International Journal of Hematology最新文献

T-cell lymphomas represent a heterogeneous group of lymphoid malignancies characterized by marked biological diversity and generally poor clinical outcomes. Recent updates to the fifth edition of the World Health Organization Classification and the 2022 International Consensus Classification have refined the disease entities based on transcription factor profiles, cytokine signatures, and molecular features. Comprehensive genomic and epigenomic analyses have revealed recurrent alterations affecting T-cell receptor signaling, epigenetic regulation, cell-cycle control, and immune pathways, thereby facilitating the development of molecularly targeted therapies. Viral oncogenesis plays a central role in selected subtypes, particularly adult T-cell leukemia-lymphoma and Epstein-Barr virus-associated natural killer/T-cell lymphomas. The accelerated development of molecularly targeted therapies has led to the introduction of several novel agents, while hematopoietic stem cell transplantation also continues to provide an important potentially curative strategy. This issue of Progress in Hematology provides a comprehensive overview of recent advances in molecular pathogenesis, viral biology, therapeutic developments, and transplantation strategies in T-cell lymphomas.

Although HLA-matched related donor transplantation (MRDT) is considered the preferred graft source when available, cord blood transplantation (CBT) is an alternative source, with several studies suggesting a potent graft-versus-leukemia effect. We compared outcomes between CBT and MRDT in acute myeloid leukemia (AML) not in remission and examined how pre-engraftment immune reaction (PIR), graft-versus-host disease (GVHD), and HLA mismatch affect CBT outcomes. We retrospectively analyzed 334 patients with AML not in remission who underwent first allo-HSCT using either single-unit CBT (n = 309) or MRDT (n = 25). At 5 years, CBT recipients showed significantly better leukemia-free survival (LFS) (42.0% vs. 17.6%) and lower relapse rates (24.6% vs. 54.0%), with no difference in NRM. Among CBT recipients, patients who developed mild PIR had a lower relapse rate compared with those without PIR (hazard ratio [HR], 0.48). In contrast, severe PIR was associated with higher NRM (HR, 3.13) and worse overall survival (HR, 2.12). Acute GVHD, chronic GVHD, and HLA disparity were not significantly associated with relapse. CBT was associated with superior LFS compared with MRDT in patients with AML not in remission, and PIR occurrence and severity were associated with CBT outcomes.

Venetoclax (VEN), a BCL-2 inhibitor, was approved in Japan in March 2021, for acute myeloid leukemia (AML). We retrospectively analyzed the impact of VEN approval on treatment patterns and outcomes in older AML patients aged 65-74 years unfit for intensive chemotherapy in Japan. Using the Hokkaido Leukemia Net database, we categorized 101 patients into pre-VEN (n = 46) and post-VEN (n = 55) cohorts, excluding those who had acute promyelocytic leukemia or received intensive chemotherapy. Following VEN approval, VEN + azacitidine (AZA) became the most frequently used initial regimen (56%). Despite higher rates of TP53 mutations and complex karyotypes (35.5%), VEN + AZA achieved comparable response rates (CR + CRi: 64.5%) and overall survival (OS, median 11.7 months) to r7 + 3 (CR + CRi: 64.5%, median OS: 13.1 months), and superior outcomes to cytarabine + aclarubicin + G-CSF (CAG, CR + CRi 37.5%, median OS 6.8 months) or AZA monotherapy (CR + CRi 12.5%, median OS 4.5 months). Early mortality at 60 days from diagnosis was lower with VEN + AZA (3.2%) than with reduced-dose cytarabine plus anthracycline (r7 + 3) (12.9%), CAG (26.7%), or AZA monotherapy (18.8%). Our findings demonstrate a substantial shift in real-world treatment practices following VEN approval and suggest that VEN + AZA is an effective option for older AML patients with adverse genetic features.

