International Journal of Hematology最新文献

The development of effective and safe therapies for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) in Japan remains a key focus of research. We conducted a phase 2, open-label, multicenter, non-comparative study to evaluate the safety and efficacy of fixed-duration venetoclax plus ibrutinib in 10 patients with previously untreated CLL/SLL (7 CLL/3 SLL). The primary endpoint was the rate of complete remission (CR)/CR with incomplete marrow recovery (CRi) assessed by the independent review committee (IRC). The median age was 72.5 (range 61-77) years. The IRC-assessed CR/CRi rate was 60.0% (95% confidence interval: 26.2-87.8%), exceeding the pre-specified efficacy threshold of 10% and meeting the primary endpoint. The median venetoclax treatment duration was 11.0 (range 2.1-17.7) months. At a median follow-up of 20.6 months, the secondary endpoints of median progression-free and overall survival were not estimated. The overall undetectable measurable residual disease rate was 60.0%. All patients experienced treatment-emergent adverse events (TEAEs), including 7 (70.0%) with grade 3/4 and 2 (20.0%) with serious TEAEs, respectively, and 1 discontinued venetoclax because of a TEAE (increased blood creatine phosphokinase). These findings suggest that venetoclax plus ibrutinib has a favorable benefit-risk profile with high efficacy and manageable safety.

Background: Heparinoid (Hirudoid®), a topical heparin-like agent, is labeled as contraindicated in bleeding disorders, yet its propensity for clinically relevant systemic anticoagulation remains uncertain.

Aim: To assess heparinoid's anticoagulant potential in blood from healthy individuals and people with hemophilia (PwH).

Methods: In normal plasma exposed to heparinoid (≤ 6.5 μg/mL) or heparin, and in plasma from PwH supplemented with FVIII or FIX (0-50 IU/dL), we quantified activated partial thromboplastin time (APTT) and adjusted maximum coagulation velocity (Ad|min1|) by clot waveform analysis. In heparinoid-treated whole blood from healthy volunteers (≤ 9 μg/mL), clotting time (CT) and clot formation time (CFT) were assessed by rotational thromboelastometry.

Results: In normal plasma, heparinoid dose-dependently prolonged APTT and reduced Ad|min1|; at the estimated C_max (2.5 μg/mL), APTT increased ~ 1.2-fold and Ad|min1| approximated the effect of ~ 0.2 IU/mL heparin. In FVIII- or FIX-supplemented plasma from PwH, Ad|min1| showed a mild, factor-level-dependent decrease (~ 85% of control). In whole blood, CT + CFT changed minimally at therapeutic concentrations. Heparin controls provided an internal benchmark for assay sensitivity.

Conclusion: At therapeutic levels, heparinoid exerts only mild anticoagulant effects in both normal and hemophilic matrices, supporting the view that topical use is unlikely to pose systemic bleeding risk in PwH.

T-cell lymphomas are clinically and biologically heterogeneous malignancies that comprise ~ 10% of non-Hodgkin lymphomas. Outcomes with first-line chemotherapy remain poor. Over the past decade, integrative genomic and epigenomic studies have defined recurrent abnormalities converging on proximal T-cell antigen receptor/costimulatory signaling to the NF-κB/NFAT, JAK/STAT, PI3K/AKT/mTOR, and NOTCH pathways, alongside pervasive alterations in chromatin modifiers and the DNA methylation machinery. In this review, we frame the biology of peripheral T-cell lymphoma as two interdependent layers, including genetic events that establish constitutive signaling programs and epigenomic remodeling that stabilizes these outputs. We overview genomic alterations across major peripheral T-cell lymphoma entities and analyze epigenomic dysregulation, focusing on DNA methylation, enhancer regulation, and polycomb-mediated gene control. We highlight adult T-cell leukemia/lymphoma as a paradigmatic dual-layer disease, summarize therapeutic approaches based on epigenetic traits, and discuss biomarker-guided strategies and challenges in translating integrated maps into durable disease control.

