our observation indicates the usefulness of this imaging technique and supports clarification of these unusual findings in AML patients, in case of need also by invasive diagnostic procedures, to enable an adequate therapeutic decision.

Predictive significance of the European LeukemiaNet classification of genetic aberrations in patients with acute myeloid leukaemia undergoing allogeneic stem cell transplantation.

OBJECTIVES: The purpose of this study was to evaluate the predictive capacity of the European LeukemiaNet (ELN) classification of genetic risk in patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (alloSCT). METHODS: We retrospectively analysed 274 patients transplanted at our centre between 2004 and 2014. RESULTS: The ELN grouping is comparable to the Southwest Oncology Group/Eastern Cooperative Oncology Group (SWOG/ECOG) stratification in predicting the outcome after alloSCT [overall P = 0.0064 for disease-free survival (DFS), overall P = 0.003 for relapse]. Patients with an intermediate-1 profile have a significantly elevated 5-yr relapse incidence as compared to favourable risk patients, that is 40% vs. 15%, [hazard ratio (HR) 2.58, P = 0.048]. An intermediate-1 risk profile is an independent predictor for relapse as determined by multivariate Cox regression analysis (HR 3.05, P = 0.023). In intermediate-1 patients, the presence of an FLT3 internal tandem duplication (FLT3-ITD) is associated with a significantly increased relapse incidence (P = 0.0323), and a lower DFS (P = 0.0465). FLT3-ITD is an independent predictor for overall survival, DFS and relapse incidence in the intermediate-1 subgroup. CONCLUSIONS: The ELN stratification of genetic risk predicts the outcome of patients with AML undergoing alloSCT. Patients with an intermediate-1 profile have a high risk for treatment failure due to relapse, which prompts the development of alternative treatment strategies.

Prospective evaluation of the SeptiFAST multiplex real-time PCR assay for surveillance and diagnosis of infections in haematological patients after allogeneic stem cell transplantation compared to routine microbiological assays and an in-house real-time PCR method.

We prospectively evaluated a multiplex real-time PCR assay (SeptiFast, SF) in a cohort of patients undergoing allo-BMT in comparison to an in-house PCR method (IH-PCR). Overall 847 blood samples (mean 8 samples/patient) from 104 patients with haematological malignancies were analysed. The majority of patients had acute leukaemia (62%) with a mean age of 52 years (54% female). Pathogens could be detected in 91 of 847 (11%) samples by SF compared to 38 of 205 (18.5%) samples by BC, and 57 of 847 (6.7%) samples by IH-PCR. Coagulase-negative staphylococci (n=41 in SF, n=29 in BC) were the most frequently detected bacteria followed by Escherichia coli (n=9 in SF, n=6 in BC). Candida albicans (n=17 in SF, n=0 in BC, n=24 in IH-PCR) was the most frequently detected fungal pathogen. SF gave positive results in 5% of samples during surveillance vs in 26% of samples during fever episodes. Overall, the majority of blood samples gave negative results in both PCR methods resulting in 93% overall agreement resulting in a negative predictive value of 0.96 (95% CI: 0.95-0.97), and a positive predictive value of 0.10 (95% CI: -0.01 to 0.21). SeptiFast appeared to be superior over BC and the IH-PCR method.

Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT.

B-cell immune dysfunction contributes to the risk of severe infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Delayed B-cell regeneration is found in patients with systemic graft-versus-host disease (GVHD) and is often accompanied by bone marrow (BM) suppression. Little is known about human BM GVHD. We analyzed the reconstitution kinetics of B-cell subsets in adult leukemic patients within 6 months after allo-HSCT. B-cell deficiency already existed before transplant and was aggravated after transplant. Onset of B-cell reconstitution characterized by transitional B-cell recovery occurred either early (months 2-3) or late (from month 6 on) and correlated highly positively with reverse transcription-polymerase chain reaction quantified numbers of κ-deleting recombination excision circles (KRECs). Delayed recovery was associated with systemic acute GVHD and full-intensity conditioning therapy. Histological analysis of BM trephines revealed increased T-cell infiltration in late recovering patients, which was associated with reduced numbers of osteoblasts. Functionally, late recovering patients displayed less pneumococcal polysaccharide-specific immunoglobin M-producing B cells on ex vivo B-cell activation than early recovering patients. Our results provide evidence for acute BM GVHD in allo-HSCT patients with infiltrating donor T cells and osteoblast destruction. This is associated with delayed B-cell reconstitution and impaired antibody response. Herein, KREC appears suitable to monitor BM B-cell output after transplant.

Peripheral blood stem cell graft compared to bone marrow after reduced intensity conditioning regimens for acute leukemia: a report from the ALWP of the EBMT.