This retrospective cohort study using the medical data vision (MDV) database included adult patients who had confirmed diagnosis of cGVHD between 2003 and 2023, were prescribed a steroid prior to diagnosis of cGVHD, and received mycophenolate mofetil (MMF), ibrutinib, or ruxolitinib as second- or later-line therapy. Duration of treatment (DoT) and steroid dose reduction during second-line therapy were assessed. Of the 1489 patients whose data were retrieved, 854 were included (median [range] age: 54 [18.0-83.0] years; males: 518 [60.7%]; mean [SD] Charlson Comorbidity Index score: 7.5 [3.5]). Data on second or later lines of treatment were available for 226 patients. The most common second-line therapy used after first-line steroid treatment was MMF (110 [48.67%]), followed by ibrutinib (88 [38.94%]) and ruxolitinib (28 [12.39%]). Median DoT (days) was 95 for MMF, 86 for ibrutinib, and 30 for ruxolitinib. Steroid doses were mostly kept below 0.5 mg/kg/day under all the 3 second-line treatments. These real-world data provide valuable insights into the management of cGVHD with the therapies currently used in Japan.

Prediction and early diagnosis are critical for the effective treatment of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) after hematopoietic stem cell transplantation (HSCT). This study aimed to investigate the utility of clinical hepatic indices easily calculated in routine practice, namely the Endothelial Activation and Stress Index (EASIX), aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4), reversed Albumin-Bilirubin grade (rALBI), Model for End-Stage Liver Disease (MELD), and MELD score and the serum sodium concentration (MELDNa). We retrospectively analyzed longitudinal clinical data from 175 allogeneic HSCTs at our institution. The 22 patients who eventually developed clinical SOS/VOD were used as the reference standard. At baseline, EASIX, APRI, FIB-4, rALBI, MELD, and MELDNa were analyzed using the receiver operating characteristic method, with resulting area under the curve (95% confidence interval) of 0.739 (0.607-0.871), 0.770 (0.641-0.898), 0.760 (0.645-0.875), 0.672 (0.530-0.815), 0.577 (0.440-0.713), and 0.642 (0.449-0.784), respectively. After HSCT, these indices were also associated with SOS/VOD, even 7 days before diagnosis (all p-values < 0.001). In conclusion, clinical hepatic indices are useful for prediction and early diagnosis of SOS/VOD in allogeneic HSCT recipients. Further studies are required to determine their optimal clinical application.

With the advent of complement inhibition therapy, the severe thrombotic complications of paroxysmal nocturnal hemoglobinuria (PNH)-once described as the most vicious acquired thrombophilic state-no longer pose the same imminent clinical threat. Nevertheless, thrombotic events still occur, albeit at much lower frequency, raising both clinical and mechanistic questions. Among the most pressing are: Under what circumstances does anti-complement therapy fail to prevent thrombosis, and which patient- or therapy-specific factors contribute to this risk? When and where should anticoagulation, anti-platelet therapy, or even prophylaxis be considered? At a mechanistic level, what are the drivers of complement-mediated thrombosis in PNH, and how do they differ from those in other thrombotic conditions involving complement activation? This review addresses these questions by summarizing current evidence on complement-induced thrombosis, integrating clinical and experimental findings. It highlights unresolved issues, including when complement blockade is insufficient and explores the distinction between complement-driven thrombotic states, such as PNH, and intrinsic complement-related diseases without thrombotic complications, such as C3 glomerulopathy. Finally, it proposes a pragmatic framework for anticoagulation and prophylaxis and provides an outlook on critical directions for basic and clinical research, with the goal of further elucidating the complex interplay between complement activation and thrombosis.

This study evaluated the efficacy and safety of high-dose romiplostim (ROMI) combined with horse anti-thymocyte globulin (hATG) and cyclosporine A (CyA) as first-line immunosuppressive therapy for aplastic anemia (AA). We retrospectively analyzed eight patients who received hATG + CyA + ROMI at a single institution between October 2023 and January 2025. ROMI was initiated at 10 μg/kg/week and escalated to 20 μg/kg. Hematologic responses were evaluated at weeks 14 and 27. At week 27, the overall response rate was 100% and the complete response rate was 85.7%. Only one episode of grade ≥ 3 anaphylaxis attributed to hATG was observed. High-dose ROMI combined with hATG and CyA demonstrated favorable efficacy and tolerability as a first-line treatment for transfusion-dependent AA. However, larger prospective studies are required to confirm these findings.

