森下 喬允

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.

Post-transplant tyrosine kinase inhibitors (TKIs) show promise in preventing relapse after allogeneic hematopoietic cell transplantation (allo-HCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, their real-world use and efficacy remain unclear. A comprehensive study across seven centers included Ph+ALL patients who underwent allo-HCT between 2002 and 2022. Post-transplant TKIs were administered in 28% of patients (49 of 173 transplanted in complete remission): 7% as prophylaxis during complete molecular remission (CMR), and 21% in response to measurable residual disease (MRD) positivity. Median first post-transplant TKI duration was 13.7 months for the prophylactic group and 4.0 months for the MRD-triggered group. Prophylactic TKIs appear particularly beneficial for patients not in CMR at allo-HCT, showing a trend towards higher 5-year relapse-free survival (RFS) compared to those not receiving prophylactic TKIs (100% vs. 73%; P = 0.11). Significant RFS differences were observed between the prophylactic, non-TKI, and MRD-triggered groups. However, patients with white blood cell counts <15000/µl at diagnosis and no additional chromosomal abnormalities-an MRD-triggered high efficacy cluster-demonstrated comparable 5-year RFS regardless of TKI strategy (100% vs. 85% vs. 80%; P = 0.87). This cluster highlights the potential effectiveness of MRD-triggered TKI administration in select low-risk patients, suggesting tailored TKI strategies based on risk factors.

Chronic graft-versus-host disease (GVHD) occurs in 30-70% of patients after allogeneic hematopoietic cell transplantation (HCT) and increases the risks of morbidity and mortality. Systemic corticosteroids are the standard initial treatment, but one-third of patients require subsequent treatment with other systemic agents. Treatment decisions are often based on physicians' experience. The expected treatment response rates in specific organs affected by chronic GVHD may inform such decisions. In this review, we identify 20 studies reporting treatment response rates in individual organs according to objective criteria, summarize the results, discuss the caveats in data interpretation, identify the unmet needs, and suggest future directions in the field. For cutaneous sclerosis, we observed large discrepancies in organ response rates according to the current NIH criteria and patient-reported improvement, highlighting the need for better measurement tools. High response rates for lung involvement with certain novel drugs deserve further investigation.

BACKGROUND: Although the Omicron variant has been reported to reduce COVID-19 severity in the general population, its impact on patients with hematologic malignancies remains uncertain, and epidemiological investigation is warranted. METHODS: We conducted a multicenter retrospective cohort study of 1, 023 patients with hematologic diseases diagnosed with COVID-19 at 22 centers in Japan between January 2020 and January 2023. Outcomes within 60 days after diagnosis including severe and/or prolonged disease, COVID-19-related mortality, and overall survival (OS) were compared between the pre-Omicron and Omicron periods. Multivariable analysis was performed to identify independent adverse prognostic factors. RESULTS: Severe and/or prolonged disease occurred in 27.5% of patients, COVID-19-related mortality was 6.3%, and OS was 91.4%. Compared with the pre-Omicron period, the Omicron period was associated with significantly lower rates of severe/prolonged disease (26.0% vs. 48.0%, P<0.01) and COVID-19-related mortality (5.0% vs. 15.0%, P<0.01), but no significant difference in OS (92.0% vs. 84.0%, P = 0.62). Age ≥60 years was the strongest predictor of severe/prolonged disease (sHR 3.08, P<0.01) and mortality (HR 8.94, P<0.01). Male sex (sHR 1.38; HR 1.82, both P<0.01) and prior bendamustine exposure (sHR 1.83; HR 1.87, both P<0.01) were also associated with both outcomes, whereas anti-CD38 antibody therapy was linked only to mortality (HR 3.65, P<0.01). CONCLUSION: In patients with hematologic diseases, the Omicron period was associated with reduced severity and COVID-19-related mortality but no improvement in OS. Older age and prior bendamustine exposure were strongly associated with adverse outcomes, highlighting the need for strict infection prevention and prompt, aggressive COVID-19 management in these high-risk populations.

BACKGROUND: To investigate whether the addition of eltrombopag (EPAG) to rabbit anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) for newly diagnosed severe aplastic anemia (SAA) improves outcomes and affects the cumulative incidence of clonal evolution (CE), we conducted a multicenter retrospective analysis. METHODS: Data were collected from 101 patients, aged 15 - 65 years, undergoing initial IST. RESULTS: No significant imbalance in age, sex, or severity was observed between the EPAG (n = 20) and non-EPAG (n = 81) groups. The median duration of EPAG administration in EPAG group was 16.1 months (range: 0.6 - 41.1 months). Six months after the initiation of IST, the complete response (CR) rate significantly improved in the EPAG group (P < 0.01). The cumulative incidence of allogeneic stem cell transplantation (allo-SCT) at 2 years and the 2-year overall survival (OS) were not significantly different between the two groups (allo-SCT, P = 0.31; OS, P = 0.64). Grade 3-4 adverse events in the EPAG group and the cumulative incidence of CE (P = 0.96) showed no increase. CONCLUSION: In summary, IST showed significantly better initial efficacy in the EPAG group. Although the addition of EPAG did not reduce the need for allo-SCT, no increase was observed in the incidence of CE with long-term EPAG use.