Increasing numbers of patients are receiving reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation. We hypothesized that the use of bone marrow graft might decrease the risk of graft-versus-host disease compared to peripheral blood after reduced intensity conditioning regimens without compromising graft-versus-leukemia effects. Patients who underwent reduced intensity conditioning regimen allogeneic hematopoietic stem cell transplantation from 2000 to 2012 for acute leukemia, and who were reported to the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation were included in the study. Eight hundred and thirty-seven patients receiving bone marrow grafts were compared with 9011 peripheral blood transplant recipients after reduced intensity conditioning regimen. Median follow up of surviving patients was 27 months. Cumulative incidence of engraftment (neutrophil ≥0.5×10(9)/L at day 60) was lower in bone marrow recipients: 88% versus 95% (P<0.0001). Grade II to IV acute graft-versus-host disease was lower in bone marrow recipients: 19% versus 24% for peripheral blood (P=0.005). In multivariate analysis, after adjusting for differences between both groups, overall survival [Hazard Ratio (HR) 0.90; P=0.05] and leukemia-free survival (HR 0.88; P=0.01) were higher in patients transplanted with peripheral blood compared to bone marrow grafts. Furthermore, peripheral blood graft was also associated with decreased risk of relapse (HR 0.78; P=0.0001). There was no significant difference in non-relapse mortality between recipients of bone marrow and peripheral blood grafts, and chronic graft-versus-host disease was significantly higher after peripheral blood grafts (HR 1.38; P<0.0001). Despite the limitation of a retrospective registry-based study, we found that peripheral blood grafts after reduced intensity conditioning regimens had better overall and leukemia-free survival than bone marrow grafts. However, there is an increase in chronic graft-versus-host disease after peripheral blood grafts. Long-term follow up is needed to clarify whether chronic graft-versus-host disease might increase the risk of late morbidity and mortality.

Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study.

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.

Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases.

Over the past 20 years, immunoablation followed by transplantation of autologous haematopoietic stem cells (ASCT) has emerged as a promising treatment option for patients with severe forms of autoimmune diseases (ADs) that insufficiently respond to standard immunosuppressive or novel biologic treatment. Meanwhile, mechanistic studies have provided the proof-of-concept that the long-term, treatment-free remissions achieved by ASCT are associated with the eradication of the autoreactive immunologic memory and a fundamental reconfiguration of the immune system. The latter comprises regeneration of naive B cells and a stable thymic reactivation with re-emergence of thymic-derived naive T cells, including Foxp3+ regulatory T cells, with new antigen receptors, i.e. immune reset. In this article, we discuss mechanistic studies that investigated how such immune renewal after ASCT may rewire a faulty immune system in ADs into a self-tolerant state, to induce long-term remissions.

Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation.

Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27(+) memory B cells despite already normalized total B cell numbers and fully recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon CD40/TLR-9-dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9-dependent activation. Drug efflux capacity of naïve B cells was diminished in cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should address the long-term sequelae of B cell defects after transplantation.

High-resolution HLA matching in hematopoietic stem cell transplantation: a retrospective collaborative analysis.

To validate current donor selection strategies based on previous international studies, we retrospectively analyzed 2646 transplantations performed for hematologic malignancies in 28 German transplant centers. Donors and recipients were high resolution typed for HLA-A, -B, -C, -DRB1, and -DQB1. The highest mortality in overall survival analysis was seen for HLA-A, -B, and DRB1 mismatches. HLA-DQB1 mismatched cases showed a trend toward higher mortality, mostly due to HLA-DQB1 antigen disparities. HLA incompatibilities at >1 locus showed additive detrimental effects. HLA mismatching had no significant effect on relapse incidence and primary graft failure. Graft source had no impact on survival end points, neither in univariate nor in multivariate analysis. Higher patient age, advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor adversely influenced outcomes in multivariate analysis. Our study confirms the association of HLA-A, -B, -C, and -DRB1 incompatibilities with adverse outcome in hematopoietic stem cell transplantation (HSCT). The relevance of HLA-DQB1 disparities in single mismatched transplantations remains unclear. Similar hazard ratios for allele and antigen mismatches (possibly with an exception for HLA-DQB1) highlight the importance of allele level typing and matching in HSCT. The number of incompatibilities and their type significantly impact survival.

Severe radiotoxicity in an allogeneic transplant recipient with a heterozygous ATM mutation.

Patients receiving radiotherapy often experience toxicity of the skin and mucous membranes. While radiotherapy is a mainstay of myeloablative conditioning for allogeneic hematopoietic stem cell transplantation (ASCT), no risk factors for radiotoxicity have been identified in this setting. Here, we report on a patient with excessive radiation-induced toxicity after ASCT who carried a heterozygous mutation in the Ataxia telangiectasia mutated (ATM) gene. This is the first case to suggest a genetic basis for increased radiotoxicity after myeloablative ASCT.

Impact of early remission by induction therapy on allogeneic stem cell transplantation for acute myeloid leukemia with an intermediate-risk karyotype in first complete remission.

For patients with acute myeloid leukemia (AML) early achievement of remission during induction treatment is an important predictor for long-term outcome irrespective of the type of consolidation therapy employed. Here, we retrospectively examined the prognostic impact of early remission (ER) vs. delayed remission (DR) in a cohort of 132 AML patients with an intermediate-risk karyotype undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1). In contrast to patients showing DR, patients achieving ER had a significantly higher 3-yr overall survival (OS) and disease-free survival (DFS) of 76% vs. 54% (P = 0.03) and 76% vs. 53% (P = 0.03). Likewise, 3 yr after alloSCT the cumulative incidence of relapse (CI-R) was significantly lower in the ER subgroup as compared to patients achieving DR, that is, 10% vs. 35% (P = 0.004), whereas non-relapse mortality (NRM) did not differ significantly. Multivariate analysis identified DR as an independent prognosticator for an inferior DFS (HR 3.37, P = 0.002) and a higher CI-R (HR 3.55, P = 0.002). Taken together, these data may indicate that the rapid achievement of remission predicts a favorable outcome in patients with intermediate-risk AML undergoing alloSCT in CR1. In turn, the adverse effect of DR may not be fully overcome by alloSCT.