Lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS) is associated with high mortality, and rapid identification may enable timely lymphoma-directed therapy. The soluble interleukin-2 receptor alpha (sIL-2Rα), measured clinically as soluble CD25 (sCD25), to ferritin ratio has been proposed as a diagnostic biomarker to distinguish LAHS from non-lymphoma-associated HLH (N-LAHS), but validation in Western populations and across lymphoma subtypes remains limited. We performed a retrospective multicenter cohort study of adults diagnosed with HLH across three United States academic institutions between 2008 and 2024. HLH was defined using HLH-2004 criteria. Laboratory values were selected at first clinical suspicion of HLH. Patients were classified as LAHS or N-LAHS, and lymphoma subtypes were annotated using institutional records. Among 126 patients, 44 (34.9%) had LAHS. LAHS cases included aggressive B-cell/classical Hodgkin lymphoma, aggressive T/NK-cell lymphoma and indolent B-cell lymphoma. Median sCD25 was significantly higher in LAHS, whereas ferritin did not differ significantly. The median sCD25/ferritin ratio was elevated in LAHS (2.2 vs. 0.4; P < 0.001). Receiver-operating-characteristic analysis calculated from our analytic cohort demonstrated an area under the curve (AUC) of 0.7431, and the Youden index identified an optimal cutoff of > 1.02 with 73% sensitivity, 73% specificity, 59.3% positive predictive value and 83.3% negative predictive value. In logistic regression, each one-unit increase in log(sCD25/ferritin) was associated with increased odds of underlying lymphoma. The sCD25/ferritin ratio is best interpreted as a risk-enrichment tool that may prioritize evaluation for occult lymphoma, but it cannot replace tissue diagnosis.

Low-grade B-cell lymphomas generally follow an indolent course. Nonetheless, they can occasionally transform into high-grade lymphoma, leading to reduced survival. Despite therapeutic advances that have improved absolute survival in high-grade transformation (HGT) lymphomas, additional survival data are needed for patients with HGT lymphoma. We aimed to perform a pooled analysis of hazard ratios (HRs) comparing HGT lymphoma with low-grade lymphoma and de novo diffuse large B-cell lymphoma (DLBCL) to obtain more robust estimates. Studies reporting overall survival (OS) data comparing HGT lymphoma with low-grade B-cell lymphoma without HGT or de novo DLBCL were identified through a database search (PubMed, Embase, Web of Science, MEDLINE, and the Cochrane Library). Articles were excluded if they met any of the following criteria: (1) not relevant to the study subject; (2) review articles, case reports, or errata; (3) non-English publications; (4) nonclinical studies; or (5) conference abstracts lacking sufficient data. Hazard ratios (HRs) were extracted and pooled. Thirty-eight datasets from 35 selected studies were pooled. The pooled HRs for OS comparing HGT with low-grade B-cell lymphoma were statistically significant and close to 2, regardless of tumor type and treatment era. In the rituximab era, the pooled HR analysis of OS comparing HGT with de novo DLBCL was statistically significant (HR = 1.12). HGT was associated with a consistently inferior prognosis in low-grade B-cell lymphomas, with an approximately twofold increase in mortality risk. The results of this analysis suggest the need for more effective therapeutic strategies for HGT lymphoma.

Despite advanced molecular diagnostics, improving outcomes for refractory acute myeloid leukemia (AML) remains challenging. Although many cancer-related genes are identified, their molecular mechanisms are not fully elucidated. Amplification is a mechanism of cancer-associated gene activation, and ectopic gene amplification may have particularly high pathological significance. However, research on ectopically amplified cancer-associated genes in leukemia remains limited. Here, we evaluated the usefulness of high-throughput chromosomal conformation capture (Hi-C) as a screening method for ectopic gene amplification and assessed whether ectopic amplification of cancer-associated genes may represent a general phenomenon in AML. We screened the U-937 and NB-4 cell lines using in situ Hi-C. Regions appearing as "high-intensity bands" in Hi-C contact maps were identified and validated using fluorescence in situ hybridization (FISH). Additionally, copy number variation analysis was performed using whole-genome sequencing (WGS) to extract cancer-associated genes with ectopic amplification. In the U-937, three genomic regions showing "high-intensity bands" were identified and confirmed as ectopic amplifications-including PDCD1LG2 (PD-L2), CD274 (PD-L1), and JAK2; that is, four copies were detected by WGS, and amplification signals were observed by FISH. In the NB-4, four such regions were detected, including MYC and KRAS, with expression level of 498 transcripts per million (TPM) and 34 TPM, respectively. Copy number variation analysis further identified multiple cancer-associated genes with ectopic amplification. Overall, these findings demonstrate the presence of ectopic amplification of cancer-associated genes in AML cell lines and support the usefulness of Hi-C as a screening method for detecting such genomic alterations.

