Blood Research最新文献

Blood cancers, including leukemia, multiple myeloma, and lymphoma, pose significant challenges owing to their heterogeneous nature and the limitations of traditional treatments. Precision medicine has emerged as a transformative approach that offers tailored therapeutic strategies based on individual patient profiles. Ex vivo drug sensitivity analysis is central to this advancement, which enables testing of patient-derived cancer cells against a panel of therapeutic agents to predict clinical responses. This review provides a comprehensive overview of the latest advancements in ex vivo drug sensitivity analyses and their application in blood cancers. We discuss the development of more comprehensive drug response metrics and the evaluation of drug combinations to identify synergistic interactions. Additionally, we present evaluation of the advanced therapeutics such as antibody-drug conjugates using ex vivo assays. This review describes the critical role of ex vivo drug sensitivity analyses in advancing precision medicine by examining technological innovations and clinical applications. Ultimately, these innovations are paving the way for more effective and individualized treatments, improving patient outcomes, and establishing new standards for the management of blood cancers.

Background: Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein-Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expression in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL.

Methods: This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment.

Results: The final analysis included six patients (four men and two women (median age, 50 years; range, 39-83 years)). Four patients were diagnosed with Epstein-Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2-31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy.

Conclusion: The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treatment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

The classic coagulation cascade model of intrinsic and extrinsic coagulation pathways, i.e. contact activation pathway and tissue factor pathway, has been widely modified. The cascade can be categorized as follows: 1) initiation by tissue factor (TF), 2) amplification by the intrinsic tenase complex, and 3) propagation on activated platelets. TF-FVIIa forms an extrinsic tenase complex and activates FX to FXa and FIX to FIXa. FXa-FVa forms a prothrombinase complex that converts prothrombin into thrombin. At this initial stage of coagulation, only small amounts of thrombin are generated owing to the low circulating levels of FVa. The generated thrombin, although in minor quantities, is sufficient to prime the subsequent coagulation reactions. Platelets and in turn FV, FVIII, and FXI are activated. Subsequently, FVIIIa binds to FIXa to form the intrinsic tenase complex, which is aided by a cofactor, FVIIIa, and activates FX at a rate 50-times higher than that of the extrinsic tenase complex, thereby amplifying thrombin generation. Thrombin cleaves fibrinogen into one fibrin monomer and two fibrinopeptides. Fibrin monomers aggregate, crosslink, and branch into an insoluble fibrin network structure. The contact activation system is initiated by FXII, which is activated upon exposure to negatively charged surfaces. Coagulation is driven by FXIIa-mediated FXI cleavage. FXIa activates FIX, which forms an intrinsic tenase complex, eventually leading to thrombin formation. The contact activation system is considered to contribute to thrombosis but is not required for hemostasis in vivo.

Purpose: Hemophilia A is a genetic disorder characterized by a lack of factor VIII (FVIII). Emicizumab, a recombinant humanized bispecific monoclonal antibody, mimics the function of FVIII. In this article, we present data on an initial real-world evaluation of emicizumab use in Korean children with severe hemophilia A without inhibitors.

Methods: This study was conducted from June 2020 to March 2024 at 4 centers in Korea. The participants were pediatric patients with severe hemophilia A without inhibitors who had received emicizumab treatment for over 6 months. The mean and median annualized bleeding rates (ABRs) and mean and median annual joint bleeding rates (AJBRs) were compared.

Results: Each of the 21 patients in the study received an emicizumab loading regimen of 3 mg/kg weekly for 4 weeks, followed by a modified maintenance regimen of which 2 patients (9.5%) received a 1.5 mg/kg weekly dose, 3 patients (14.3%) received a 6 mg/kg dose every 4 weeks, and the remaining 16 patients (76.2%) received a 3 mg/kg dose every 2 weeks. Before emicizumab prophylaxis initiation, the mean and median ABRs for all patients were 7.04 (SD ± 5.83) and 6.52 (range 0-21.74), respectively. After receiving emicizumab treatment, the mean and mediam ABRs decreased to 0.41 and zero, respectively. Additionally, 85.7% of the patients achieved no bleeding events within 6 months of starting the treatment.

Conclusion: These first real-world data in Korea indicate that emicizumab is effective and safe for pediatric patients with severe hemophilia A without inhibitors.

Background: SM-like (LSM) genes a family of RNA-binding proteins, are involved in mRNA regulation and can function as oncogenes by altering mRNA stability. However, their roles in B-cell progression and tumorigenesis remain poorly understood.

Methods: We analyzed gene expression profiles and overall survival data of 123 patients with mantle cell lymphoma (MCL). The LSM index was developed to assess its potential as a prognostic marker of MCL survival.

Results: Five of the eight LSM genes were identified as potential prognostic markers for survival in MCL, with particular emphasis on the LSM.index. The expression levels of these LSM genes demonstrated their potential utility as classifiers of MCL. The LSM.index-high group exhibited both poorer survival rates and lower RNA levels than did the overall transcript profile. Notably, LSM1 and LSM8 were overexpressed in the LSM.index-high group, with LSM1 showing 2.5-fold increase (p < 0.001) and LSM8 depicting 1.8-fold increase (p < 0.01) than those in the LSM.index-low group. Furthermore, elevated LSM gene expression was associated with increased cell division and RNA splicing pathway activity.

Conclusions: The LSM.index demonstrates potential as a prognostic marker for survival in patients with MCL. Elevated expression of LSM genes, particularly LSM1 and LSM8, may be linked to poor survival outcomes through their involvement in cell division and RNA splicing pathways. These findings suggest that LSM genes may contribute to the aggressive behavior of MCL and represent potential targets for therapeutic interventions.

