Blood advances最新文献

Effective transition programs are essential for adolescents and young adults with sickle cell disease (SCD), yet their long-term impact remains unexplored. The St. Jude SCD Transition Program provides structured transition interventions, including disease education, personal health record (PHR) communication training, transition skills-building, academic guidance, and early adult care introduction for patients aged 12-25 . This 13-year retrospective cohort study evaluated program effectiveness on first adult visit attendance, successful adult care transfer, adult ambulatory and acute care utilization, and health-related quality of life (HRQOL). Among 638 patients, 74.5% attended their first adult visit and 40.0% successfully transferred to adult care (2 visits within the first-year post-transfer). Increased participation in nearly all transition interventions was associated with first adult visit attendance, and all interventions were associated with successful transfer. In-person SCD education and early introduction to adult care were independently associated with first adult visit attendance, while in-person SCD education and PHR training were independently associated with successful transfer. A predictive model incorporating intervention exposure and demographics yielded an area under the curve of 0.81 for attendance at the first adult visit (95% CI: 0.75-0.88; sensitivity 0.76, specificity 0.70). PHR training was associated with adult ambulatory utilization up to 3 years post-transfer and improved early adulthood HRQOL. No interventions were associated with acute care utilization. Transition interventions improving disease literacy, communication, and care transfer processes are linked to better transition outcomes and HRQOL, though sustained adult care engagement remains low. Future research is needed to promote adult care engagement.

Despite decades of research, the precise cellular origins of coagulation factor VIII (FVIII), deficient in the inherited bleeding disorder hemophilia A (HA), have remained controversial. Early studies proposed that FVIII comes from hepatocytes, similar to most other coagulation factors. More recent data pointed to liver sinusoidal endothelial cells (LSECs) as the primary source of FVIII, but conflicting reports and methodological limitations have obscured a clear understanding of hepatic and extrahepatic FVIII expression. Discordance between natural FVIII biosynthesis sites and cellular targets of adeno-associated viral (AAV) vectors has been implicated in efficacy limitations of current gene therapies for hemophilia A. Here, we developed and employed a novel gene-edited F8 promoter-reporter mouse model, humanized mice, and human tissue samples to definitively map FVIII-producing cells. We found that FVIII originates primarily from LSECs, not hepatocytes, corroborating most recent reports. Additionally, we detected the F8 reporter in renal endothelial cells. Further, we identified a striking microanatomical variation in FVIII expression between LSECs situated in different hepatic lobular zones, revealing that FVIII synthesis is predominantly localized to LSECs in Zones 2 and 3 of hepatic lobules in both mice and humans, with minimal expression in Zone 1. This zonal pattern was maintained even in the context of steatohepatitis. Our work clarifies the primary cellular source of FVIII and unravels the microheterogeneity of FVIII expression within the liver, providing insights for optimizing gene therapy strategies for hemophilia A that aim to induce FVIII production in its natural endogenous expression sites.

Allogeneic hematopoietic stem cell transplantation is used for consolidation in children and adolescents with refractory or early relapsed ALK-positive anaplastic large cell lymphoma (ALCL). The immune system plays a major role in the sustained control of the disease. We therefore retrospectively analyzed whether the type of conditioning, donor type, and in-vivo T-cell depletion correlate with outcome in a large population-based cohort of 57 children with CNS-negative ALCL relapse transplanted between 2005-2022. Progression-free (PFS) and overall survival from transplantation were 84±10% and 91±8% at 3 years, respectively. Conditioning was based on total body irradiation (TBI) in 30 patients and on chemotherapy in 27 patients, mainly with reduced-toxicity conditioning (RTC; Treosulfan, Fludarabine, and Thiotepa). PFS and graft-vs.-host disease-and event-free survival (GEFS) were comparable between TBI and chemotherapy, 87±6% versus 81±8%, (p=0.62) and 67±9 versus 74±8 (p=0.63), respectively. Patients with transplantation from unrelated donors with rabbit anti-human T lymphocyte globulin (ATLG) had superior PFS and GEFS compared to those receiving grafts from matched sibling donors without ATLG:94±7% versus 67±22% (p=0.0007), and 82±13% versus 44±24% (p=0.011), respectively. Progression during frontline chemotherapy, minimal residual disease, and remission status at allogeneic SCT were not associated with outcome. PFS and survival of eight additional patients with CNS-positive disease were 50% and 62%, respectively. Non-relapse mortality was 5.6% for all 65 patients and cumulative incidence of grade II-IV acute GvHD was 25%. Our data support the use of TBI-free conditioning and suggest improved outcomes with unrelated donors receiving ATLG prophylaxis. NCT00317408.

