Therapeutic Advances in Hematology最新文献

Background: Decitabine and cedazuridine (DEC-C) is the only oral hypomethylating agent (HMA) approved for myelodysplastic syndromes (MDS) in the United States. The other HMAs approved for MDS, decitabine and azacitidine, are administered intravenously (IV) or subcutaneously (SC).

Objectives: This study examined real-world outcomes among MDS patients treated with oral DEC-C compared to IV/SC HMAs.

Design: Adult patients diagnosed with MDS who received HMAs as their first treatment on or after July 1, 2020 through February 2024 in ConcertAI's RWD360^® electronic medical records dataset linked to open claims were included in the study.

Methods: We used propensity score matching (PSM) to balance potential confounders. Kaplan-Meier survival analysis was utilized to compare real-world overall survival (rwOS), acute myeloid leukemia (AML)-free survival, and time to next treatment (rwTTNT) among patients treated with oral DEC-C and IV/SC HMAs.

Results: A total of 2101 patients with MDS were included, with 405 treated with oral DEC-C and 1696 treated with IV/SC HMA. After PSM, there were 399 patients in each treatment group; demographic and clinical factors were well balanced. Patients treated with oral DEC-C had a similar median rwOS (22.7 months vs 19.5 months; p = 0.57) and AML-free survival (16.1 months vs 14.3 months; p = 0.10) compared with patients who received IV/SC HMA; however, there were nonsignificant trends in favor of oral DEC-C. The median rwTTNT was significantly longer for the oral DEC-C patients than for the IV/SC HMA patients (9.3 months vs 7.8 months, respectively; p = 0.02).

Conclusion: This real-world study is the largest to date to examine clinical outcomes among MDS patients who initiated oral DEC-C compared to IV/SC HMAs. While study results indicate comparable rwOS and AML-free survival among patients treated with oral DEC-C or with IV/SC HMAs, patients treated with oral DEC-C had a significantly longer rwTTNT. These findings support the use of oral DEC-C as an alternative to parenteral HMA therapy.

Background: Hemophilia A (HA) management remains challenging in northeastern India due to limited access to specialized care. Emicizumab, a bispecific monoclonal antibody, offers prophylactic benefits for patients with or without factor VIII (FVIII) inhibitors.

Objectives: The study aimed to assess the long-term effectiveness, safety, and patient-reported outcomes of emicizumab prophylaxis in people with HA with or without inhibitors.

Design: This 12-month follow-up from a noninterventional, real-world observational study builds on previously published 6-month data and was conducted at the Department of General Medicine, Assam Medical College and Hospital, India.

Methods: Forty pediatric patients with moderate-to-severe HA, including those with inhibitors, receiving emicizumab prophylaxis were followed at a treatment center. The outcomes assessed at baseline, 6 months, and 12 months included annualized bleeding rate (ABR), Hemophilia Joint Health Score (HJHS), Functional Independence Score in Hemophilia (FISH), European QoL-5 dimensional-5 level (EQ-5D-5L) score and visual analog scale (VAS). Subgroup analyses explored age- and inhibitor-status based differences. Data were analyzed using appropriate statistical tests to compare outcomes across time points and subgroups.

Results: The mean ABR reduced significantly from 11.48 at baseline to 0.05 at 12 months (p < 0.001), with all patients showing improvement. Joint and target joint bleeds were eliminated. HJHS improved from mean 12.0 ± 5.23 to 4.6 ± 3.13, and FISH increased from 27.5 ± 2.11 to 30.6 ± 1.39 (both p < 0.001). EQ-5D-5L index and VAS scores also showed significant gains. Notably, age-related disparities in ABR, evident with FVIII therapy, were no longer apparent after emicizumab therapy, highlighting its uniform effectiveness from early childhood.

Conclusion: This 12-month follow-up study from northeastern India confirms the sustained efficacy and safety of emicizumab in reducing bleeds and improving outcomes in children with HA. The findings underscore its value in underserved settings, supporting broader implementation in similar healthcare environments.