Peripheral T-cell lymphomas (PTCLs) are biologically diverse and clinically aggressive, and are difficult to control long-term with conventional immunochemotherapy. Hematopoietic cell transplantation (HCT) is a key treatment option. Autologous HCT (auto-HCT) as first-line consolidation has shown durable progression-free survival in phase 2 studies and in the auto-HCT arm of the randomized AATT trial (intent-to-treat PFS 30-49%), although its routine use after complete metabolic response remains controversial. A phase 3 trial comparing auto-HCT with observation is ongoing. For relapsed/refractory PTCL, expert consensus supports allogeneic HCT (allo-HCT) as the treatment of choice for eligible patients, with early referral and limited salvage therapy. While complete remission is ideal, partial remission is acceptable. Upfront allo-HCT is not recommended for unselected PTCL in light of the results of the AATT trial, but adult T-cell leukemia-lymphoma (ATL) is an exception. Multiple studies have shown graft-versus-ATL effects, supporting allo-HCT in aggressive ATL. Donor sources now include unrelated and haploidentical donors, with outcomes comparable to matched siblings. Despite advances, relapse after HCT remains a major challenge. Novel maintenance strategies and optimized transplant approaches are needed to further improve outcomes in PTCL and ATL.

Immunotherapy has revolutionized cancer treatments, yet checkpoint inhibitors and CAR-T cells have shown limited efficacy in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). This limited efficacy is primarily due to the absence of lineage-specific antigens and the presence of suppressive microenvironments. Innate immunity offers a promising alternative, as it acts independently of neoantigens. The key players such as macrophages, dendritic cells, and natural killer (NK) cells not only eliminate malignant cells but also remodel the microenvironment to enhance antileukemic activity. This review highlights recent advances in understanding innate immune mechanisms in AML and MDS and explores therapeutic strategies designed to leverage these pathways, aiming to broaden the scope of immunotherapy.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT), and glucocorticoids remain the standard first-line treatment. However, glucocorticoid responses vary widely and are influenced by genetic polymorphisms in glucocorticoid signaling pathways. Their impact after cord blood transplantation (CBT) is unclear. We retrospectively analyzed adult patients who underwent single-unit CBT at our institution between 2005 and 2023 with available donor or recipient DNA. Genotyping of NR3C1 (rs33388) and GLCCI1 (rs37972, rs37973) was performed using TaqMan® assays. In univariate analyses, donor GLCCI1 rs37973 AG/AA genotypes were associated with a higher incidence of grades II to IV acute GVHD but a lower incidence of chronic GVHD compared with GG donors. Multivariate analysis confirmed that GLCCI1 rs37973 AG/AA donors had a significantly reduced risk of chronic GVHD (hazard ratio 0.57, 95% confidence interval 0.35-0.93, P = 0.025). Among 30 patients who developed grades III to IV acute GVHD treated with glucocorticoids, recipient NR3C1 rs33388 TT genotype was associated with significantly lower overall survival compared with AT/AA (24.4% vs. 63.5% at 5 years, P = 0.044). These findings suggest that donor GLCCI1 rs37973 and recipient NR3C1 rs33388 polymorphisms may influence GVHD risk and survival after CBT.

Evidence regarding the efficacy and safety of DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) therapy for relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) is critically lacking. This retrospective study analyzed 78 patients with r/r DLBCL who received DeVIC therapy at a single institution. The overall response rate was 37.2%, comprising 21.8% complete and 15.4% partial responses. A total of 15 (19.2%) patients proceeded to transplantation or cellular therapy. The 3-year overall survival and progression-free survival were 28.2 and 18.0%, respectively. Multivariable analyses identified refractoriness to prior therapy and elevated serum lactate dehydrogenase (LDH) levels as significant predictors of poor response and survival. Decision tree models confirmed these findings, revealing that relapsed cases with low LDH had the most favorable outcomes. Hematological toxicities were frequent, with febrile neutropenia in 52.6% and infection-related mortality in 3.8% of patients. Those with central nervous system involvement had a dismal prognosis, underscoring the need for novel therapeutic approaches. These findings highlight the potential role of DeVIC therapy in selected patients with r/r DLBCL and provide insights into optimizing bridging strategies and subsequent immunocellular therapies.

