Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P<0.00; respectively 0.976; P<0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of ‘no-graft-versus-host disease’.Leukemia advance online publication, 7 April 2017; doi:10.1038/leu.2017.79

Pre-transplantation Risks and Transplant-Techniques in Haematopoietic Stem Cell Transplantation for Acute Leukaemia

Background: The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres. Methods: This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1–75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome. Findings: Treatment groups differed significantly from baseline population (p < 0.001), and within groups regarding patient-, disease-, donor-, and centre-related pre-transplantation risk factors (p < 0.001); choice of technique did depend on pre-transplantation risk factors and centre (p < 0.001). Probability of overall survival at 5 years decreased systematically and significantly with increasing pre-transplantation risk score (score 2 vs 0/1 HR: 1·2, 95% c.i. [1·1–1·.3], p = 0.002; score 3 vs 0/1 HR: 1·5, 95% c.i. [1·3–1·7], p < 0.001; score 4/5/6 vs 0/1 HR: 1·9, 95% c.i. [1·6–2·2], p < 0.001) with no significant differences between treatment groups (likelihood ratio test on interaction: p = 0.40). Overall survival was significantly associated with selection steps and completeness of information (p < 0.001). Interpretation: Patients' pre-transplantation risk factors determine survival, independent of transplant techniques. Transplant techniques should be regarded as centre policy, not stratification factor in benchmarking. Selection criteria and completeness of data bias outcome. Outcomes may be improved more effectively through better identifying pre-transplantation factors as opposed to refinement of transplant techniques. Funding: The study was funded by EBMT

Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare fatal autorecessive disease. Halter et al. report outcomes from all known haematopoietic stem cell transplantations worldwide from sibling or unrelated donors for MNGIE between 2005 and 2011. In some of the recipients, correction of the underlying metabolic defect results in gradual clinical improvemen

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

Importance: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. Objective: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. Design, Setting, and Participants: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation–registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. Interventions: HSCT vs intravenous pulse cyclophosphamide. Main Outcomes and Measures: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. Results: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. Conclusions and Relevance: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. Trial Registration: isrctn.org Identifier: ISRCTN5437125

Effect of beta-blockers, Ca2+ antagonists, and benzodiazepines on bleeding incidence in patients with chemotherapy induced thrombocytopenia

Beta-1-adrenoreceptor antagonists, Ca(2+) antagonists, and benzodiazepines negatively affect platelet aggregation in vitro. Few data exists on whether platelet function in vivo is relevantly influenced by exposure to any these substances. We analysed in three cohorts of 100 patients each treated with allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT, and intensive chemotherapy, respectively, whether treatment with these drugs was associated with an increased risk of bleeding. Cumulative incidences of bleeding in the three cohorts were 47 +/- 5% after allogeneic transplants, 30 +/- 5% after autologous transplant, and 46 +/- 5% after chemotherapy (p = 0.008). Exposure to beta-blockers (hazard ratio [HR] 0.71, p = 0.32), Ca(2+) antagonists (HR 0.90, p = 0.73), and benzodiazepines (HR 1.18, p = 0.29) did not significantly increase the risk of bleeding in any cohort. Instead, bleeding risk was determined by platelet count, presence of inflammation, azotemia, presence of graft-versus-host disease and treatment with low-molecular weight heparin. After correcting for these factors, no differences in bleeding risk were seen between the three cohorts. In conclusion, therapy with Beta-1-adrenoreceptor antagonists, Ca(2+) antagonists, and benzodiazepines did not appear to significantly increase the risk for hemorrhagic complications in patients with iatrogenic severe thrombocytopenia

Leukocyte count and risk of thrombosis in patients undergoing haematopoietic stem cell transplantation or intensive chemotherapy

Elevated white blood cell count has recently been established as an independent risk factor for thromboembolic events in patients with myeloproliferative syndromes. Thrombotic events occur frequently in patients with haematological malignancies undergoing intensive cytoreductive treatment. We evaluated retrospectively the association of leukocyte counts and thrombosis in three cohorts of 100 patients each undergoing autologous or allogeneic haematopoietic stem cell transplantation or chemotherapy, respectively. A total of 26 thromboembolic events were recorded, 10 in recipients of allogeneic transplants, five in autografted patients, and 11 in the chemotherapy group. Fifteen events were central venous catheter related. Non-catheter related thrombotic events were pulmonary embolism (N=5), hepatic veno-occlusive disease (N=2), deep-vein thrombosis (N=1), stroke (N=1), ovarian vein thrombosis (N=1), and left ventricular thrombosis (N=1). Hazard rates showed two peaks, a first during cytoreduction in all groups, and a second after engraftment in transplanted patients. Time-dependent multivariable Cox analysis confirmed an association of leukocytosis with development of thrombosis (hazard ratio for leukocyte count < 11G/l: 9.73, 95% confidence interval 1.98-47.9, p=0.005). The risk associated with leukocytosis was independent from C-reactive protein level. Thrombocyte count and type of treatment (allogeneic vs. autologous transplantation vs. chemotherapy) had no significant influence on thrombosis development. In three cohorts of patients undergoing intensive cytoreductive treatment for haematological malignancy, leukocyte count was strongly associated with development of thrombotic complications

Treatment of acute myelogenous leukemia. An EBMT-EORTC retrospective analysis of chemotherapy versus allogeneic or autologous bone marrow transplantation

In a retrospective analysis, patients with acute myelogenous leukemia (AML), treated in first complete remission (CR) with chemotherapy or with allogeneic or autologous bone marrow transplantation were compared with respect to their leukemia-free survival from CR. Two hundred and thirty-six patients treated with chemotherapy according to the EORTC AML-5 and AML-6 trials were included. The data of the transplanted patients were taken from two EBMT registries; 453 with an allogeneic and 182 with an autologous BMT. The very different sources of the data (trials and registries) forced us to be cautious in our conclusions. However, for the patient cohorts analyzed in the present study, BMT patients tended to have a better leukemia-free survival than chemotherapy patients. This was especially the case for the allogeneic BMT after 6 months of transplant. © 1989.SCOPUS: ar.jinfo:eu-repo/semantics/publishe