The Role of Complement in HSCT-TMA : Basic Science to Clinical Practice

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a common complication occurring post-HSCT and is associated with substantial morbidity and mortality if not promptly identified and treated. Emerging evidence suggests a central role for the complement system in the pathogenesis of HSCT-TMA. The complement system has also been shown to interact with other pathways and processes including coagulation and inflammation, all of which are activated following HSCT. Three endothelial cell-damaging "hits" are required for HSCT-TMA genesis: a genetic predisposition or existing damage, an endothelial cell-damaging conditioning regimen, and additional damaging insults. Numerous risk factors for the development of HSCT-TMA have been identified (including primary diagnosis, graft type, and conditioning regimen) and validated lists of relatively simple diagnostic signs and symptoms exist, many utilizing routine clinical and laboratory assessments. Despite the relative ease with which HSCT-TMA can be screened for, it is often overlooked or masked by other common post-transplant conditions. Recent evidence that patients with HSCT-TMA may also concurrently present with these differential diagnoses only serve to further confound its identification and treatment. HSCT-TMA may be treated, or even prevented, by removing or ameliorating triggering "hits", and recent studies have also shown substantial utility of complement-targeted therapies in this patient population. Further investigation into optimal management and treatment strategies is needed. Greater awareness of TMA post-HSCT is urgently needed to improve patient outcomes; the objective of this article is to clarify current understanding, explain underlying complement biology and provide simple tools to aid the early recognition, management, and monitoring of HSCT-TMA.Peer reviewe

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

Effects of nilotinib on regulatory T cells: the dose matters

<p>Abstract</p> <p>Background</p> <p>Nilotinib is a tyrosine kinase inhibitor with high target specificity. Here, we characterized the effects of nilotinib for the first time on CD4⁺CD25⁺regulatory T cells (Tregs) which regulate anti-tumor/leukemia immune responses.</p> <p>Design and Methods</p> <p>Carboxyfluorescein diacetate succinimidyl ester (CFSE) and 5-bromo-2-deoxy -uridine (BrdU) were used to assess the proliferation and cell cycle distribution of Tregs. The expression of the transcription factor forkhead box P3 (FoxP3) and the glucocorticoid-induced tumor necrosis factor receptor (GITR) were measured by flow cytometry. Western blotting analysis was used to detect the effects of nilotinib on the signal transduction cascade of T-cell receptor (TCR) in Tregs.</p> <p>Results</p> <p>Nilotinib inhibited the proliferation and suppressive capacity of Tregs in a dose-dependent manner. However, the production of cytokines secreted by Tregs and CD4⁺CD25^-T cells was only inhibited at high concentrations of nilotinib exceeding the mean therapeutic serum concentrations of the drug in patients. Only high doses of nilotinib arrested both Tregs and CD4⁺CD25^-T cells in the G₀/G₁phase and down-regulated the expression of FoxP3 and GITR. In western blotting analysis, nilotinib did not show significant inhibitory effects on TCR signaling events in Tregs and CD4⁺CD25^-T cells.</p> <p>Conclusions</p> <p>These findings indicate that nilotinib does not hamper the function of Tregs at clinical relevant doses, while long-term administration of nilotinib still needs to be investigated.</p

Survival of Patients with Acute Myeloid Leukemia Relapsing after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study

AbstractAcute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990 to 2010) during first or second complete remission (CR) to identify factors associated with longer postrelapse survival. Median time to post-HCT relapse was 7 months (range, 1 to 177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy alone (n = 660), donor lymphocyte infusion (DLI) ± chemotherapy (n = 202), or second alloHCT ± chemotherapy ± DLI (n = 369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 months (range, <1 to 193). Survival for all patients was 23% at 1 year after relapse; however, 3-year overall survival correlated with time from HCT to relapse (4% for relapse during the 1- to 6-month period, 12% during the 6-month to 2-year period, 26% during the 2- to 3-year period, and 38% for ≥3 years). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (relative risk, .55 for 6 months to 2 years; relative risk, .39 for 2 to 3 years; and relative risk, .28 for ≥3 years; P < .0001) and a first HCT using reduced-intensity conditioning (relative risk, .77; 95% confidence interval [CI], .66 to .88; P = .0002). In contrast, inferior survival was associated with age >40 years (relative risk, 1.42; 95% CI, 1.24 to 1.64; P < .0001), active graft-versus-host disease at relapse (relative risk, 1.25; 95% CI, 1.13 to 1.39; P < .0001), adverse cytogenetics (relative risk, 1.37; 95% CI, 1.09 to 1.71; P = .0062), mismatched unrelated donor (relative risk, 1.61; 95% CI, 1.22 to 2.13; P = .0008), and use of cord blood for first HCT (relative risk, 1.23; 95% CI, 1.06 to 1.42; P = .0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 months after their initial alloHCT had better survival and may benefit from intensive therapy, such as second alloHCT ± DLI

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95% CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.</p

Allogeneic hematopoietic cell transplantation for patients with TP53 mutant or deleted chronic lymphocytic leukemia : Results of a prospective observational study

Non peer reviewe

Safety and Efficacy of Donor T Cells Engineered with Herpes Simplex Virus Thymidine-Kinase Suicide Gene (TK Cells) Given after T-Cell Depleted (TCD) Haploidentical Hematopoietic Transplantation (Haplo-HSCT): Results of a 14-Year Follow-Up in 45 Patients

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The Human Leukocyte Antigen-DPB1 Degree of Compatibility Is Determined by Its Expression Level and Mismatch Permissiveness: A German Multicenter Analysis

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided

Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning : a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation

Background: Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods: We analyzed long-term outcomes in a cohort of 1423 AML patients, age >= 50 years, after SCT from HLA-matched siblings, during the years 1997-2005, median follow-up 8.3 years (0.1-17). Results: The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27-35) and 32 % (28-35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18-25) and 21 % (18-24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65-76) and 73 % (67-78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions: Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.Peer reviewe

Fludarabine-treosulfan compared to thiotepa-busulfan-fludarabine or FLAMSA as conditioning regimen for patients with primary refractory or relapsed acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease. Methods: We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML. Results: Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p = 0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2 years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p = 0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p = 0.01; p = 0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III–IV aGVHD (p = 0.02) and cGVHD (p = 0.006), with no influence on relapse. Conclusions: In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk