Therapeutic Advances in Hematology最新文献

Background: Quality of life (QoL) is of paramount importance in the management of patients with chronic myeloid leukemia (CML), as most patients receive lifelong treatment. Despite this, information on patient experiences and involvement in treatment decision making is lacking.

Objectives: The global Chronic Myeloid Leukemia Survey on Unmet Needs (CML SUN) evaluated the unmet needs and concerns of patients diagnosed with CML in chronic phase (CP) and their treating physicians. Here, we present the results of the CML SUN survey from respondents in South Korea.

Design and methods: Patients with CML-CP (aged ⩾18 years; receiving a second- or later-line tyrosine kinase inhibitor [TKI]) and hematologists (treated ⩾10 patients with CML-CP over the last year) were invited to complete an online survey. Separate surveys were used for patients and physicians, with both covering CML diagnosis, treatment, impact on everyday life, and shared decision making.

Results: Forty patients and ten physicians in South Korea completed the surveys. Patients' top treatment goals were maintaining QoL and stopping or slowing down disease progression, while physicians emphasized achievement of molecular responses. More than half of physicians reported making treatment decisions with little or no input from their patients. Between 17% and 31% of patients reported that their physician only described one treatment for them. Although most patients were satisfied with their current treatment, a significant proportion believed it impacted their QoL. The top factors for patients when considering a treatment switch were maintaining QoL and living normally, while physicians again focused on achieving molecular responses.

Conclusion: The results highlight the significant impact of ATP-competitive TKIs on patients' QoL and provide useful insights into CML treatment in South Korea. The differences in patient and physician perspectives emphasize the need for shared treatment decisions that balance efficacy and tolerability to enhance QoL and to minimize unnecessary treatment switching.

Adeno-associated virus (AAV) gene therapy is a promising approach for hemophilia, offering the potential for sustained therapeutic expression of coagulation factors. However, both variability and durability of transgene expression remain a challenge, limiting treatment predictability. Comparative preclinical and human liver biopsy studies suggest that transcriptional efficiency, rather than vector genome copy number (VCN), is a primary determinant of variability and durability in treatment response. Despite the presence of vector genomes in hepatocytes, transcriptional output varies significantly across species and individuals, indicating that VCN alone is insufficient to predict therapeutic efficacy. This review synthesizes findings from preclinical models (mice, dogs, non-human primates (NHPs), and human hepatocytes) and clinical liver biopsy studies to examine mechanisms influencing AAV gene therapy variability and durability. While vector genome retention is relatively comparable across species, transcriptional efficiency declines in higher species, particularly in NHPs, dogs, and humans. Beyond transcription, vector genome loss, hepatocyte turnover, immune responses, and cellular stress (e.g., endoplasmic reticulum (ER) stress) may contribute to intraindividual declines in transgene expression over time. Recent findings also highlight the role of epigenetic modifications, vector integration patterns, and translational shutdown linked to protein-folding stress in influencing durability. Expression patterns show greater long-term stability with factor IX (FIX) gene therapy compared to factor VIII (FVIII), which often declines more sharply. Distinctions may reflect differences in protein biosynthetic burden and cellular stress responses, particularly for FVIII. Most FIX trials use the highly active Padua variant, enabling lower expression levels with potentially less cellular stress, while the tendency of FVIII to misfold and trigger ER stress may contribute to transcriptional or translational shutdown over time. Integrating insights from preclinical models, human liver biopsies, and ongoing clinical trials, this review refines our understanding of AAV gene therapy variability and durability, ultimately guiding next-generation gene therapies to enhance long-term clinical efficacy.

Hemophilia A and B are rare, X-linked bleeding disorders characterized by deficiencies in coagulation factor VIII (FVIII) and factor IX (FIX), respectively. Numerous advances have helped to reduce disease burden. However, hemophilia B is not as well studied as hemophilia A, likely reflecting its lower prevalence. Clinical management of hemophilia B has often relied on inference and extrapolation from hemophilia A. Despite being part of the same tenase complex, as enzyme (FIX) and cofactor (FVIII) when activated, with the main task being to activate factor X in the intrinsic pathway, the FIX and FVIII proteins display several molecular differences. These have the potential to impact the clinical phenotype of hemophilia, affect monitoring, and influence treatment options. Consequently, hemophilia B presents several outstanding challenges, requiring a greater degree of understanding and/or attention across a range of areas. Some of these challenges relate to the FIX molecule, with more knowledge needed in relation to: the biological/clinical impact of underlying genetic changes; hemostatic implications of the extravascular distribution of FIX; and FIX clearance. Other challenges relate to clinical management: determining the best ways to monitor the true biological activity of FIX; clarifying the relationship between FIX plasma levels and clinical outcomes when treating patients; inhibitors; affected girls and women; and appreciating the value of novel treatment approaches, while considering possible breakthrough bleeds, thrombosis, and monitoring. In addition, concerted effort is required to address global disparities, which can particularly affect hemophilia B. Identifying such challenges may help to facilitate research that will further existing knowledge, with better understanding being crucial for achieving health equity between hemophilia A and B.