Essential thrombocytosis (ET) is a rare myeloproliferative disease in children, and there are few standard management guidelines. We herein report a case series of 10 pediatric patients with ET diagnosed at our institution over a period of 13 years. All patients fulfilled the World Health Organization diagnostic criteria for ET, and none harbored the canonical ET mutations JAK2 V617F, CALR, or MPL. Overall, 7 of the 10 patients received treatment for ET, and during follow-up, 3 of these 7 patients discontinued cytoreductive therapy. No patient experienced hemorrhagic or thrombotic complications. Our case series emphasizes that the genetic features of pediatric ET may differ significantly from those of adult ET, and that treatment cessation is a possibility for some patients.

Purpose: Hepatitis B is a major prognostic factor after hematopoietic stem cell transplantation (HSCT). Currently, no consensus exists regarding the management of various scenarios that can lead to reverse seroconversion of the hepatitis B surface antigen (HBsAg-RS). This study focused on HBsAg-RS, which serves as an indicator of active hepatitis, and aimed to obtain exploratory information on the associated patient and treatment factors.

Methods: This single-center retrospective study utilized clinical data extracted from the electronic medical records of Seoul St. Mary's Hospital, Korea. Patients who underwent HSCT between January 2013 and December 2018 and tested negative for hepatitis B surface antigen (HBsAg) before undergoing HSCT were included. The associations between HBsAg-RS and demographic information, baseline hepatitis B serological markers, and vaccination status were statistically analyzed.

Results: This study included 1,344 patients, of whom 83.3% tested positive for the hepatitis B surface antibody (HBsAb) during HSCT. HBsAg-RS occurred in 2.2% of HBsAb-negative patients and 3.0% of HBsAb-positive patients, indicating no significant difference in reactivation rates according to HBsAb status. However, positivity for hepatitis B core antibody (HBcAb) was significantly associated with hepatitis B reactivation (HBsAg-RS rate: 8.0%). The vaccination rates were highest in patients who were negative for both HBsAb and HBcAb and had a transient protective effect.

Conclusion: The sufficient patient population enabled the identification of an association between baseline HBcAb positivity and the development of HBsAg-RS. Further prospective studies are warranted to determine optimal vaccination strategies for preventing HBsAg-RS.

Purpose: This real-world analysis described the Hemophilia A (HA) population in Italy, evaluating drug utilization and consumption of factor VIII (FVIII) products of patients under prophylaxis and on-demand therapy.

Methods: From Jan-2017 to Jun-2022, male patients with HA were identified through prescriptions of FVIII products [extended half-life FVIII, standard half-life recombinant FVIII, and plasma-derived FVIII (EHL FVIII, SHL rFVIII, and pdFVIII, respectively)], or emicizumab or FVIII plus von Willebrand factor or HA-related hospitalization using administrative flows of Italian healthcare entities. Patients on treatment with FVIII products during 2021-2022 were stratified by treatment regimen (prophylaxis/on-demand). The mean annual consumption expressed in International Units (IU) of EHL FVIII and SHL FVIII in patients treated during 2021-2022 having at least 12-month follow-up were assessed.

Results: Among included HA patients, 145 (39.5%) received EHL FVIII and 222 (60.5%) SHL FVIII. Of 165 patients on prophylaxis, 105 (64%) received an EHL FVIII and 60 (36%) an SHL FVIII. The mean annual consumption of FVIII was 336,700 IU (median 319,000 IU) for EHL FVIII and 440,267 IU (median 360,500 IU) for SHL FVIII. Specifically, for patients on EHL FVIII, the most common drugs were efmoroctocog alfa (N = 51) and damoctocog alfa pegol (N = 50), followed by turoctocog alfa pegol (N = 25) and rurioctocog alfa pegol (N = 19). Of 702 HA patients initially treated with FVIII products, 74 (10.5%) switched to emicizumab during follow-up.

Conclusion: These findings revealed an extensive use of EHL FVIII products, suggesting growing efforts from clinicians to optimize prophylactic strategies and achieve better bleeding protection.

Purpose: This study aimed to investigate the pharmacokinetics (PK) of factor VIII (FVIII) in Korean patients, as limited information is available on the PK of FVIII in this population.

Methods: We collected the FVIII PK results from patients with moderate-to-severe hemophilia A using myPKFiT. PK variations were assessed according to age, blood type, inhibitor history, von Willebrand factor antigen (vWF:Ag) level, and body mass index. Additionally, the correlation between the PK profile and prophylaxis regimen was specifically analyzed for each product in severe cases.

Results: The PK data of 48 and 81 patients treated with octocog alfa and rurioctocog alfa pegol, respectively, were obtained. The median half-lives of octocog alfa and rurioctocog alfa pegol were 9.9 (range: 6.3-15.2) h and 15.3 (range: 10.4-23.9) h, respectively. The PK profiles for each product did not differ according to age group; however, blood type-O patients had shorter half-lives and time to 1% compared to non-blood type-O patients. In regression analysis, the PK of octocog alfa showed a statistically significant difference according to age, whereas the PK of rurioctocog alfa pegol correlated with vWF:Ag. Only the frequency of rurioctocog alfa pegol use showed a statistically significant difference in relation to time to 1%, although the coefficient of determination was small.

Conclusion: This study confirmed significant interpatient variation in the PK of FVIII among Korean patients with hemophilia A. To achieve optimized prophylaxis, personalizing the regimen based on the PK profile of each individual patient is essential.