The impact of resolved hepatitis B virus (HBV) infection, defined as pretreatment hepatitis B surface antigen (HBsAg) negativity with antibody to hepatitis B core antigen (anti-HBc) positivity, on the clinical characteristics and outcomes of diffuse large B-cell lymphoma (DLBCL) remains unclear. JCOG0601 was a randomized phase II/III trial showing no improvement in progression-free survival (PFS) with dose-dense rituximab plus CHOP in previously untreated DLBCL. This supplementary analysis of JCOG0601 evaluated whether baseline anti-HBc positivity affects PFS and overall survival (OS) in patients with HBsAg-negative DLBCL treated with rituximab-containing CHOP-based therapy. Among 406 eligible patients randomly assigned in JCOG0601, 405 with available baseline HBV serologic data were included. Baseline characteristics and outcomes were compared according to anti-HBc status. Of the 405 patients, 87 were anti-HBc-positive and 318 were anti-HBc-negative. Anti-HBc-positive patients were older than anti-HBc-negative patients (median age, 63 vs. 61 years; p = 0.008). No significant differences in PFS or OS were observed between the two groups (3-year PFS, 78% vs. 81%; 3-year OS, 90% vs. 90%). HBV reactivation occurred in five anti-HBc-positive patients. Baseline anti-HBc positivity was more common in older patients but was not associated with inferior outcomes in HBsAg-negative DLBCL treated with rituximab-containing CHOP-based therapy.Clinical trial registration: JCOG0601 was registered in the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019).

Although the Endothelial Activation and Stress Index (EASIX) correlates with patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT), its prognostic value at neutrophil engraftment remains unclear. Elevated C-reactive protein (CRP) levels and hypophosphatemia at neutrophil engraftment correlate with worse outcomes after allo-HSCT. P-m-EASIX, which incorporates CRP, phosphorus, lactate dehydrogenase, and platelet count, may therefore correlate with outcomes after allo-HSCT. We retrospectively investigated the association between P-m-EASIX at neutrophil engraftment and outcomes in 114 patients who underwent their first allo-HSCT at our institution. P-m-EASIX at neutrophil engraftment was significantly higher in non-survivors than in survivors after allo-HSCT. In multivariate analyses, a P-m-EASIX ≥ 0.24 at neutrophil engraftment was an independent predictor of poor overall survival (hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.56-4.99; P < 0.01) and an independent risk factor for non-relapse mortality (HR, 3.66; 95% CI, 1.33-10.06; P = 0.01). This study shows that the P-m-EASIX at neutrophil engraftment correlates with outcomes after allo-HSCT.

The prognosis of chronic myeloid leukemia (CML) has greatly improved with the introduction of tyrosine kinase inhibitors (TKIs), but the high incidence of cardiovascular events, including arterial occlusive events (AOEs), has raised significant concerns. To better understand such adverse events, we analyzed patient comorbidities and TKI prescribing patterns to report safety information including AOE incidence rates for each TKI, time to first recorded AOE, and risk factors for AOEs by treatment line. We used logistic regression analysis with real-world data from a large cohort of 2113 CML patients treated with TKIs to identify risk factors for AOEs by treatment line. The proportions of patients with AOEs increased with each successive treatment line (8.5% for first-line, 12.5% for second-line, and 14.7% for third-line). In the multivariate model, age, sex, dyslipidemia, and hypertension were associated with AOEs in first-line treatment; age and hypertension in second-line treatment; and diabetes in third-line treatment. These results suggest that early therapeutic intervention may be beneficial to prevent AOEs in CML patients with these risk factors.

Relapse remains the leading cause of treatment failure after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. Post-transplant treatment may provide a third anti-leukemic effect after conditioning-related cytotoxicity has waned and before graft-versus-leukemia immunity is fully established. Prophylactic maintenance is initiated in high-risk patients despite undetectable measurable residual disease (MRD), whereas pre-emptive treatment is triggered by the detection of MRD or declining donor chimerism. Hypomethylating agents (HMAs) are biologically attractive and feasible with post-transplant-adapted dosing, but prophylactic azacitidine did not improve relapse-free or overall survival in a randomized trial. Newer decitabine-based, oral HMA, and venetoclax-containing strategies require confirmation. FMS-like tyrosine kinase 3 (FLT3) inhibitors have the strongest prospective evidence in a molecularly selected population. The QuANTUM-First trial supports quizartinib throughout induction, consolidation, and continuation, including after transplantation, whereas the MORPHO trial directly evaluated post-transplant gilteritinib and identified its clearest benefit in patients with detectable peri-transplant FLT3-internal tandem duplication (FLT3-ITD) MRD. This review traces the evolution of relapse prevention strategies and proposes a practical framework integrating baseline risk, serial MRD assessment, targetable biology, immune intervention, and post-transplant feasibility.

