Therapeutic Advances in Hematology最新文献

Background: Hemophilia A is caused by coagulation factor VIII (FVIII) deficiency and increases bleeding risk during invasive procedures.

Objectives: To investigate FVIII concentrate use and bleeding outcomes for invasive procedures after valoctocogene roxaparvovec gene transfer.

Design: This manuscript presents post hoc analysis of the phase III GENEr8-1 trial.

Methods: A post hoc analysis was performed for GENEr8-1, a global, single-arm, open-label, phase III trial that enrolled 134 adults with severe hemophilia A. FVIII activity and bleeding were evaluated after 2 years of follow-up. Invasive procedures were reviewed and categorized as major or minor. FVIII activity was measured with a chromogenic assay. Bleeding was self-reported by participants. Principal investigators completed questionnaires about perioperative management.

Results: In total, 111 invasive procedures were performed in 65 participants during GENEr8-1 as of the data cut. Procedures performed with FVIII treatment included 33 minor and 11 major procedures. The remaining 67 invasive procedures were minor and performed without FVIII treatment. When considering these 67 minor procedures, 43/46 investigators completing the questionnaires reported that the gene-therapy-derived FVIII activity was sufficient for the type of procedure. Minor procedures performed without FVIII treatment were associated with participants' higher mean endogenous FVIII activity (50.5 IU/dL) compared with major procedures (14.2 IU/dL) or minor procedures (16.4 IU/dL) performed with concomitant FVIII. Fourteen participants experienced 18 procedure-related bleeds (13 co-occurring with FVIII use). Participants who received FVIII treatment for procedure-related bleeds had numerically lower mean endogenous FVIII activity than those who did not receive FVIII treatment.

Conclusion: Invasive procedures were safely performed in participants following treatment with valoctocogene roxaparvovec. The questionnaire responses from investigators generally suggest they used endogenous FVIII activity derived from valoctocogene roxaparvovec to inform clinical decisions in a manner comparable to exogenously administered FVIII, and more commonly prescribed supplementary FVIII concentrate in the peri-procedural period for participants with lower FVIII activity levels.

Background: Beta-thalassemias (BTs) are characterized by deficient or absent synthesis of the beta-globin subunit, leading to anemia. Patient characteristics and treatment patterns in these patients may vary.

Objective: This retrospective study evaluated demographics, clinical characteristics, and treatment patterns in patients with transfusion-dependent BT (TDT) and non-transfusion-dependent BT (NTDT).

Methods: Medical records of adults with TDT or NTDT in the United Kingdom, France, Germany, Spain, and Canada with ⩾5 years of history within the practice were evaluated.

Results: Among patients with TDT (N = 118), mean (standard deviation (SD)) age was 36.1 (11.9) years, and 28.8% were female; among patients with NTDT (N = 96), mean (SD) age was 36.6 (9.8) years, and 38.5% were female. Among patients with TDT, 21.2% received transfusions every 2 weeks or more frequently, 28.8% every 3 weeks, 26.3% every 4 weeks, and 21.2% less frequently than 4 weeks. Patients with TDT had a mean (SD) of 2.4 (0.6) units of blood transfused per transfusion, with a pretransfusion hemoglobin (Hb) level of 6.9 (1.3). In total, 84.4% of patients with NTDT had at least one transfusion, and the mean (SD) number of transfusions among patients with NTDT was 15.9 (15.9). Among patients with NTDT, the mean (SD) units of blood per transfusion were 2.2 (0.6) units, and the mean (SD) Hb level prior to transfusion was 7.4 (1.2) g/dL. Iron chelation therapy was received by 70.3% of TDT patients and 45.8% of NTDT patients.

Conclusion: This study found that both patients with NTDT and TDT have low pretransfusion Hb levels. A high number of patients, especially patients with TDT, were not treated according to the current recommendations on target hemoglobin level, thereby highlighting the importance of national reference centers for improving long-term outcomes and quality of life in these patients.

Background: Acute graft-versus-host disease (aGvHD) is the primary cause of mortality following allogeneic hematopoietic cell transplantation (HCT).

Objectives: This study aimed to predict the risk of aGvHD after HCT in patients with thalassemia major using a novel predictive nomogram.

Design: A retrospective study was used to develop the prediction model.