Currently, no established treatments for disseminated intravascular coagulation (DIC) specifically target fibrinolysis. We previously demonstrated that prophylactic administration of tissue plasminogen activator (tPA) to a lipopolysaccharide (LPS)-induced rat DIC model improved DIC pathophysiology. However, the optimal duration of tPA administration and its effectiveness when administered therapeutically remain unclear. In the present study, we investigated whether tPA remains effective when administered at the same dosage over different durations, and whether therapeutic administration is also effective. We found that both prophylactic and therapeutic administration of tPA increased D-dimer levels, reduced serum creatinine and the renal glomerular fibrin deposition rate, suppressed the formation of thrombin-antithrombin complex and interleukin-6, and attenuated decreases in platelet count. Furthermore, with both prophylactic and therapeutic administration of tPA, most markers of DIC pathophysiology demonstrated greater improvements with longer administration of tPA, from 15 min to 8 h. No bleeding tendency was observed based on urinary hemoglobin levels. These results suggest that a lower tPA dose rate and longer duration of administration may enhance efficacy and safety in the LPS-induced rat DIC model. A reduced dosage and extended duration of tPA administration could represent a new treatment option for clinical DIC and warrants further investigation.

The development of chimeric antigen receptor (CAR)-T cell products is accelerating worldwide. CAR-T cell therapy represents one of the most significant therapeutic advances, as it elicits remarkably effective and durable clinical responses. Approved CAR-T cell products target one of two antigens on B cells: CD19 or B cell maturation antigen (BCMA). In Japan, all CAR-T cell products are approved for the treatment of relapsed or refractory hematologic malignancies, including acute lymphoblastic leukemia, B cell lymphomas, and multiple myeloma. Although CAR-T cell therapy is indisputably one of the most recommended therapies, it has faced scrutiny for its high cost and several unresolved issues. This article outlines issues with and important considerations for CAR-T cell products reviewed by the Pharmaceuticals and Medical Devices Agency. We describe the approval process for CAR-T cell products; differences in indications for their use, including optimal clinical use guidelines; and manufacture of CAR-T cells, especially out-of-specification products. We also describe key considerations in the regulatory review of CAR-T cell products, with a focus on clinical evaluation.

Ropeginterferon alfa-2b, a monopegylated interferon α-2b, is a cytoreductive treatment for polycythemia vera (PV). In Japan, the current regimen involves titration in 50-µg increments every 2 weeks until reaching the maximum dose (500 µg), which requires considerable time. This phase 3b, open-label, single-arm, multicenter study (October 2023-July 2024) assessed the efficacy and safety of a three-step dose escalation regimen (day 1: 250 µg, week 2: 350 µg, week 4: 500 µg) of ropeginterferon alfa-2b in Japanese patients with PV (NCT06002490). Twenty-one patients were included (mean age: 57 years); most (95.2%) received ropeginterferon alfa-2b for at least 24 weeks. The complete hematologic response rate (primary endpoint; hematocrit < 45%, no phlebotomy in the previous 12 weeks, platelet count ≤ 400 × 10⁹/L, and white blood cell count ≤ 10 × 10⁹/L) was 23.8% (95% confidence interval 8.2, 47.2) at week 12 and 57.1% (34.0, 78.2) at week 24. Most patients (90.5%) reached the maximum dose of 500 µg by week 4. All patients had treatment-emergent adverse events, but none led to death, treatment discontinuation, or study withdrawal. This three-step dose escalation regimen of ropeginterferon alfa-2b has the potential to provide faster therapeutic effects in patients with PV without additional safety concerns.