Relapse after a first allogeneic hematopoietic stem cell transplantation (HSCT1) remains a major therapeutic challenge in acute leukemia, and second transplantation (HSCT2) is frequently considered for selected patients. Although pre-transplant nutritional status has been associated with outcomes after HSCT2, the prognostic significance of changes in nutritional status between relapse and HSCT2 remains unclear. This multicenter retrospective study analyzed 67 patients with acute myeloid leukemia or acute lymphoblastic leukemia who underwent HSCT2 after relapse following HSCT1. Nutritional status was evaluated using serum albumin, Geriatric Nutritional Risk Index (GNRI), and body mass index (BMI) at relapse and before HSCT2. In multivariate analysis, declines in serum albumin and GNRI during this interval were independently associated with inferior overall survival, whereas BMI decline was not significant. Declines in albumin and GNRI were significantly associated with impaired performance status, but not associated with disease status at HSCT2 or treatment intensity after relapse. A composite model integrating nutritional decline and disease status at HSCT2 stratified patients into distinct prognostic groups. These findings suggest that declines in nutrition-associated indices during the relapse-to-HSCT2 interval may reflect impaired physiological reserve and provide additional prognostic information beyond disease status at transplantation.

Severe motor and intellectual disabilities (SMID) are a heterogeneous group of disorders characterized by profound motor and cognitive impairment. Although routine coagulation tests are often normal, immobility, use of antiseizure medication (ASM), and poor nutrition may affect hemostasis. However, global coagulation potential in pediatric SMID patients remains unclear. This study evaluated coagulation function in 28 children with Oshima class 1 SMID. Routine coagulation tests and clot waveform analysis (CWA), including clotting time (CT), maximum coagulation velocity (|min1|), and maximum coagulation acceleration (|min2|) were performed. Factor XIII activity (FXIII:C) was measured. Associations with ASM number, valproic acid (VPA) use, BMI z-score, and total number of administered medications were examined. Multivariable regression was adjusted for age, BMI z-score, and home mechanical ventilation. Prothrombin and activated partial thromboplastin times were largely normal. CWA showed prolonged CT in 7 of 28 patients and decreased |min1| and |min2| values in 4 and 7 patients, respectively. CT was not associated with the number of ASMs used, VPA use, BMI z-score, or total medications after adjustment. In contrast, lower FXIII:C remained associated with the total number of administered medications after adjustment. Further studies are required to clarify this association and its clinical significance.

Hemophilia is an inherited bleeding disorder caused by deficiency of coagulation factor VIII or IX and results in impaired thrombin generation and recurrent bleeding. Prophylactic factor replacement remains the standard treatment; however, its limitations, including the burden of intravenous treatment, inhibitor development, and residual bleeding, necessitate alternative strategies. Non-factor therapies restore hemostatic balance independently of factor replacement. These agents include factor VIIIa-mimetic bispecific antibodies and rebalancing therapies that enhance thrombin generation by inhibiting anticoagulant pathways such as tissue factor pathway inhibitor or antithrombin. Regardless of inhibitor status, non-factor therapies reduce bleeding rates, provide sustained prophylactic efficacy, and improve quality of life in patients with hemophilia A or B. However, several significant challenges remain unresolved. Because these therapies modify physiological procoagulant and anticoagulant pathways, excessive rebalancing may increase thrombotic risk, particularly when additional factor concentrates or bypassing agents are used for breakthrough bleeding or surgery. Furthermore, standardized laboratory assays for assessing global hemostatic potential are lacking, and long-term safety, optimal patient selection, and perioperative management require further clarification. Therefore, this review summarizes current and emerging non-factor therapies for hemophilia, focusing on their mechanisms of action, clinical evidence, safety considerations, unmet needs, and future perspectives for safe implementation in clinical practice.

Cytokine release syndrome (CRS) is a common complication following allogeneic hematopoietic cell transplantation (allo-HCT) with posttransplant cyclophosphamide (PTCy). However, its incidence, risk factors, and clinical significance remain incompletely characterized. We retrospectively analyzed 362 adult patients with acute leukemia in complete remission who underwent PTCy-based allo-HCT at a single center between 2020 and 2025. CRS was observed in 69 patients (19.1%); all cases were grade 1-2 by the 2019 ASTCT criteria. Incidence differed significantly by donor type: 39.5% in haploidentical, 15.4% in mismatched unrelated (MMUD), 8.0% in matched unrelated, and 1.4% in matched related donor recipients (p < 0.001). On multivariable analysis, CRS risk increased with HLA disparity versus matched donors (MMUD OR 2.92, p = 0.026; haploidentical OR 12.2, p < 0.001), and was higher with peripheral blood than bone marrow grafts (OR 3.59, p = 0.025). CRS was associated with higher incidence of grade II-IV acute graft-versus-host disease (aGVHD) (35 vs 18%, p = 0.002), while survival, non-relapse mortality, and relapse incidence did not differ significantly. Histological examination of CRS-associated cutaneous lesions demonstrated perivascular lymphocytic dermatitis without features of aGVHD. Ruxolitinib administration for extensive cutaneous involvement was associated with resolution of skin manifestations. HLA mismatch and peripheral blood grafts are associated with CRS, which may precede subsequent aGVHD.