Methods: We performed retrospective analyses on 402 consecutive thalassemia patients who underwent HCT. Risk factors for aGvHD were analyzed using Cox proportional regression models. T-lymphocyte subsets were collected from 240 patients at the time of neutrophil engraftment. Least Absolute Shrinkage and Selection Operator regression was utilized to screen the indices, with cut-off values established through restricted cubic spline (RCS) regression. The predictive model was developed by integrating these T-lymphocyte subsets with clinical features, aiming to enhance the accuracy of aGvHD risk prediction.

Results: Among 402 thalassemia patients analyzed post-transplantation, significant independent risk factors for aGvHD included matched unrelated donors, haploid-related donors, peripheral blood stem cell infusions, and donor age older than 40 years. Our RCS analysis indicated a marked increase in aGvHD risk when CD4+ T-cell counts exceeded 36 cells/μL and CD8+ T-cell counts exceeded 43 cells/μL during neutrophil engraftment. The integration of T-lymphocyte subsets with clinical risk factors into a Cox regression model demonstrated good predictive performance for assessing aGvHD risk.

Conclusion: This study presents a novel model designed to predict aGvHD in thalassemia patients post-transplantation by utilizing T-lymphocyte data at the time of engraftment. The model facilitates the creation of personalized treatment plans, aiming to minimize the incidence of aGvHD and improve patient outcomes.

Background: Chemotherapy-induced thrombocytopenia (CIT) commonly exacerbates the difficulty of cancer treatment, increasing bleeding risks and potentially reducing chemotherapy dosage, ultimately impacting its efficacy. However, there are limited studies about avatrombopag application in acute lymphoblastic leukemia (ALL) CIT.

Objectives: We aimed to evaluate the efficacy and safety of avatrombopag in treating CIT patients diagnosed with ALL.

Design: This retrospective study, using propensity score matching, included 42 pairs of cases treated with and without avatrombopag (CAT: 54 cases, CAT+: 30 cases).

Methods: Data of CIT-ALL children were retrospectively collected. The primary endpoint was platelet count (PC) response rate on day 10 ± 2 (defined as an increase of PC to ⩾75 × 10⁹/L with the exclusion of platelet transfusion). Secondary efficacy endpoints, safety endpoints, and factors that predict PC response were also analyzed.

Results: In the avatrombopag group, the PC response rate was prominently higher on day 10 ± 2 (89.1%) versus the control group (56.4%, p = 0.005). On day 10 ± 2, the difference in median PC change from baseline was predominantly distinct in the avatrombopag group compared to the control group (p = 0.001). In the avatrombopag group, platelet recovery to ⩾25 and ⩾50 × 10⁹/L was faster (p = 0.001, p = 0.002), and quicker platelet reaching ⩾75 × 10⁹/L and ⩾100 × 10⁹/L was achieved (p = 0.023, p = 0.011). The avatrombopag group not only increased the nadir PC (p = 0.009) but also reduced the total platelet transfusion compared to the control group (p = 0.047). Only one case (2.4%) experienced bleeding events after medication. Nine cases of secondary thrombocythemia were noted without other adverse events. There was no difference in event-free survival between the two groups (p = 0.648). Drug administration was prediction factor for PC response.

Conclusion: Avatrombopag is a potentially safe and effective treatment option for CIT in pediatric ALL.

Background: Although hemophilia A mainly affects males, carriers (defined as females with hemophilia A, as well as symptomatic or asymptomatic hemophilia A carriers) are at risk of excessive bleeding, particularly during trauma or during surgical procedures. Clinical trials have focused on male patients with severe disease, and data for females are limited. Improved, evidence-based treatment guidelines for management of hemophilia A carriers are required.

Objectives and design: The NuDIMENSION study is a phase IV, prospective, open-label, single-arm study that will evaluate the perioperative efficacy and safety of simoctocog alfa (Nuwiq^®), a recombinant factor VIII (FVIII), in women/girls with hemophilia A undergoing major surgery. The study will be conducted at approximately 15 centers worldwide. Women/girls aged ⩾12 years, with mild or moderate hemophilia A (residual FVIII activity (FVIII:C) ⩾1% to <40%) and with no current/past FVIII inhibitors are eligible. All patients must be scheduled to undergo a major surgical procedure during which simoctocog alfa will be administered.