Warm autoimmune hemolytic anemia (wAIHA) is characterized by autoantibodies against proteins that comprise the Rh antigen system along with hemolysis. The presence of specific autoantibodies, especially autoantibodies with anti-e specificity, is rare. The pathophysiology, management, and outcomes in this condition, including with transfusion of e-antigen positive packed red blood cells (pRBCs), remain poorly understood. A 63-year-old woman presented with fatigue, jaundice, tea-colored urine, and dyspnea. She was diagnosed with wAIHA with anti-e specificity and developed worsening hemolysis after receiving a unit of e-antigen positive pRBCs with a drop in hemoglobin from 85 to 71 g/L. She achieved a complete response with a tapering course of prednisone and folate. We conducted a systematic review of the literature by searching MEDLINE, EMBASE, and Cochrane for articles on management of wAIHA with anti-e specificity published between 1946 and 2025. We identified eighteen cases of wAIHA mediated through autoantibodies with anti-e specificity, only one of which demonstrated hemolysis after transfusion with e-antigen positive pRBCs. Treatment with corticosteroids and rituximab was effective in many of these cases. This is the one of the few cases to demonstrate increased hemolysis after transfusion with e-antigen positive pRBCs in a patient with wAIHA and autoantibodies with anti-e specificity. In these patients, transfusion of e-antigen positive pRBCs should be avoided and if transfusion is necessary, it will be important to closely monitor for worsening hemolysis. Additionally, our case and those reported in the literature highlight the effectiveness of standard corticosteroid treatment for this rare type of wAIHA.

Objective: This study aimed to investigate the recurrence patterns of diffuse large B-cell lymphoma (DLBCL) and assess the significance of clinical manifestation consistency at the time of recurrence.

Methods: A total of 141 patients who were newly diagnosed with DLBCL between January 2015 and October 2024 and who initially achieved complete remission but eventually developed relapsed disease during follow-up were retrospectively identified, their recurrence circumstances were assessed, and their clinical manifestations at diagnosis and recurrence were compared. The timing of recurrence was categorized as within 1 year of postchemotherapy or later.

Results: A total of 113 (80.1%) patients presented with clinical manifestations leading to the diagnosis of recurrence. A total of 87 (61.7%) patients presented similar clinical manifestations at recurrence to those observed during initial diagnosis. Importantly, for patients who relapsed within 1 year of chemotherapy, those with inconsistent manifestations at recurrence had significantly poorer prognoses and lower survival rates (complete remission (CR) rate, 7.4%; 1-year overall survival (OS), 37.5%; 1-year progression-free survival (PFS), 18.5%) than those with consistent manifestations (CR rate, 20.8%; 1-year OS, 34.0%; 1-year PFS, 22.6%; PFS, p = 0.046; OS, p = 0.049). In contrast, for patients whose recurrence occurred more than 1 year postchemotherapy, consistent manifestations were associated with better survival outcomes (CR rate, 44.1%; 1-year OS, 61.8%; 1-year PFS, 52.9%).

Conclusion: The timing of recurrence and the consistency of clinical manifestations are important factors influencing the prognosis of DLBCL. Specifically, early recurrence with inconsistent manifestations is associated with worse outcomes, whereas recurrence with consistent manifestations 1 year postchemotherapy is correlated with an improved prognosis.

Background: Efanesoctocog alfa is a first-in-class high-sustained factor VIII (FVIII) replacement therapy. In the phase III XTEND-1 (NCT04161495) study, once-weekly efanesoctocog alfa prophylaxis (50 IU/kg) was well-tolerated and achieved high-sustained factor levels in the normal to near-normal range (>40%) for most of the week.

Objective: To report outcomes in previously treated participants with severe haemophilia A aged ⩾12 years from an observational study who switched to efanesoctocog alfa prophylaxis during XTEND-1.