The European LeukemiaNet (ELN) recommendations have been instrumental in shaping the diagnosis, risk stratification, and management of Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Over the past two decades, these recommendations have evolved from consensus-based frameworks focused on response standardization to increasingly sophisticated, evidence-based and biologically informed approaches. Early efforts primarily aimed to harmonize response criteria across clinical studies, establishing a foundation for consistent therapeutic evaluation. Subsequent updates introduced risk-adapted treatment strategies centered on thrombotic risk, reflecting the major determinants of morbidity and mortality in these disorders. However, the limitations of surrogate endpoints prompted a shift toward clinically meaningful outcomes, including symptom burden, vascular events, and disease progression. More recent advances have been driven by the integration of molecular genetics and the adoption of structured evidence-based methodologies, enabling refined diagnostic classification and more accurate prognostic assessment. Contemporary ELN frameworks increasingly incorporate dynamic clinical parameters, genomic profiling, and emerging biomarkers, supporting a transition toward individualized, risk-adapted therapeutic strategies. Beyond their role in standardizing MPN management, ELN recommendations have also influenced clinical trial design, endpoint selection, risk stratification, and therapeutic decision-making. Evidence from prospective studies and real-world cohorts supports the clinical applicability of these frameworks, although their implementation remains heterogeneous across healthcare settings. This review provides a comprehensive and critical overview of the evolution and implementation of ELN recommendations, highlighting their impact on clinical research and routine practice, current limitations, and future directions toward precision medicine in Philadelphia-negative MPNs.

R-GDP has been established as an effective salvage treatment for Rel/Ref DLBCL. We aimed to clarify the efficacy of R-GDP therapy. We included 41 consecutive patients with Rel/Ref DLBCL, who received R-GDP therapy as salvage chemotherapy at our hospital between January 2014 and August 2024. Thirty-three patients received R-GDP therapy as a 2nd-line regimen, whereas 8 received R-GDP as a 3rd or later-line regimen. The ORR was 70.7%. 23 out of 25 relapsed patients (92%) responded to R-GDP therapy, whereas only 6 out of 16 refractory patients responded (37.5%). With regard to the duration of response, the response rates in 19 patients with late relapse (at least 12 months) and 6 with early relapse (less than 12 months) were 94.7% and 83.3% (p = 0.43). Overall, the 2-year PFS and OS rates were 48.8% and 74.2%, respectively. 18 responders underwent ASCT with a 2-year PFS after ASCT of 61.2%. Although CAR-T is recommended in patients with Rel/Ref DLBCL, R-GDP is a realistic option given the limited availability of immediate CAR-T therapy. Further studies including genomic profiles are warranted to identify factors that can predict a response to R-GDP in Rel/Ref DLBCL.

Treatment options after venetoclax-hypomethylating agent (Ven-HMA) failure in acute myeloid leukemia (AML) remain limited, with a median overall survival of 2-3 months. Cladribine targets biologically distinct leukemia stem cells, including monocytic populations implicated in venetoclax resistance. We conducted a multicenter retrospective study across six Israeli academic centers to evaluate cladribine-based salvage therapy, predominantly cladribine, low-dose cytarabine, and venetoclax (CAV), in 31 patients with relapsed/refractory AML. Median age was 70 years (range 21-81); 87% had prior venetoclax exposure, 61% had undergone prior allogeneic transplantation, and 55% were classified as ELN-2022 adverse risk. After a single treatment course, the composite complete remission rate (CRc) was 45% and the overall response rate was 52%. Median overall survival was 5 months, with a 1-year survival of 30%. Patients achieving CRc had significantly longer survival (16.2 vs. 2.9 months; p < 0.0001). Twelve patients (39%) were bridged to cellular therapy, with a median survival of 12.6 months. Toxicity was predominantly hematological; invasive fungal infection occurred in 23% and was associated with fluconazole rather than mold active prophylaxis. The 30-day mortality was 19%. Cladribine-based salvage demonstrates clinically meaningful activity after Ven-HMA failure and can bridge patients to cellular therapy.