Recent therapeutic advances, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor-T-cell therapies, have transformed the treatment landscape of multiple myeloma (MM). Beyond direct cytotoxicity, these agents profoundly reshape the bone marrow immune microenvironment, which plays a decisive role in disease initiation, progression, and therapeutic response. MM cells thrive within this specialized niche by recruiting and reprogramming regulatory T cells, myeloid-derived suppressor cells, dendritic cells, and macrophages to suppress antitumor immunity while simultaneously driving functional exhaustion of effector T cells and impairing natural killer cell cytotoxicity. Accumulating evidence demonstrates that these immune alterations emerge even at precursor stages, such as monoclonal gammopathy of undetermined significance and smoldering MM, progressively intensifying disease evolution. In this review, we synthesize recent insights into immune cell dynamics during MM progression, highlighting both regulatory and effector compartments. We further discuss how contemporary therapies modulate these immune interactions, underscoring their dual roles in fostering immune activation while, at times, sustaining immunosuppressive pathways. A comprehensive understanding of the immune landscape in MM will be critical to optimizing existing treatments, overcoming therapeutic resistance, and guiding the development of next-generation immunotherapies.

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard first-line therapy; however, many patients develop steroid-refractory or steroid-dependent disease, underscoring the need for more effective and better-tolerated treatments. Ruxolitinib has emerged as the most evidence-supported option for steroid-refractory cGVHD, with the phase 3 REACH3 trial demonstrating higher response rates, durable disease control, and clinically meaningful improvements in symptom burden compared with best available therapy. Belumosudil and axatilimab have also shown encouraging efficacy and safety in heavily pretreated populations. The addition of novel agents to standard corticosteroid-based therapy has been explored in clinical trials. Interest in combination strategies, such as ruxolitinib with extracorporeal photopheresis or belumosudil, is increasing, though prospective studies are required to define their role. Key challenges include optimizing long-term safety, mitigating infectious complications, and preserving the graft-versus-leukemia effect. This review summarizes current therapeutic strategies and discusses evolving treatment algorithms, emphasizing practical considerations in therapy selection. Approaches targeting specific pathogenic mechanisms, combining agents with distinct mechanisms of action, and incorporating biomarker-driven strategies are expected to further improve outcomes and quality of life for patients with cGVHD.

Although chimeric antigen receptor (CAR)-T cell therapies are highly effective for B-cell lymphoma, they frequently cause cytokine release syndrome (CRS). High-grade CRS is serious and may require intensive care, yet reliable early predictive markers remain elusive. To identify risk factors for high-grade CRS, we retrospectively analyzed B-cell lymphoma patients who received CD19 CAR-T cell therapy. Of 106 patients analyzed, CRS occurred in 93 (88%), Grade ≥ 2 CRS in 28 (26%), and Grade ≥ 3 CRS in 6 (6%). Reticulocyte counts at infusion were significantly lower in patients who developed Grade ≥ 2 CRS (1.85 vs. 2.80 × 10⁴/µL, p = 0.02). Multivariate analysis identified low reticulocyte count (< 15,000/µL; HR 2.21; 95% CI 1.01-4.86; p = 0.048), high metabolic tumor volume (> 100 mL), and use of axicabtagene ciloleucel as independent risk factors for Grade ≥ 2 CRS. Stratification by the reticulocyte cutoff showed higher 30-day cumulative incidence of CRS in patients with low counts, for both Grade ≥ 2 (42.9% vs. 19.7%, p = 0.012) and Grade ≥ 3 CRS (17.9% vs. 1.3%, p < 0.001). KyoTox-CRS, a risk-scoring system integrating these factors, effectively stratified these CRS risks. Early prediction of high-grade CRS based on the reticulocyte count at infusion may help to guide optimal risk-based management of CAR-T cell therapy.