The development of BCR::ABL1 tyrosine kinase inhibitors (TKIs) has transformed chronic myeloid leukemia into a chronic disease with near-normal life expectancy. More recently, treatment-free remission (TFR), defined as sustained molecular remission even after TKI discontinuation, has emerged as a realistic therapeutic goal and a type of functional cure. Landmark studies, including STIM1, A-STIM, EURO-SKI, ENESTfreedom, DADI, and J-SKI, have established the feasibility and safety of TFR. Their results showed that approximately half of eligible patients can successfully discontinue therapy. However, the reliable prediction of TFR success remains a major challenge. Accumulating evidence indicates that durable TFR reflects a dynamic equilibrium between residual leukemic stem cells (LSCs) and host immune surveillance. Natural killer cells and T-cell immunity contribute to maintaining remission after TKI discontinuation. Conversely, immune exhaustion and the persistence of LSCs are associated with molecular relapse. Emerging biomarkers, including immune profiling, immunogenetic markers, and minimal residual disease kinetics, may improve relapse-risk stratification. To increase the proportion of patients who achieve durable TFR, future efforts should focus on the development of risk-adapted consolidation strategies incorporating optimized TKI therapy, immune modulation, and LSC-targeted approaches.

Hyperammonemic encephalopathy is a rare but often fatal complication in patients with hematological malignancies receiving intensive therapy, and its underlying mechanism is often unclear. We report the case of a woman in her 40 s with acute myeloid leukemia who developed fulminant nonhepatic hyperammonemia during high-dose cytarabine consolidation in association with previously unrecognized partial ornithine transcarbamylase (OTC) deficiency. On day 5 of consolidation, she developed rapidly progressive altered consciousness with marked hyperammonemia, preserved hepatic and renal function, and no evidence of active sepsis. Brain magnetic resonance imaging showed cortical abnormalities more consistent with metabolic encephalopathy than cytarabine-associated neurotoxicity or posterior reversible encephalopathy syndrome. Despite supportive therapy, serum ammonia increased further, followed by seizures, diffuse cerebral edema, and death. Metabolic evaluation suggested a urea cycle disorder, and genetic testing identified a heterozygous pathogenic OTC variant, indicating an underlying inherited metabolic predisposition. Reported adult cases of severe nonhepatic hyperammonemia in hematological malignancies have largely been considered idiopathic or infection-related, whereas genetically confirmed urea cycle disorders remain rare. This case expands the spectrum of chemotherapy-associated nonhepatic hyperammonemia and suggests that occult inherited metabolic predisposition may contribute to its pathogenesis, highlighting the importance of early recognition of hyperammonemia in unexplained encephalopathy during intensive chemotherapy.

Cellular immunotherapy has substantially changed the treatment of B-cell leukemias, lymphomas, and multiple myeloma. The success of chimeric antigen receptor (CAR)-T cell therapy in these diseases has been supported by suitable target antigens, including CD19 in B-cell malignancies and B-cell maturation antigen in multiple myeloma. In contrast, comparable progress has not yet been achieved in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), in part because an optimal target with clinically manageable on-target effects on normal cells has not been identified. Nevertheless, identification of an appropriate target could enable major therapeutic advances with CAR-T cell therapy in myeloid malignancies. To further harness the potential of cellular immunotherapy in AML/MDS, a multifaceted approach may be required. In parallel with CAR-T cell development, CAR-NK cells, T-cell receptor-engineered T cells, NK cells and other innate immune approaches are actively explored, while allogeneic hematopoietic stem cell transplantation remains an established form of cellular immunotherapy for AML/MDS. These approaches may be developed in parallel and, where appropriate, integrated with molecularly targeted and other pharmacologic therapies. This issue of Progress in Hematology reviews these emerging directions and their potential to expand cellular therapy for AML/MDS.

Current therapies for acute graft-versus-host disease (aGVHD) are limited by suboptimal efficacy or excessive immunosuppression. In this retrospective, exploratory, hypothesis-generating case series, we evaluated belumosudil, a selective Rho-associated coiled-coil kinase 2 inhibitor, in eight patients with aGVHD. All patients had gastrointestinal involvement, and 62.5% had grade IV aGVHD. Seven patients (87.5%) had received prior systemic therapy, including Janus kinase inhibitors. At day 28, the overall response rate was 100%, with six patients (75.0%) achieving complete response. The median time to response was 13.5 days (range, 7-28). Responses were sustained through day 56 in evaluable patients (5/5 complete responders). At a median follow-up of 269 days (range, 25-335), the median failure-free survival was 123.5 days (95% CI, 30.0 to not estimable). No grade ≥3 treatment-related adverse events occurred. In one patient with post-transplant relapse, immunosuppressive agents were tapered to promote a graft-versus-leukemia (GVL) effect. This patient developed stage 4 skin and stage 1 gastrointestinal aGVHD that resolved with belumosudil, with subsequent minimal residual disease negativity and complete response. This exploratory case series suggests that belumosudil-based therapy may have activity in aGVHD, with possible GVL activity in one case, warranting further investigation.