We conducted a phase 1-2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tildrakizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft versus host disease (GVHD) prophylaxis. Fifty patients were enrolled between March 2020 and June 2023 with a median age of 56 (range 19-64). All patients received myeloablative busulfan-based conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. Patients were treated with tildrakizumab on an extended subcutaneous administration schedule for five doses which was well tolerated. The cumulative incidences of grades II-IV and III-IV acute graft versus host disease were 14% (95% CI 7-28) and 4% (95% CI 1-16) at day 100, respectively. The incidence of chronic GVHD requiring systemic immune suppression was 52.7% (95% CI 40.4-68.9) at twelve months. The one-year probabilities of overall, disease-free, and GVHD-free relapse-free survival were 80% (95% CI 70-92), 78% (95% CI 67-90), and 19.3% (90% CI 11.8-31.4), respectively. Pharmacokinetic analysis revealed that the half-life of tildrakizumab approximated 28 days without formation of detectable anti-tildrakizumab neutralizing antibodies. Comparative examination of fecal microbial composition in tildrakizumab and a similarly transplanted cohort treated with tocilizumab prophylaxis demonstrated that both cytokine blockade strategies had a low frequency of enterococcal dominance. We conclude that tildrakizumab resulted in a low incidence of acute GVHD and attenuation of microbiome dominance with potentially pathogenic organisms but did not mitigate the emergence of chronic GVHD as administered on this dosing schedule. NCT04112810.

The hallmark of ERCC6L2 disease (ED) is a highly penetrant progression from bone marrow failure (BMF) to erythroid-predominant, TP53-mutated myeloid malignancy with a dismal prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only potentially curative option, but concerns exist regarding transplant-related toxicities due to the underlying DNA repair defect. This is the first study to report a systematic analysis of HSCT in ED. We conducted a retrospective multicenter study involving 45 patients with ED who underwent HSCT in 2004-2024. The primary outcomes were overall survival (OS), transplant-related toxicity, and non-relapse mortality (NRM). The 1-year and 3-year OS were 79% (95% confidence interval [CI], 66-91) and 54% (95% CI, 35-73), respectively. Prior history of excess blasts significantly predicted inferior survival (hazard ratio [HR], 6.8; 95% CI, 2.2-20.3; P<0.001), with a median survival of 12 months (95% CI, 0-24). Grade 3-5 endothelial toxicities occurred in 27% of patients and were associated with higher NRM (HR, 7.7; 95% CI, 1.5-38.8; P=0.016). The use of non-treosulfan-based myeloablative conditioning (MAC) regimens increased the risk of endothelial complications compared to reduced-intensity conditioning (RIC) (HR, 4.9; 95% CI, 1.1-22.0; P=0.040), whereas outcomes with treosulfan-based MAC were comparable to RIC. In summary, allogeneic HSCT is a viable curative strategy for ED when performed before transformation to an aggressive malignancy i.e. myelodysplasia with excess blasts or acute myeloid leukemia. However, the elevated incidence of endothelial toxicity highlights the importance of optimizing conditioning intensity and enhancing peritransplant monitoring in this population.

