Blood advances最新文献

Abstract: In 2014, the first patient received a CD22 chimeric antigen receptor (CAR) T-cell product. As one of the earliest approaches targeting an antigen other than CD19, this trial addressed an unmet need while providing insights into CAR T-cell efficacy, impact of manufacturing changes, and management of inflammatory toxicities over its 10-year span. This final chapter provides a comprehensive review of the collective findings. Across 78 patients with B-cell acute lymphoblastic leukemia who received infusion, cytokine release syndrome was observed in 66 (84.6%) patients, whereas 28 (35.9%) had immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), and 18 (23.1%) had reversible neurotoxicity. Complete response was achieved in 54 (70.1%) patients by day 28, of whom 45 (83.3%) were measurable residual disease negative. Median overall survival was 13.6 months, and median relapse-free survival was 6.1 months. Pharmacokinetics revealed peak CAR T-cell expansion at a median of 14 days (range, 12-50), with no variation by dose. Interestingly, toxicities, CAR T-cell expansion, and disease response did not correlate with baseline disease burden. Additionally, although early intervention approaches to mitigate IEC-HS severity for this construct appeared promising, further study is needed. Given the critical importance of CD22 targeting, this experience serves as a foundation for new approaches targeting CD22 while providing ongoing support for dual-targeting approaches and insights into toxicity mitigation. This trial was registered at www.ClinicalTrials.gov as NCT02315612.

Abstract: Hereditary hemorrhagic telangiectasia (HHT) causes severe recurrent epistaxis, chronic gastrointestinal bleeding, solid organ arteriovenous malformations, and significant anemia. Although it is the second most common inherited bleeding disorder worldwide, no approved therapies exist. The multicenter, US randomized, controlled PATH-HHT trial demonstrated efficacy of short-term pomalidomide treatment of epistaxis in HHT. However, questions regarding long-term safety, effectiveness, and utility for HHT-associated gastrointestinal bleeding remain. The PATH-HHT ATLAS (after trial longitudinal assessment study) was a multicenter US longitudinal observational study evaluating patients enrolled in PATH-HHT who continued pomalidomide after PATH-HHT through a poststudy drug access program, with ongoing close monitoring per PATH-HHT protocol and as mandated by the US Food and Drug Administration. Sixty-two patients treated with pomalidomide for HHT for up to 4.4 years were included. Significant, durable improvements in mean epistaxis severity score (5.55 points [baseline] to 2.80 points [month 12]; P< .0001) and mean hematologic support score (9.11 red cell unit equivalents [RUEs] during 6 months pretreatment to 5.73 RUEs [months 7-12]; P = .0056) were observed. Pomalidomide was less effective for gastrointestinal bleeding than for epistaxis, particularly in patients with high red blood cell transfusion requirements. Thirty-one patients (50%) underwent dose reduction from 4 mg daily, primarily due to neutropenia, but most maintained effectiveness at 2 or 3 mg daily. Over 105.2 patient-years of pomalidomide treatment, 0 patients developed peripheral neuropathy, 1 developed venous thromboembolism, and 5 developed serious infections. In conclusion, pomalidomide was effective for HHT-associated epistaxis over extended durations, albeit with nontrivial potential toxicities, and may be considered for certain patients with HHT. This trial was registered at www.clinicaltrials.gov as NCT07018401.

Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. While genomics and transcriptomics have delineated parts of the MCL disease spectrum, the proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 MCL patients and 4 healthy donors to investigate the translational and post-translational dimensions of MCL. Our study identified 1,296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed IGHV mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multi-omics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared to single-omics models (concordance index 0.83 vs. 0.74). This study provides the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

The phase 1 portion of SENTRY/XPORT-MF-034 (NCT04562389) evaluated the exportin 1 inhibitor selinexor (40 mg/60 mg once weekly) plus ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis (n = 24). Primary endpoints were maximum tolerated selinexor dose, recommended clinical trial dose, and safety. No dose-limiting toxicities were reported. Common adverse events were nausea, fatigue, anemia, thrombocytopenia, constipation, vomiting, and headache. Nausea was transient, mainly grade 1, and managed by prophylactic antiemetics. Four deaths occurred, all unrelated to study treatment. Selinexor 60 mg in combination with ruxolitinib was identified as the recommended phase 3 dose based on safety, efficacy, and exposure-response analyses. Overall safety profiles and grades of clinically significant adverse events were similar and generally manageable regardless of selinexor dose. A greater proportion of patients achieved spleen volume reduction equal to or greater than 35% (SVR35) and total symptom score reduction equal to or greater than 50% (TSS50) at Week 24 in the 60-mg selinexor group (79% and 58%) compared with the 40-mg group (38% and 25%). Among evaluable patients who received suboptimal ruxolitinib ≤5 mg twice-daily in the selinexor 60-mg group, SVR35 was observed in 100% (6/6) of patients and TSS50 was observed in 75% (3/4) of patients.

The introduction of emicizumab, a bispecific antibody that mimics factor VIII (FVIII) function, has raised critical questions regarding the potential for FVIII inhibitor development when patients receiving emicizumab prophylaxis are administered FVIII during high-risk clinical scenarios. To investigate this concern, we developed a novel human hemophilia A mouse model (HemoAhfIX/hfX) by adeno-associated virus (AAV) delivery of human F9 and F10 genes as episomal copies, which expressed sufficient levels of human FIX and FX (158.0 ± 57.9 IU/dL and 372.8 ± 170.7 IU/dL, respectively, at 12 weeks). Emicizumab treatment in HemoAhfIX/hfX mice significantly shortened activated partial thromboplastin time and partially restored thrombin generation capacity. Using a two-factor factorial design, 55 mice were assigned to four treatment groups: (A) FVIII prophylaxis, (B) FVIII on-demand, (C) emicizumab with FVIII prophylaxis, and (D) emicizumab with FVIII on-demand. On-demand groups received weekly knee joint puncture injuries to simulate bleeding episodes throughout the experimental period. While most animals developed high-titer inhibitors, limiting the detection of inter-group differences in inhibitor development rates, inhibitor titers varied significantly across treatment groups (p = 0.0098), with notably lower levels in emicizumab-treated mice (p = 0.0006). Additionally, emicizumab treatment preserved joint architecture, evidenced by reduced synovitis. These findings demonstrate that emicizumab therapy is associated with attenuated inhibitor titers and enhanced joint preservation against bleeding in HemoAhfIX/hfX mice, establishing this model as a valuable platform for preclinical evaluation of emicizumab-based therapeutic strategies.