Methods and analysis: The primary endpoint is overall perioperative hemostatic efficacy ("success" or "failure") of simoctocog alfa. Hemostatic efficacy will be assessed at the end of surgery and at the end of the postoperative period (i.e., completion of wound healing), with overall adjudication by an Independent Data Monitoring Committee. Safety endpoints will include the incidences of thrombotic events and FVIII inhibitor development. The aim is to recruit 28 patients to achieve 26 evaluable surgeries.

Ethics: Ethical approval will be received from institutional review boards/independent ethics committees, and the study will be conducted in compliance with the Declaration of Helsinki.

Discussion: Data from NuDIMENSION will generate much-needed evidence on surgical management of women/girls with hemophilia A, which will help to enable the development of treatment guidelines specific for such patients.

Trial registration: CT EU 2022-502061-17-00; NCT05936580.

Background: Systematically documented data on real-world use of emicizumab, a bispecific antibody factor (F)VIII mimetic, are still lacking in people with severe haemophilia A (PwSHA). Smart medication, a real-time, online platform, monitors treatment administration and outcomes for people with haemophilia A in Germany.

Objective: To evaluate annualised bleeding rates (ABRs) and annualised joint bleeding rates (AJBRs), using data documented in the smart medication eDiary, for PwSHA receiving emicizumab.

Design: Data for 97 PwSHA without FVIII inhibitors who started emicizumab treatment between 1 January 2018 and 31 March 2023, with >24 weeks of documentation after switching from FVIII replacement, were collected in the smart medication eDiary. Those with ⩾24 weeks of pre-emicizumab data were included for analysis 24 weeks before and after switching.

Methods: The primary objective was to evaluate ABR and AJBR for treated bleeds. The proportion of bleed-free participants was calculated and administration frequency for FVIII and emicizumab were collected. The mean dosing frequencies for FVIII replacement and emicizumab were also evaluated.

Results: The mean calculated ABR and AJBR were 0.64 and 0.39, respectively, after initiating emicizumab. For those with documentation before starting emicizumab (n = 58), ABR decreased by 79.6% and AJBR decreased by 90.8%. The proportion of bleed-free participants increased by 21.3%, and joint bleed-free participants increased by 18.2%. The median FVIII dosing frequency was every 3.5 days (n = 54; range: 1.0-20.8); median emicizumab dosing frequency was every 11.2 days (N = 97; range: 6.6-29.4).

Conclusion: Real-world data collected using the smart medication eDiary provide insights into efficacy outcomes after switching from FVIII replacement to emicizumab prophylaxis. Bleeds, including joint bleeds, decreased after switching.

Background: Progress in improving risk stratification methods for patients with cytogenetically normal acute myeloid leukaemia (CN-AML) remains limited. This study investigates the prognostic significance and potential functional mechanism of malic enzyme 1 (ME1) in CN-AML.

Methods: Gene expression and clinical data of patients with CN-AML were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, which were subjected to analysis. The prognostic significance of ME1 was assessed through Kaplan-Meier survival analysis, as well as univariate and multivariate Cox regression analyses. A novel risk model based on ME1 expression levels was developed using TCGA data for predicting CN-AML prognosis. Furthermore, the impact of ME1 silencing on AML cell lines was investigated using the Cell Counting Kit-8 assay and flow cytometry. Gene set enrichment analysis (GSEA) analysis and Western blotting were performed to explore the mechanism of ME1 in CN-AML.

Results: CN-AML patients expressing higher ME1 levels exhibited shorter event-free survival (EFS) and overall survival (OS) compared to those with lower ME1 expression in the TCGA and multiple GEO datasets (all p < 0.05). Univariate and multivariate Cox regression analyses indicated that ME1 expression served as an independent prognostic factor for the EFS (p = 0.024 in TCGA, p = 0.035 in GSE6891) and OS (p = 0.039 in TCGA, p = 0.008 in GSE6891) in patients with CN-AML. The developed risk model demonstrated that patients with CN-AML in the high-risk group had worse survival than those in the low-risk group (hazard ratio: 2.67, 95% confidence interval: 1.54-4.65, p < 0.001) and exhibited strong predictive accuracy for 1-, 3- and 5-year OS (area under the curve = 0.69, 0.75, 0.79, respectively). ME1 knockdown significantly inhibited proliferation and increased apoptosis in AML cells (all p < 0.05). GSEA and Western blotting demonstrated that ME1 regulates the IL-6/JAK2/STAT3 pathway in CN-AML.

