Blood advances最新文献

In plasma, the zymogens factor XII (FXII) and prekallikrein reciprocally convert each other to the proteases FXIIa and plasma kallikrein (PKa). PKa cleaves high-molecular-weight kininogen (HK) to release bradykinin, which contributes to regulation of blood vessel tone and permeability. Plasma FXII is normally in a "closed" conformation that limits activation by PKa. When FXII binds to a surface during contact activation it assumes an "open" conformation that increases the rate of activation by PKa. Mutations in FXII that disrupt the closed conformation have been identified in patients with conditions associated with excessive bradykinin formation. Using FXII structures predicted by AlphaFold, we generated models for the closed form of human FXII that we tested with site-directed mutagenesis. The best model predicts multiple interactions between the fibronectin type 2, kringle and catalytic domains involving highly conserved amino acids that restrict access to the FXII activation cleavage sites. Based on the model, we expressed FXII with single amino acid substitutions and studied their effects on FXII activation by PKa. Replacements for Arg36 in the fibronectin type 2 domain; Glu225, Asp253 or Trp268 in the kringle domain, or Lys346 near the activation cleavage site were activated >10-fold faster by PKa than wild type FXII. Adding these proteins to plasma resulted in rapid HK cleavage due to markedly enhanced reciprocal activation with PK. The results support a model that explains the behavior of FXII in solution. Conformational changes involving the identified amino acids likely occur when FXII binds to a surface to facilitate activation.

In this study, we first analyzed data from 147 patients with solitary plasmacytomas treated at the Mayo Clinic between 2005 and 2022 and then expanded our investigation through a systematic review and meta-analysis of 62 studies, encompassing 3,487 patients from the years 1960 to 2022. Our findings reveal that patients with up to 10% clonal plasma cells in their bone marrow (BM), denoted as plasmacytoma +, had a significantly reduced median disease-free survival (DFS) of 15.7 months vs. 79 months, p<0.05, observed in patients with true solitary plasmacytomas, with no clonal cells in the BM. Risk factors identified for shorter DFS included the presence of clonal plasma cells in the marrow and a DFLC > 5 mg/dl. The meta-analysis portion of our study highlighted a male predominance among patients, with a median age of 58, and confirmed radiation therapy as the predominant treatment modality. We also found that DFS rates at 3, 5, and 10 years were 66.9%, 55%, and 42.1%, respectively, and noted a significant difference in outcomes between patients with bone and extramedullary plasmacytomas, with the latter group exhibiting better survival rates. This dual-faceted approach provides a thorough overview of survival rates and critical risk factors for plasmacytoma patients, underscoring the vital role of accurate disease staging at diagnosis and the impact of tumor location on patient prognosis.

The Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) conducted the SAKK 35/10 randomized phase-2 trial (NCT0137605) to compare rituximab (R) alone versus R plus lenalidomide (L) as initial treatment for follicular lymphoma (FL). Patients with grade 1-3a FL, requiring systemic therapy, were randomized to either R (n=77; 375 mg/m2 IV x 1, weeks 1-4) or RL (n=77; R on the same schedule and L at 15 mg daily continuously). Responders (evaluated at 10 weeks) repeated R during weeks 12-15 with or without L (for a total of 18 weeks). Both arms had 47% of patients with a poor risk score on the FL International Prognostic Index (FLIPI). The primary endpoint, complete response (CR)/CR unconfirmed (CRu) rates at 6 months were superior with the combination, and now after a median follow-up of 9.5 years, have translated into a longer duration of response (DoR, median not reached vs 3.2 years; hazard ratio (HR)=0.42, 95% confidence interval (95%CI): 0.21-0.86; p=0.014), progression-free survival (PFS, 9.3 vs 2.3 years HR=0.57, 95% CI: 0.37-0.89; p=0.0128), and time-to-next treatment (TTNT, median not reached vs 2.1 years; HR=0.43, 95% CI: 0.27-0.67; p<0.001). Over 60% of RL responders remained in first CR at 10 years. OS was similar in both arms (77% vs 78% at 10 years, p=0.881). Toxicity was more common with RL but manageable. The SAKK 35/10 trial's long-term results confirmed a durable benefit of a short-term chemotherapy-free first-line RL regimen in symptomatic FL.

Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory large B-cell lymphoma (R/R LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days versus 28 to <40 days versus 40+ days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt 40+ days was associated with significantly lower complete response rate compared with V2Vt <28 days (odds ratio [OR] 0.61) or 28 to <40 days (OR 0.66) and significantly worse overall survival compared with V2Vt <28 days (hazard ratio [HR] 1.33) or 28 to <40 days (HR 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt 28 to <40 days or 40+ days compared with <28 days (OR 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Interferon alpha (IFNa) is approved for the therapy of patients (pts) with polycythemia vera (PV), a subtype of myeloproliferative neoplasms (MPN). Some pts achieve molecular responses (MR), but clonal factors sensitizing for MR remain elusive. We integrated colony formation and differentiation assays with single-cell RNA seq and genotyping in PV-derived cells vs. healthy controls (HC) to dissect how IFNa targets diseased clones during erythroid differentiation. IFNa significantly decreased colony growth in MPN and HC, with variable transcriptional responses observed in individual colonies. scRNAseq of colonies demonstrated more mature erythroid PV-derived colonies compared with HC. JAK2V617F-mutant cells exhibited upregulated STAT5A, heme, and G2M checkpoint pathways compared to JAK2WT cells from the same pts. Subgroup analysis revealed that IFNa significantly decreased immature erythrocytic cells in PV (basophilic erythroblasts p<0.05; polychromatic erythroblasts p<0.05) but not in HC. CD71-/CD235a+ cells from HC (p<0.05) but not from PV pts were inhibited by IFNa, and number of reticulocytes was less affected in PV. Robust IFNa responses persisted throughout differentiation, leading to significant apoptosis in PV. Apoptotic cells displayed downregulation of ribosomal genes. This link between apoptosis and ribosomal genes was corroborated through analysis of mitochondrial variants demonstrating IFNa-induced eradication of specific clones, characterized by elevated expression of ribosomal genes. Our findings indicate that PV-derived clones either undergo apoptosis or pass through differentiation, overall reducing cycling mutant cells over long-term treatment. Further, the significance of ribosomal genes and clonal prerequisites in IFNa's therapeutic mechanism is underscored, shedding light on the intricate dynamics of IFNa treatment in PV.

High-grade-B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double hit [HGBL-DH] or triple hit [HGBL-TH]), or not otherwise specified (HGBL-NOS), are considered to be more aggressive diseases among large B-cell lymphomas (LBCL). CD19-targeting Chimeric Antigen Receptor (CAR) T-cells have changed the prognosis of chemoresistant LBCL. Clinical and pathological data of patients treated for relapsed/refractory LBCL or HGBL in third line or more, all characterized by FISH, were collected from the French DESCAR-T registry. Between January 2018 and November 2022, 228 patients were included across 14 centers, 73 with HGBL (28 HGBL-DH MYC-BCL2, 14 HGBL-TH, 8 HGBL-DH MYC-BCL6, 23 HGBL-NOS) and 155 with non-HGBL. Median follow-up was 18.5 months [95% CI, 14.3-23.4] from the date of infusion. Progression-free survival (PFS) and overall survival (OS) were not significantly different between HGBL and non-HGBL, at respectively 3.2 months [95% CI, 2.8-6.0] vs 4.5 months [95% CI, 3.1-8.7] (p = 0.103) and 15.4 months [95% CI, 5.6-32.4] vs 18.3 months [95% CI, 8.5-NR]. From the date of eligibility, the median OS was inferior for patients with HGBL-TH/DH MYC-BCL2 at 6.6 months vs 18.5 months for HGBL-NOS vs 13.6 months for HGBL-DH MYC-BCL6 vs 11.8 months for LBCL (p = 0.037). However, infused patients presented the same outcome. CAR T-cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes, especially in HGBL-TH/DH MYC-BCL2. This observation supports considering the potential benefit of using CAR-T earlier in the course of the disease.

To assess efficacy and safety of dapsone in adult immune thrombocytopenia (ITP), a multicenter randomized controlled trial (RCT) and a real-word study cohort were performed. Participants were adults with primary ITP, transient response to corticosteroids ± intravenous immunoglobulin, and a platelet count ≤ 30x109/L (or ≤ 50x109/L with bleeding). Patients in the RCT were randomized in arm A (prednisone x3weeks+dapsone for 12 months) or arm B (prednisone alone). The observational study involved dapsone initiation at 100 mg/d with standard follow-up. The primary endpoint was the response rate (platelet count >30x109/L and ≥2×baseline) at 52 weeks, with the response rate at 24 weeks and adverse events as secondary endpoints. The RCT enrolled 93 patients (54.8% female), median age 48.5 years (46 in arm A, 47 in arm B). In the intention-to-treat analysis, 78.3% of patients in group A discontinued dapsone after a median of 4.6 weeks due to adverse events (66.7%) or lack of efficacy (33.3%). The response rate at week 52 was 21.7% (95% CI:10.9%-36.4%) in group A versus 8.5% (95% CI:2.7%-18.6%) in group B (p=0.17). The observational study, which was conducted after the end of the RCT, included 46 patients (52.2% female), median age 50.7 years. Adverse events occurred in 30.4%, leading to discontinuation of dapsone in 23.9%, and 13.6% (95% CI: 5.2%-27.4%) met the primary efficacy endpoint. Results from both studies showed an unfavorable risk-benefit ratio for the use of dapsone in adult primary ITP and suggest that, whenever available, second-line options should be used. NCT02627417, NCT02877706.