Von Willebrand disease (VWD) is an inherited bleeding disorder resulting from a deficiency in von Willebrand factor (VWF), either quantitative or qualitative. Recombinant VWF (rVWF) presents a novel therapeutic option for patients with VWD. Produced in Chinese hamster ovary cells, rVWF is free of animal or human plasma proteins, thus eliminating the risk of pathogen transmission. It preserves the full range of VWF multimers, including ultra-large multimers, which are essential for hemostasis. Research indicates that rVWF demonstrates superior pharmacokinetics and pharmacodynamics compared to plasma-derived VWF, offering a longer terminal half-life, enhanced platelet adhesion and aggregation, and more robust factor VIII stabilization. These properties contribute to rVWF's increased hemostatic efficacy in managing bleeding episodes and perioperative surgical bleeding in adults and children with VWD, as well as the routine prophylaxis for adults to reduce the frequency of bleeding episodes. Furthermore, rVWF is well-tolerated with a low thrombotic risk, making it a promising treatment option and addressing a significant clinical need globally.

Background: Anti-thymocyte globulin (ATG) is used as prophylaxis for graft-versus-host disease (GvHD) and graft failure (GF) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with transfusion-dependent thalassemia (TDT). However, the optimal dose of ATG remains unknown.

Objectives: To compare the 3-year overall survival (OS) of 8 mg/kg and 10 mg/kg ATG in allo-HSCT for patients with TDT.

Methods: We compared two different doses of ATG for patients with TDT undergoing allo-HSCT from HLA-matched sibling donors (MSDs). Between 2015 and 2023, 147 patients were randomized to the 8 mg/kg ATG group and 148 patients to the 10 mg/kg ATG group. Primary endpoints were 3-year OS and thalassemia-free survival (TFS). Survival analysis for OS and TFS was performed using the Kaplan-Meier method.

Results: The 8 and 10 mg/kg ATG groups had similar 3-year OS and TFS (both 98.6% (95% confidence interval [CI]: 96.8-100) vs 95.3% (95% CI: 91.9-98.7), p = 0.066). There were no significant differences in graft-versus-host disease and GF between groups. In the subgroup with co-transplantation of cord blood (CB) and bone marrow (BM) as stem cell sources, the 8 mg/kg ATG group had higher 3-year OS and TFS than the 10 mg/kg ATG group (both 100% (95% CI: not applicable) vs 86.5% (95% CI: 75.5-98.2), p = 0.012).

Conclusion: This study provides evidence that an 8 mg/kg ATG is an effective treatment for TDT transplanted from MSDs. A notable finding was the superior survival associated with the 8 mg/kg ATG in the CB and BM co-transplantation. These results provide critical evidence for guiding ATG dosing strategies in allo-HSCT for TDT, particularly in the context of stem cell source selection.

Design: Open-label, randomized clinical trial.

Trial registration: ChiCTR-IPR-15005779 (Chinese Clinical Trial Registry; https://www.chictr.org.cn/showproj.html?proj=10208; date of registration: December 29, 2014).

Background: Patients with β-thalassemia major remain at risk for endothelial dysfunction and cardiac injury due to iron overload, oxidative stress, and chronic inflammation, even with iron-chelation therapy. Assessing vascular and cardiac serum biomarkers provides a practical tool to understand disease mechanisms and guide management.

Objectives: This study aims to identify reliable diagnostic markers for endothelial dysfunction in β-thalassemia major patients, a known risk factor for cardiovascular disease.

Design: Case-control, cross-sectional study.

Methods: Serum markers of endothelial dysfunction and cardiac damage, along with lipid profiles, were assessed. In addition, the expression of genes encoding enzymes related to cellular antioxidant defense and ferroptosis was evaluated.

