稲本 賢弘

We recently demonstrated early administration of calcineurin inhibitors (CNIs) after murine allogeneic hematopoietic cell transplantation (allo-HCT) inhibits terminal exhaustion of donor T cells and hampers tolerance induction. However, the role of CNIs in regulating T-cell exhaustion in clinical allo-HCT remains to be clarified. It also remains to be elucidated why posttransplant cyclophosphamide (PTCy) could reduce chronic graft-versus-host disease (cGVHD), despite the administration of CNIs. In this study, we explored the impact of CNIs on donor T-cell exhaustion after PTCy-based haploidentical HCT. In mice, early administration of cyclosporine before PTCy preserved a population of Ly6C⁺ donor T cells with less exhausted characteristics, as has been shown in non-PTCy allo-HCT. In single-cell analysis of clinical samples from patients undergoing HLA-haploidentical peripheral blood stem cell transplantation with PTCy (PTCy-haplo-PBSCT), early administration of tacrolimus prior to PTCy promoted the expansion of effector-like CD8+ intermediate exhausted T cells (Tex-int) and CD4⁺ cytotoxic T cells (CTLs), with the former enriched for both effector- and exhaustion-associated and the latter for effector- and CD4⁺ CTL-specific gene signatures. These subsets retained high responsiveness to TCR stimulation and PD-1 blockade, and their expansion on day 28 predicted subsequent cGVHD. In contrast, delaying tacrolimus administration on day 5 after PTCy-haplo-PBSCT significantly reduced the expansion of these effector-like T cells. These findings indicate early CNI exposure favors the persistence of incompletely exhausted and clonally expanded donor T cells with pathogenic potential. Tex-int and CD4⁺ CTLs may serve as prognostic biomarkers of cGVHD risk and as promising targets for preemptive therapy of cGVHD.

Letermovir is used for cytomegalovirus prophylaxis after allogeneic hematopoietic cell transplantation (HCT) and reportedly increases tacrolimus exposure. Isavuconazole, a mold-active triazole antifungal, also inhibits cytochrome P450 3A and may affect tacrolimus pharmacokinetics. This retrospective study evaluated tacrolimus concentration-to-dose (C/D) ratios pre- and post-conversion from continuous intravenous infusion to oral administration in allogeneic HCT recipients receiving isavuconazole. Forty-five patients were stratified according to letermovir coadministration into the isavuconazole-alone group (ISCZ-alone; n = 9) and the isavuconazole with letermovir group (ISCZ + LMV; n = 36). The median C/Dciv ratios were 17.00 and 16.40 (ng/ml)/(mg/day), respectively (P = 0.81); the median C/Dpo ratios were 3.25 and 2.60 (ng/ml)/(mg/day), respectively (P = 0.77); and the median (C/Dpo)/(C/Dciv) ratios were 0.154 and 0.173, respectively (P = 0.72). Sensitivity analyses yielded consistent findings. Letermovir coadministration was not associated with significant differences in tacrolimus C/D ratios pre- or post-conversion to oral administration in allogeneic HCT recipients receiving isavuconazole.

The National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) Consensus Project established response criteria that enabled clinical trials and facilitated regulatory approval of multiple therapies. Nonetheless, organ-specific assessments have limitations, particularly for severe sclerotic skin involvement. Cutaneous manifestations occur in approximately half of patients with chronic GVHD but are difficult to evaluate due to heterogeneous clinical features. To address these challenges, the NIH Consensus Skin Task Force convened from 2024 to 2025 to refine skin response measures for use in clinical trials. This report (1) summarizes current diagnosis and scoring of skin chronic GVHD, (2) reviews existing response assessments, (3) identifies gaps in their performance, (4) proposes refinements to the 2014 NIH skin response criteria, and (5) outlines future directions incorporating patient-reported outcomes, novel technologies, and biomarker research. Current NIH scoring relies on a 4-point body surface area (BSA) scale and a 3-point sclerosis features scale. While standardized, these measures have limited sensitivity to clinically meaningful change. Proposed refinements include: (1) separate BSA assessments for epidermal involvement and sclerotic features; (2) modification of sclerosis descriptors, with removal of impaired mobility and specification of GVHD-related ulceration, and addition of sclerosis-associated edema with or without erythema; and (3) replacement of the exploratory severity scale with two new clinician instruments. The Sclerosis Quality and Physical Signs scale (0 to 10) captures qualitative physical changes, while the Sclerosis Daily Function Impact scale (0 to 4) evaluates functional compromise. These proposed refinements aim to improve the accuracy, reproducibility, and clinical relevance of skin chronic GVHD assessments, strengthening trial endpoints and patient care.

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.

This retrospective study evaluated 11 patients who received valemetostat, a novel selective dual inhibitor of the enhancer of zeste homologs 1 and 2, as a salvage therapy for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic cell transplantation (allo-HCT). The median age of the patients at allo-HCT was 64 (range: 43-70) years. The median interval between allo-HCT and valemetostat therapy was 210 (range: 35-682) days. The median lactate dehydrogenase and soluble interleukin-2 receptor levels were 238 (range: 184-298) U/L and 818 (range: 435-2193) U/mL, respectively. Eight patients initially received valemetostat at a reduced dose because of thrombocytopenia. The median treatment duration was 156 (range: 39-645) days, with five patients continuing treatment. The best response rate was 73%, including clinical responses (complete or partial response) in six patients and molecular responses defined by clearance of blood measurable residual disease in two patients. The reasons for treatment discontinuation were adverse events (cytomegalovirus infection, pericardial effusion, and dysgeusia) (n = 3) and progressive disease (n = 3). None of the patients developed graft-versus-host disease. The median overall survival after valemetostat therapy was 294 (range: 56-645) days. At the last follow-up, four patients were alive without disease, four were alive with disease, and three died due to progressive disease. Hence, valemetostat is a promising salvage therapy for relapsed adult T-cell leukemia/lymphoma after allo-HCT.