Expression levels of human leukocyte antigen (HLA) are associated with susceptibility to various diseases and outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). However, there has been no comprehensive analysis of the effect of the expression levels of the HLA-A, -B, -C, and -DRB1 alleles in unrelated (UR)-HCT. Using the Capture RNA-Seq method, we analyzed the gene expression of HLA alleles in 443 healthy donors and determined the allele-specific transcription levels (AST levels). We assigned median (M)-AST levels to HLA typing data of patients who received a transplant from HLA-A, -B, -C, and -DRB1-matched unrelated donors using transplant registry data. All 6,084 patients were divided into low, middle, and high tertile groups according to the distribution of the sum of the two alleles of the M-AST level for each HLA locus and the sum of the eight alleles of the M-AST level for all four loci. The risk of grade II-IV acute graft-versus-host disease (GVHD) was significantly higher in the middle group (hazard ratio, 1.11; P = 0.044) and high group (hazard ratio, 1.20; P < 0.001) than in the low group for the sum of the HLA-A, -B, -C, and -DRB1 loci. Similar results were observed at the HLA-A, -B, -C, and -DRB1 loci. Higher transcription levels were also associated with a lower risk of relapse at the HLA-B, -C, and -DRB1 loci. Our data suggest that a high transcription level of patient and/or donor HLA may evoke strong alloimmune responses and affect UR-HCT outcomes.

CPX-351 was approved for treatment of acute myeloid leukemia (AML) using now-outdated definitions of AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML. We evaluated whether the overall survival (OS) benefit of CPX-351 over 7+3 is confined to molecularly-defined AML subgroups by performing DNA sequencing in 184 patients enrolled in the pivotal phase 3 randomized trial. Patients were categorized hierarchically based on gene mutations: (1) TP53-AML, (2) DDX41-AML, (3) myelodysplasia-related AML (AML-MR) defined by WHO 5th edition, or (4) other-AML. TP53-AML was subclassified as single (TP53single) or multihit (TP53multi) based on the number of alleles altered via mutation, deletion, or copy-neutral loss of heterozygosity. Two-year OS differed significantly across molecular subgroups: TP53-AML (7%), AML-MR (19%), other-AML (37%), and DDX41-AML (70%) p<0.001. CPX-351 improved survival in AML-MR patients compared to 7+3 (median: 9.7 vs 6.8 months, p=0.037), with no benefit in TP53-AML or other-AML. For patients undergoing transplantation, CPX-351 improved 2-year survival (76% vs 27%; p<0.01), an effect primarily observed in AML-MR. Multivariable analysis confirmed the independent association with survival of both CPX-351 and HCT in AML-MR. TP53multi demonstrated significantly worse survival than TP53single (median 3.8 vs 7.0 months; p=0.004). The OS benefit of CPX-351 observed in the trial was driven by AML-MR with no benefit of CPX-351 in TP53-AML, where the primary prognostic factor was allelic state. Clinical Trial Information: NCT01696084.

Platelet transfusion is a necessary life sustaining therapy for extreme thrombocytopenia from multiple etiologies. However, refractoriness develops in some patients such that transfused platelets are rapidly cleared, and refractory patients are at risk for catastrophic hemorrhage. One cause of refractoriness is humoral immunization to MHC-I alloantigens. However, approximately 50% of patients with alloantibodies to MHC-I do not become refractory. The factors that determine whether an alloimmunized patient is refractory remain undefined. Both mice and humans encode four distinct IgG subclasses, each with different effector function characteristics. In this report we forward the hypothesis that IgG subclass composition of alloantisera affects refractoriness. A novel panel of mice was generated with mutated effector function for different murine IgG subclasses. Elimination of effector function of IgG2c (but not IgG1 or IgG2b) eliminated the ability of alloantisera to clear transfused platelets. Together, these data demonstrate the differential platelet clearing activity of distinct IgG subclasses in vivo and support the hypothesis that differences in IgG subclass affect whether alloimmunization results in refractoriness to platelet transfusion.