Conclusion: Elevated ME1 expression serves as an indicator of poorer prognosis in patients with CN-AML, potentially facilitating leukaemogenesis through the IL-6/JAK2/STAT3 pathway. This suggests that ME1 could be a promising prognostic biomarker and therapeutic target for CN-AML.

Background: Multiple myeloma is a malignant haematological neoplasm characterised by clonal proliferation of plasma cells, with a complex clinical picture, and a significant impact on patient survival, in which the prognosis evaluation of patients is of great importance.

Objectives: In this single-centre retrospective analysis, performed in a group of newly diagnosed multiple myeloma patients, we examined several clinical and laboratory parameters in order to evaluate their trend according to survival of patients.

Design: We collected data from 190 newly diagnosed multiple myeloma evaluated at the Hematology Division of the 'Paolo Giaccone' University Hospital of Palermo from 1 January 2017 to 30 September 2022. Specifically, we performed our analysis in the entire cohort of patients and also in the specific disease isotype.

Methods: We evaluated simple and low-cost laboratory and haemorheological parameters, the latter obtained in a calculated way. The primary endpoint was to evaluate the trend and the differences of these parameters in the study population, divided into two specific groups, deceased and survivors after a specific observation period of almost 7 years.

Results: In the entire cohort of multiple myeloma patients, we observed a mortality rate of 40%, of whom 36.4% were men and 43.1% were women. Among the patients who died, in comparison with those who survived, it is significantly evident the increase in age, in red cell distribution width (RDW), RDW%/albumin ratio and in the RDW%/haemoglobin ratio; moreover, in the same patients subgroup, we observed a reduction in haematocrit, total serum protein, calculated whole blood viscosity (evaluated according to the de Simone formula), serum albumin, albumin/fibrinogen ratio and in haemoglobin levels.

Conclusion: The obtained data can represent a possible starting point for subsequent targeted analyses, aimed at studying the prognostic value of each individual parameter considered, favouring an increasingly complete and immediate prognostic evaluation of patients.

Background: Immune tolerance induction (ITI) is the gold standard for inhibitor eradication to restore the clinical efficacy of factor replacement therapy in haemophilia. However, as ITI often requires frequent administration over extended periods, it can be considered burdensome for patients and healthcare resources. Therefore, there is a need to optimise ITI treatment, particularly in patients who failed previous ITI attempts.

Objectives: The ReITIrate study aimed to prospectively evaluate rescue ITI with efmoroctocog alfa, an extended half-life recombinant FVIII Fc fusion protein (herein rFVIIIFc), within a limited 60-week timeframe in patients with severe haemophilia A and inhibitors who failed previous ITI attempts.

Design: ReITIrate was a phase IV, open-label, single-arm, interventional, multicentre study.

Methods: Primary endpoint was ITI success (negative titre, <0.6 BU/mL; incremental recovery >66%; elimination half-life ⩾7 hours) within 60 weeks. Exploratory immunophenotype analyses were performed to characterise anti-drug antibodies (ADA) and cellular immune responses.

Results: Nine of 16 enrolled subjects completed the ITI period during ReITIrate, of which one subject attained all 3 ITI success criteria after 46 weeks with no relapse. Two subjects achieved partial success (one subject met 2/3 success criteria; one met all criteria, but not simultaneously, with inhibitor recurrence). One additional subject (ITI failure) achieved negative inhibitor titre. Across these four subjects, median (range) time to negative titre was 19 (11-60) weeks. No new safety concerns were identified. IgG4 was the major contributor to the ADA IgG response. Subjects with partial/complete ITI success had fewer IgG subclasses involved than those who failed/withdrew. Immunophenotyping indicated an increase in regulatory T-cells (CD4⁺CD25⁺CD127^low), supporting the ability to perform sensitive blood sampling to identify immune tolerance markers.

Conclusion: This study demonstrates that ITI with rFVIIIFc given within a limited timeframe has potential benefit in a difficult-to-treat inhibitor haemophilia population who failed previous ITI attempts.

Trial registration: NCT03103542.