HemaSphere最新文献

This study aimed to evaluate the impact of the myelodysplasia-related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1-mutated (NPM1^mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1^mut AML patients (median age: 59 years) entered into the prospective AMLSG 09-09 treatment trial. Most commonly co-mutated genes were DNMT3A (49.8%), FLT3-TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable-risk NPM1^mut AML, multivariable analysis for event-free survival (EFS) identified age (p < 0.001), DNMT3A^R882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co-mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on NPM1^mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas DNMT3A^R882, MYC, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (p < 0.001), DNMT3A^R882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co-mutation (p = 0.037). In 2022 ELN favorable-risk NPM1^mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1^mut MRD status post cycle 2; DNMT3A^R882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1^mut MRD status.

Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4⁺ T helper (T_H) cells > 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels >4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed T_H cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper T_H cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, p < 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, p < 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, p = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.

Limited data are available on VWF activity (VWF:Act) and factor VIII (FVIII:C) levels during delivery after VWF/FVIII concentrate administration in women with von Willebrand disease (VWD). We aimed to evaluate treatment with a specific VWF/FVIII concentrate on factor levels in women with VWD during delivery and the postpartum period. A retrospective single-center study was conducted between January 1, 2008, and August 1, 2022. Pregnant women treated with Haemate®P during delivery were included if they had ≥2 consecutive VWF:Act and FVIII:C measurements post-infusion. VWF:Act/FVIII:C levels were compared to predefined target levels. A population pharmacokinetic (PopPK) model was developed, estimating VWF and FVIII pharmacokinetics after Haemate®P administration. Nineteen women were included. Targeted VWF:Act/FVIII:C peak levels were achieved after the first infusion (≥1.00 IU/mL, n = 12; ≥1.50 IU/mL, n = 5), and all VWF:Act/FVIII:C trough levels remained ≥0.50 IU/mL during first 72 h of treatment. All women had pretreatment FVIII:C levels ≥1.00 IU/mL, except one woman with type 2N, which was significantly higher than FVIII:C levels during the third trimester (median increase: 0.42 IU/mL, interquartile range: [0.12–0.92]). FVIII:C trough levels increased during treatment, median 2.05 IU/mL [1.65–2.71]. Nine women (47%) experienced postpartum hemorrhage and no thrombosis occurred. A one-compartment PopPK model adequately described VWF:Act/FVIII:C levels. Targeted VWF:Act/FVIII:C peak levels were achieved with the prescribed dosing regimens. VWF clearance was similar to that in nonpregnant individuals. Both pretreatment and FVIIIC trough levels during treatment were high with reduced FVIII clearance. Monitoring VWF:Act/FVIII:C levels is recommended for optimizing target levels and enriching the current PopPK model, improving VWF:Act/FVIII:C level predictions, and achieving more effective dosing.

Chronic lymphocytic leukemia (CLL) is an incurable progressive malignancy of CD5⁺ B cells with a birth rate between 0.1% and 1% of the entire clone per day. However, the phenotype and functional characteristics of proliferating CLL cells remain incompletely understood. Here, we stained peripheral blood CLL cells for ki67 and DNA content and found that CLL cells in G1-phase have a CXCR4^loCD5^hi phenotype, while CLL cells in S/G2/M-phase express high levels of both CXCR4 and CD5. Induction of proliferation in vitro using CD40L stimulation results in high ki67 levels in CXCR4^loCD5^hi cells with CXCR4 expression increasing as CLL cells progress through S and G2/M-phases, while CXCR4^hiCD5^lo CLL cells remained quiescent. Dye dilution experiments revealed an accumulation of Ki67^hi-divided cells in the CXCR4^hiCD5^hi fraction. In Eµ-TCL1 transgenic mice, the CXCR4^hiCD5^hi fraction expressed high levels of ki67 and was expanded in enlarged spleens of diseased animals. Human peripheral blood CXCR4^hiCD5^hi CLL cells express increased levels of IgM and the chemokine receptors CCR7 and CXCR5 and migrate efficiently toward CCL21. We found higher levels of CXCR4 in patients with progressive disease and the CXCR4^hiCD5^hi fraction was expanded upon clinical relapse. Thus, this study defines the phenotype and functional characteristics of dividing CLL cells identifying a novel subclonal population that underlies CLL pathogenesis and may drive clinical outcomes.

Despite advances in allogeneic hematopoietic cell transplantation (HCT), poor graft function (PGF) remains an important complication with substantial morbidity and mortality. The investigation of preventive and therapeutic PGF treatments is hindered by inconsistencies in reported incidence and outcomes across studies, which may be explained by heterogeneity in PGF definition. To assess the impact of definition heterogeneity, we conducted a multicenter study, analyzing over 35.000 longitudinal blood counts from 427 pediatric and 405 adult HCT recipients. We compared the incidence, risk factors, and outcome of PGF, based on the three most common definitions. We identified 97 pediatric and 75 adult HCT recipients fulfilling at least one PGF definition. The 2-year cumulative incidence of PGF varied significantly depending on the definition used, ranging from 6.8% to 20% in children and 4.9% to 18% in adults. Two-year mortality for PGF patients ranged from 33% to 40% in children and 46% to 65% in adults. Notably, PGF patients identified solely by lenient definitions had similar mortality to HCT recipients with good graft function. Risk factors for PGF also varied by definition in both cohorts, and included older recipient age and cord blood transplantation. In conclusion, our study demonstrates that differences in PGF definition significantly impact the reported incidence, risk factors, and outcome. This underscores the need to harmonize PGF definitions across scientific studies, clinical practice, and transplant registries. Future studies, using standardized, quantitative thresholds for PGF, are required to determine optimal treatment strategies for both mild and severe forms of PGF.