Design: Paired assessment of participants from an observational study who enrolled in the phase III XTEND-1 study.

Methods: Seventy-eight participants switched from marketed standard half-life (SHL) or extended half-life (EHL) FVIII prophylaxis to once-weekly efanesoctocog alfa prophylaxis (50 IU/kg). Endpoints included annualized bleed rates (ABRs), treatment of bleeding episodes, injection frequency and FVIII consumption.

Results: Pre-study, 44 (56%) and 34 (44%) participants received SHL FVIII or EHL FVIII prophylaxis, respectively. In the overall population, a significant reduction in ABR from 2.96 to 0.69 (p < 0.0001) was observed following the switch to efanesoctocog alfa prophylaxis as well as reductions in spontaneous, traumatic, joint and spontaneous joint ABRs (p < 0.0001). Significant reductions in mean weekly injection frequency were observed, from 2.8 to 1.0 in the SHL FVIII cohort (p < 0.0001) and from 1.8 to 1.0 in the EHL FVIII cohort (p < 0.0001). Mean annualized factor consumption reduced by 47% in the SHL FVIII cohort and 30% in the EHL FVIII cohort.

Conclusion: Collectively, the results of this post hoc analysis demonstrate the benefits of once-weekly efanesoctocog alfa prophylaxis over SHL or EHL FVIII prophylaxis on bleed rates, injection frequency and consumption.

Trial registration: Observational study: 242HA201/OBS16221; XTEND-1: NCT04161495 (https://clinicaltrials.gov/study/NCT04161495).

Background: Conditioning regimen selection significantly impacts the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. However, comparative evidence between Busulfan-Fludarabine and Busulfan-Cyclophosphamide remains inconclusive.

Objectives: To compare the efficacy and safety of Busulfan-Fludarabine versus Busulfan-Cyclophosphamide as conditioning regimens prior to HSCT.

Design: Systematic review and meta-analysis conducted in accordance with PRISMA 2020 guidelines.

Data sources and methods: MEDLINE, CENTRAL, and Embase were searched through October 2024. Eligible studies included randomized controlled trials and cohort studies comparing Busulfan-Fludarabine and Busulfan-Cyclophosphamide in HSCT recipients. Primary outcomes included overall survival and acute graft-versus-host disease (GVHD). Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. Risk of bias was assessed using RoB 2.0 and the Newcastle-Ottawa Scale.

Results: Eighteen studies (6 randomized controlled trials, 12 cohorts) comprising 2888 patients (1539 received Busulfan-Fludarabine, 1349 received Busulfan-Cyclophosphamide) were included. Busulfan-Fludarabine showed higher 1-year overall survival (RR 1.13, 95% CI: 1.01-1.26), but no significant difference at 2 or 5 years. Grade III-IV acute GVHD was significantly lower with Busulfan-Cyclophosphamide (RR 0.45, 95% CI: 0.21-0.98). Busulfan-Fludarabine resulted in lower 5-year non-relapse mortality (RR 0.63, 95% CI: 0.48-0.83), and significantly reduced pulmonary and gastrointestinal toxicities. Event-free survival favored Busulfan-Fludarabine at 2 and 5 years. No significant differences were found for relapse-related mortality, chronic GVHD, cytomegalovirus infection, or total mortality. Meta-regression identified conditioning regimen and graft source as contributors to 1-year survival variability.

Conclusion: Busulfan-Fludarabine offers early survival and toxicity advantages, while Busulfan-Cyclophosphamide may reduce severe acute GVHD. Conditioning regimen selection should consider patient-specific factors. Further prospective trials are needed to guide clinical decisions.

Trial registration: PROSPERO ID: CRD42025630836.

Objective: Here, we aimed to evaluate the prognostic values of the endothelial activation and stress index (EASIX) and its derivatives, modified EASIX (mEASIX) and simplified EASIX (sEASIX), in patients with multiple myeloma (MM).

Methods: The data of 134 newly diagnosed MM patients between January 2020 and December 2024 were retrospectively analyzed. Patients were divided into groups based on EASIX and its derivatives, and the outcomes of survival rates in groups were compared. Optimal cut-off points were determined using the receiver-operating characteristic analysis, and mortality predictive values of the scores were investigated. The independent prognostic factors were evaluated through univariate and multivariate Cox regression analyses.

