International Journal of Hematology最新文献

Pericardial effusion (PCE) is a serious complication after allogeneic hematopoietic cell transplantation, but its etiology is not fully understood, particularly the role of viral reactivation. We investigated the presence of DNA viruses in pericardial fluid from nine umbilical cord blood transplant recipients who underwent pericardiocentesis. Multiplex PCR detected DNA viruses in seven patients (78%), with Epstein-Barr virus being most common. The clinical context of viral detection appeared to differ by onset timing. In early-onset PCE (< 100 days), viral presence was often systemic and likely secondary to severe inflammation. In contrast, late-onset cases frequently occurred with chronic graft-versus-host disease and showed localized viral reactivation within the pericardium. These findings suggest DNA viruses are potential contributors to post-transplant PCE. Viral evaluation of pericardial fluid should be considered in these patients as it may influence therapeutic strategies.

Functional hyposplenism, defined as impaired splenic function in the absence of splenectomy, increases susceptibility to life-threatening infections. Although Howell-Jolly bodies (HJBs) are well-established markers for this condition, the predictive value of spleen volume for infection risk remains unclear. We retrospectively analyzed 95 non-splenectomized patients with HJBs from 2014 to 2024. We measured spleen volume by computed tomography and compared results with ideal values. We evaluated the associations between splenic volume and infections using univariate and multivariate logistic regression analyses. The median patient age was 66 years (range, 16-95); 72% were male. The median spleen volume was 34 mL, lower than the ideal median of 210 mL. Forty-eight percent of patients experienced at least one infection. Univariate analysis identified age ≥ 65 years and spleen volume < 34 mL as significantly associated with sepsis. Both factors remained independent predictors in multivariate analysis (age ≥ 65: odds ratio [OR], p = 0.039; spleen volume < 34 mL: OR 3.0, p = 0.047). Age ≥ 65 also predicted any infection (OR 3.1, p = 0.013), while low spleen volume demonstrated a trend toward significance (OR 2.2, p = 0.064). In non-splenectomized patients with HJBs, reduced spleen volume and older age independently increase susceptibility to sepsis. Computed tomography-based measurements may help identify functional hyposplenism and guide targeted prophylactic measures.

Chronic myeloid leukemia (CML) and BCR::ABL1-negative MPN were thought to be mutually exclusive, but synchronous and sequential cases have been reported. We screened 35,001 patients for BCR::ABL1 fusion or JAK2, CALR, or MPL mutations to investigate the sequential development of CML and BCR::ABL1 negative-MPNs. We discovered that 5.6% had primary CML followed by BCR::ABL1-negative MPN, and 5.8% had the reverse sequence. Notably, we identified higher JAK2 variant allele frequencies (VAFs) in patients developing secondary CML. Previous MPN did not compromise the effectiveness of tyrosine kinase inhibitors (TKI) in treating secondary CML. The emergence of secondary MPN appeared to be unrelated to JAK2 VAF progression or BCR::ABL1 transcript levels. Our research indicates that newly detected leukocytosis or thrombocytosis should prompt consideration of secondary MPN. It also showed that secondary CML had no negative impact on response to therapy when patients were treated according to CML guidelines.

CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. The safety of CPX-351 in Japanese patients was verified by comparing safety data from the Japanese phase 1/2 study and the global phase 3 study. This analysis included 47 patients in the safety analysis set of the Japanese study and 153 patients who received CPX-351 and were included in the intention-to-treat analysis for the global study. In both the Japanese and global studies, the most frequent adverse events were febrile neutropenia (FN) (Japanese: 85.1%, global: 70.0%) and pneumonia (25.5% and 24.2%). Median time to occurrence was 8 and 11 days for FN, and 17 and 23 days for pneumonia. Median time to hematologic recovery was 36 and 41 days for neutrophils (> 1000/μL), and 36 and 44 days for platelets (> 100,000/μL). In the global study, univariate analysis was performed after one cycle of induction therapy to investigate factors that delay neutrophil and platelet recovery, but no specific factors were identified. In these analyses, the pattern and frequency of adverse events were similar in Japanese and non-Japanese patients, with no need for race- or region-specific management.

Systemic chronic active Epstein-Barr virus disease (sCAEBV) is an intractable disorder characterized by clonal proliferation of EBV-infected T- and NK-cells, leading to persistent systemic inflammation and progression to hemophagocytic lymphohistiocytosis (HLH). The EBV genome encodes 40 mature microRNAs known as miR-BARTs. The expression of miR-BARTs has been reported in other EBV-positive diseases and is associated with tumorigenesis. In this study, we investigated the expression of miR-BARTs in sCAEBV. Expression of miR-BARTs was highly abundant in 4 sCAEBV-derived EBV-positive T- or NK-cell lines and in EBV-infected T- or NK-cells from 23 sCAEBV patients. The highest expression levels were observed for miR-BART7-3p. Sequence analysis revealed no deletions in the EBV genome encoding miR-BARTs. Inhibition of miR-BART7-3p altered the expression of immune-related genes in sCAEBV-derived cell lines. Abundant miR-BART expression was also observed in patients' plasma, with miR-BART7-3p showing the highest levels. Notably, miR-BART7-3p expression was detected in macrophages within the spleen of an sCAEBV patient with HLH. These findings suggest that miR-BARTs are highly expressed and secreted by EBV-infected cells in sCAEBV. We hypothesize that secreted miR-BARTs may be taken up by monocytes, potentially regulating their functions and contributing to inflammation in sCAEBV. Further studies are needed to elucidate these mechanisms.