Results: Sixty transfusion-dependent β-thalassemia major patients on iron-chelation therapy and 20 healthy controls participated in the study. Significant differences among control, splenectomized, and non-splenectomized β-thalassemia groups were observed for erythrocyte sedimentation rate (ESR), high mobility group box 1 (HMGB-1), interleukin-10 (IL-10), interleukin-18, fibroblast growth factor 21 (FGF21), soluble suppression of tumorigenicity 2 (sST2), and soluble vascular cell adhesion molecule-1 (sVCAM-1), but not interleukin-23, interleukin-33, or calprotectin. Receiver operating characteristic (ROC) analysis showed AUCs of 0.991, 0.990, 0.848, and 0.831 for IL-10, ESR, sST2, and sVCAM-1, respectively (p < 0.05). Hypertriglyceridemia with decreased low-density lipoprotein and total cholesterol was noted in β-thalassemia groups. The expression of SLC7A11, KEAP1, and HO-1 genes was elevated, while NRF2 and GPX4 showed no significant change. HO-1 showed a significant inverse correlation with HMGB-1 (r = -0.405, p = 0.001), KEAP1 was positively correlated with sST2 (r = 0.282, p = 0.029), and GPX4 was correlated with FGF21 (r = 0.255, p = 0.049); no other significant associations were found.

Conclusion: β-thalassemia major patients exhibit significant endothelial and cardiac injury markers, altered lipid profiles, and selective upregulation of antioxidant and ferroptosis-related genes.

Objective: This systematic literature review analyzed real-world evidence on autologous stem cell transplantation (ASCT) for newly diagnosed multiple myeloma (ndMM) in China.

Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, major English and Chinese databases were searched for observational studies published between 2015 and 2025 that included Chinese ndMM patients eligible for ASCT. Extracted data covered patient characteristics, treatment responses, and survival outcomes associated with ASCT and non-ASCT treatments. Single-arm meta-analysis with a random-effects model was used for evidence synthesis and pooled outcomes of the treatments for the same phase were compared using Cochran's Q or chi-square tests.

Results: Eighty-eight observational studies (2015-2025) were included. Data were pooled using single-arm meta-analysis and the pooled outcomes for ASCT and non-ASCT treatments were compared using Cochran's Q or chi-square tests. Compared to patients receiving non-ASCT treatments, ASCT recipients were younger (54.5 years vs 61.4 years), had more early-stage disease (International Staging System (ISS) I: 25.8% vs 15.1%), more t(11;14) (14.1% vs 6.0%), and fewer complex karyotypes (2.9% vs 31.7%). Plerixafor plus granulocyte colony-stimulating factor (G-CSF) significantly improved mobilization success over cyclophosphamide plus G-CSF (73.6% vs 49.5%), though with slightly delayed engraftment. ASCT was associated with superior treatment response (complete response: 78.5% vs 45.3%; very good partial response (⩾VGPR): 98.6% vs 75.0%) and higher 5-year overall survival rate (70.6% vs 41.3%) and 5-year progression-free survival rate (41.3% vs 18.0%). Advanced revised-ISS stage, IgD subtype, and suboptimal pre-ASCT response were associated with poorer survival prognosis in ASCT recipients.

Conclusion: Chinese ASCT recipients had more favorable baseline profiles and achieved significantly better clinical outcomes than those receiving non-ASCT treatments. Plerixafor-based mobilization enhanced stem cell collection success. However, advanced stage, IgD subtype, and inadequate pre-ASCT response could discount the effectiveness of ASCT.

Inplasy registration number: INPLASY2025110069.

In haploidentical hematopoietic stem cell transplantation, preexisting donor-specific anti-HLA antibodies (DSAs) in recipients have been associated with graft rejection, poor graft function (PGF), and unfavorable clinical outcomes, with relatively well-established consensus strategies for its management. However, reports on the emergence of de novo DSAs after transplantation and the corresponding therapeutic approaches remain limited. Here, we describe a case of a 14-year-old patient with myelodysplastic syndrome who developed de novo DSAs as early as day 15 post-transplantation, with a peak mean fluorescence intensity of 12,280, which was associated with PGF. To reduce DSA levels, plasma exchange combined with intravenous immunoglobulin and rituximab was administered, followed by a series of interventions including mesenchymal stem cell infusion. These measures facilitated graft function recovery, controlled transplant-related complications, and ultimately led to successful engraftment.

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.