Results: The optimal cut-off point for EASIX was detected as >1.03, and survival times were significantly shorter in patients with higher EASIX scores (p < 0.001). Even so, the optimal cut-off point for mEASIX was >26.5, showing higher specificity (area under curve (AUC) = 0.663; p = 0.003). The sEASIX score predicted lower mortality (AUC = 0.586; p = 0.123). In multivariate analysis, high EASIX scores, not performing autologous stem cell transplantation, and not receiving immunomodulatory therapy were identified as independent negative prognostic factors for survival.

Conclusion: EASIX, especially mEASIX, is a valuable prognostic tool for predicting survival in MM patients. EASIX can be easily integrated into clinical practice due to its simple computability and reliance on commonly used laboratory parameters. However, larger prospective studies are needed to determine how these scores can be integrated with traditional prognostic systems such as the International Staging System (ISS) and Revised-ISS.

Background: Individuals diagnosed with relapsed or refractory large B-cell lymphoma (R/R LBCL) typically exhibit a dismal prognosis when treated with conventional therapeutic modalities. CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has brought about a paradigm shift in the treatment paradigm of this disease. Nevertheless, a comprehensive assessment of the efficacy and safety profiles of diverse CAR-T products (e.g., axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel)) is imperative.

Objective: This systematic review aims to systematically summarize and evaluate the efficacy and safety of CAR T-cell therapies for R/R LBCL through systematic review and meta-analytic approaches.

Design: This is a systematic review and meta-analysis.

Data sources and methods: Relevant studies were identified by systematically searching PubMed and Web of Science until November 29, 2023. Cohort studies and clinical trials were incorporated, with the inclusion of single-arm studies. CAR T-cell therapies are involved in tisa-cel, axi-cel, and liso-cel. Proportions and their 95% confidence intervals were calculated using standard meta-analytic approaches.

Results: Thirty-seven studies were included in meta-analyses, liso-cel demonstrated equivalent overall survival rates (70.3%) to axi-cel (65.6%) at 12 months post-treatment, whereas tisa-cel was 48.0%. Objective response rate for liso-cel was comparable to axi-cel (79.0% vs 76.8%, p _{meta-regression} = 0.74), both of which were notably higher than those observed for tisa-cel (58.3%, both p _{meta-regression} < 0.05). Regarding safety assessments, liso-cel exhibited the lowest cytokine release syndrome rate at 43.0%, followed by tisa-cel at 70.9%, and axi-cel at 87.9%. However, tisa-cel had the lowest incidence of neurologic events (14.9%), in contrast to liso-cel (21.1%) and axi-cel (52.3%).

Conclusion: Based on the available evidence, liso-cel has shown promising efficacy and a manageable safety profile in patients with R/R LBCL, when compared to axi-cel and tisa-cel. However, real-world data on liso-cel are limited.

Aplastic anemia is a bone marrow failure disorder marked by cytopenias that impair oxygen delivery, immune defense, and hemostasis. Standard therapy traditionally combines immunosuppression with or without hematopoietic stem cell transplantation, and more recently incorporates thrombopoietin receptor agonists to stimulate residual hematopoiesis. Eltrombopag improved outcomes when added to immunosuppressive therapy, but its association with hepatotoxicity limits its suitability for patients with underlying liver disease or elevated baseline liver enzymes. Avatrombopag is a newer oral thrombopoietin receptor agonist that does not require dietary restrictions and does not undergo significant hepatic metabolism, which offers a potential therapeutic advantage in settings where liver function is compromised. This review evaluated ten clinical studies published from 2023 to October 2025 that investigated avatrombopag in acquired aplastic anemia across varied patient populations, including treatment-naive, relapsed or refractory cases, older adults, and patients with secondary aplastic anemia related to chemoradiation. Across these studies, overall response rates ranged from 55% to 85%, and complete response rates reached up to one-third of treated patients. Response onset typically occurred within 1-2 months, which aligns with clinical decision timelines for assessing therapeutic benefit. Avatrombopag supported reductions in transfusion requirements and sustained hematologic improvement in both severe and non-severe disease. Patients previously intolerant or non-responsive to eltrombopag also demonstrated clinical improvement, which suggests pharmacologic differences translate into meaningful therapeutic effects. Importantly, avatrombopag demonstrated a favorable safety profile in all reviewed settings. Reports did not identify clinically relevant hepatotoxicity, clonal evolution, or treatment-limiting adverse effects. Its tolerability in patients with liver dysfunction distinguishes it from earlier agents in this drug class. Ongoing trials will clarify optimal dosing strategies and define its future role within first-line therapy and salvage treatment pathways for aplastic anemia.