This study investigated the anti-tumor effects of andrographolide, a diterpene lactone derived from Andrographis paniculata, on T-cell acute lymphoblastic leukemia (T-ALL) cells. Andrographolide induced dose-dependent cytotoxicity and morphological changes in the T-ALL cell line Jurkat cells, including cell shrinkage and chromatin condensation. Mechanistically, andrographolide triggers apoptosis through reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, and cytochrome c release. These effects were reversed by the ROS inhibitor N-acetyl-L-cysteine (NAC), indicating that andrographolide induces apoptosis through a ROS-dependent apoptotic pathway. In contrast, NAC treatment did not reverse cytarabine- and vincristine-induced apoptosis or the ROS-dependent apoptotic pathway in Jurkat cells. Intriguingly, andrographolide also induced ferroptosis, as evidenced by increased expression of the ferroptosis marker fatty acid-CoA ligase 4 and ultrastructural changes such as reduced mitochondrial area and disappearance of cristae. These effects were likewise reversed by NAC, further implicating ROS in the ferroptotic process. In MOLT-4 cells, where andrographolide suppressed viability, increased Annexin V positivity and ROS levels, and upregulated FACL4 expression in a NAC-sensitive manner. Unlike cytarabine and vincristine, andrographolide did not significantly alter cell cycle distribution. In conclusion, andrographolide induces both apoptosis and ferroptosis in T-ALL cells via ROS-dependent mechanisms that are distinct from those of conventional chemotherapeutic agents. These dual actions position andrographolide as a candidate for standalone or combination therapy in T-ALL.

Ph-like ALL is a high-risk subtype with diverse genomic alterations, including CRLF2 rearrangements, JAK2/EPOR mutations, and ABL-class fusions, which are targetable but underdiagnosed in low and middle-income countries (LMICs). This meta-analysis (78 studies, 15,201 patients, 42 countries) highlights disparities in detection and outcomes between high-income countries (HICs) and LMICs. HICs use comprehensive profiling (RNA-seq: 90-95% sensitivity), while LMICs rely on limited FISH/qPCR, detecting only 30-50% of cases due to cost barriers ($1200 vs. $15-42 for LMIC-adapted assays), infrastructure gaps, and delayed turnaround (4-6 weeks vs. < 7 days). CRLF2 rearrangements are found in 50-60% of cases in HMICs vs. 20-30% in LMICs (p < 0.001), while ABL-class fusions are missed in 75% of LMIC patients. Undiagnosed Ph-like ALL correlates with worse survival (5-year OS: 35-45% in LMICs vs. 60-65% in HICs) due to chemotherapy overuse instead of TKIs (e.g., dasatinib improves EFS by 30%). A tiered diagnostic approach, initial CRLF2 flow cytometry ($15, 80% sensitivity), confirmatory PHi-RACE PCR ($42, 95.2% sensitivity), and selective NGS referral could bridge 85% of the detection gap at 90% cost reduction. Cost-effective tools, subsidized NGS networks, workforce training, and WHO-endorsed guidelines could prevent 40-50% of relapses in LMICs.

Post-transplant lymphoproliferative disorders (PTLDs) typically arise months to years after solid-organ transplantation and are frequently driven by Epstein-Barr virus (EBV). However, EBV-negative monomorphic PTLDs are increasingly recognized as an alternative pathogenesis. We report a case of a 64-year-old man who underwent liver transplantation and was found to have a minute focus of diffuse large B-cell lymphoma (DLBCL) in the resected gallbladder. Given the absence of residual disease and the patient's postoperative frailty, close observation was chosen. Three months later, the patient developed an aggressive clinical relapse characterized by Burkitt-like features, including massive effusions and gastric wall thickening. Retrospective analysis using a 398-gene panel (DISCAVar) revealed that both the initial and recurrent lesions shared an IGH::MYC rearrangement, while the recurrent tumor acquired additional Burkitt lymphoma (BL)-associated mutations (TP53, TCF3, CCND3, DDX3X) absent in the original lesion. These alterations spanned all three molecular subgroups of BL and suggest rapid clonal evolution from a pre-existing MYC-positive clone under post-transplant immunosuppression. Despite treatment with dose-modified EPOCH, the patient's condition deteriorated, and he died 108 days after treatment initiation. This case underscores the value of longitudinal molecular analysis in understanding the pathogenesis of EBV-negative PTLD and identifying high-risk clones before clinical transformation.

JAK2V617F is the major driver mutation in polycythemia vera, and detection of this mutation is one of the most important keys for the diagnosis of this disease. In addition, JAK2V617F mutation is highlighted as a molecular marker for monitoring treatment. Clinical studies of the JAK inhibitor ruxolitinib and two recently introduced new forms of alfa interferon, pegylated interferon alfa 2b and ropeginterferon alfa 2b, demonstrated that treatment with these agents induced a molecular response, defined as a more than 50% reduction in the JAK2V617F allele burden from baseline, in approximately 60% of patients. In addition, some patients achieved a complete molecular response, defined as the disappearance of the mutation. More importantly, achievement of a molecular response was positively correlated with improved thrombosis-free and progression-free survival in PV patients. To date, controlling hematological parameters, especially maintaining hematocrit levels below 45%, has been the gold standard surrogate endpoint in PV treatment. With new treatment options and knowledge, molecular response should be incorporated as a new therapeutic surrogate endpoint in the management of PV.

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.