The growing incidence of Non-Hodgkin lymphomas (NHL) in recent times has brought attention to the need for thorough investigations of their genetic associations with autoimmune and rheumatologic conditions, such as systemic lupus, celiac disease, and Sjögren's syndrome. Our study is the first of its type in this field since it uses machine learning to investigate these relationships in great detail. Firstly, we have developed a new genetic dataset, specifically designed to uncover the genetic intricacies of NHL and rheumatologic diseases, offering unprecedented insights into their molecular mechanisms. Following this, we introduced the Clustered-Based Binary Grey Wolf Optimizer (CB-BGWO), a novel method that significantly revolutionizes the feature selection process in genetic analysis. This optimizer significantly improves the accuracy and efficiency of identifying important genetic variables affecting the interaction between rheumatologic and NHL illnesses. This methodological advance not only increases the analytical power but also creates a new standard for genetic research methods. Our findings address a significant gap in the literature and offer valuable insights that could positively support future treatment strategies and research paths. By illuminating the complex genetic connections between NHL and significant rheumatologic conditions, this work contributes to a better understanding and treatment of these complex diseases.

Plasma Epstein-Barr virus (EBV) DNA levels predict the prognosis of extranodal NK/T-cell lymphoma, nasal type (NK/TCL), but its role in other peripheral T-cell lymphomas (PTCL) remains undetermined. This study aimed to determine the prognostic impact of plasma EBV DNA in PTCL patients.

We retrospectively enrolled 134 PTCL patients diagnosed between April 2008 and March 2022, with plasma EBV DNA data available at diagnosis in 124 patients and during post-treatment follow-up in 73 patients.

International Prognostic Index or prognostic index for T-cell lymphoma scores > 1 was associated with higher median plasma EBV DNA levels in all analyzed patients. Plasma EBV DNA positivity at the time of diagnosis was not associated with treatment response, overall survival (OS), or progression-free survival (PFS) in non-NK/TCL patients. In NK/TCL patients, an EBV DNA level < 3255 copies/mL at diagnosis was significantly associated with higher five-year PFS (64.2% vs. 16.7%, p < 0.001) and OS rates (64.4% vs. 20.8%, p < 0.001). Plasma EBV DNA positivity at the time of complete remission and during post-treatment follow-up was significantly linked to lower PFS and OS rates in NK/TCL patients. Multivariate analysis revealed that advanced-stage disease, elevated β2-microglobulin, and EBV DNA level ≥ 3255 copies/mL at diagnosis were independent predictors for OS and PFS in NK/TCL patients.

Plasma EBV DNA at diagnosis and during follow-up predict survival for NK/TCL patients but not for patients with other PTCL subtypes. Detection and monitoring of plasma EBV DNA levels at diagnosis and post-treatment follow-up for NK/TCL patients is recommended.

Histiocytic sarcoma (HS) is a rare and aggressive malignant neoplasm from histiocytic cells. This case report describes a 52-year-old male with HS involving multiple abdominal sites, diagnosed through imaging, histopathology, and immunohistochemical analysis, which identified a KRAS mutation. The patient underwent surgical resection followed by 6 cycles of ICE chemotherapy, resulting in significant clinical improvement and reduction of tumor burden. This case highlights the clinical presentation, diagnostic challenges, and potential treatment approach for this rare malignancy.

Composite lymphoma containing both B-cell lymphoma and extranodal natural killer/T-cell lymphoma (ENKTL) is extremely rare. Clonal evolution and tumor microenvironment (TME) features have not been reported previously. The present study reports one case of the heterochronous occurrence of follicular lymphoma (FL) and ENKTL and one case of the simultaneous occurrence of diffuse large B-cell lymphoma (DLBCL) and ENKTL. The results of targeted DNA sequencing demonstrated the genetic features and dynamic clonal evolution of each component. Notably, in the case of ENKTL secondary from FL, predominant clones harbored in ENKTL were already present at the initial diagnosis of FL and expanded to full clonal prevalence afterward in ENKTL. In the case of synchronous DLBCL and ENKTL, predominant clones in ENKTL were exclusive to those clones dominating in DLBCL. Multiple immunofluorescence and CIBERSORT analyses depicted TME features and showed that CD68+ macrophages were abundant in FL, DLBCL and ENKTL. The present report could broaden our understanding of composite lymphoma.

Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Pathological grade is a critical determinant of clinical outcomes and decision-making of follicular lymphoma (FL). This study aimed to develop a deep learning model as a digital biopsy for the non-invasive identification of FL grade.

This study retrospectively included 513 FL patients from five independent hospital centers, randomly divided into training, internal validation, and external validation cohorts. A multimodal fusion Transformer model was developed integrating 3D PET tumor images with tabular data to predict FL grade. Additionally, the model is equipped with explainable modules, including Gradient-weighted Class Activation Mapping (Grad-CAM) for PET images, SHapley Additive exPlanations analysis for tabular data, and the calculation of predictive contribution ratios for both modalities, to enhance clinical interpretability and reliability. The predictive performance was evaluated using the area under the receiver operating characteristic curve (AUC) and accuracy, and its prognostic value was also assessed.

The Transformer model demonstrated high accuracy in grading FL, with AUCs of 0.964-0.985 and accuracies of 90.2-96.7% in the training cohort, and similar performance in the validation cohorts (AUCs: 0.936-0.971, accuracies: 86.4-97.0%). Ablation studies confirmed that the fusion model outperformed single-modality models (AUCs: 0.974 - 0.956, accuracies: 89.8%-85.8%). Interpretability analysis revealed that PET images contributed 81-89% of the predictive value. Grad-CAM highlighted the tumor and peri-tumor regions. The model also effectively stratified patients by survival risk (P < 0.05), highlighting its prognostic value.

Our study developed an explainable multimodal fusion Transformer model for accurate grading and prognosis of FL, with the potential to aid clinical decision-making.

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), demonstrated clinically meaningful antitumor responses in covalent BTKi pretreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the global phase 1/2 BRUIN study. In this multi-center, open-label, phase 2 trial, we investigated the efficacy and safety of pirtobrutinib in Chinese patients with BTKi pretreated relapsed/refractory (R/R) MCL, CLL/SLL, or other B-cell malignancies. All patients received pirtobrutinib once daily in continuous 28-day cycles. The primary endpoint was the overall response rate (ORR). Efficacy was assessed in patients with MCL and CLL/SLL with prior BTKi treatment and safety in all enrolled patients who received at least one dose of pirtobrutinib. Among 35 patients with covalent BTKis (cBTKi) pretreated MCL, the ORR was 62.9% (95% CI: 44.9, 78.5), the median duration of response (DOR) was not reached, and the 12-month DOR rate was 59.7% (95% CI: 35.3, 77.5). Among 11 patients with cBTKi pretreated CLL/SLL, the ORR was 63.6% (95% CI: 30.8, 89.1), and the 12-month DOR rate was 83.3% (95% CI: 27.3, 97.5). The most common adverse events in the safety population (n = 87) were anemia (32.2%) and neutrophil count decreased (31.0%). Grade ≥3 hemorrhage occurred in 2.3% of patients and there were no cases of atrial fibrillation/flutter. Pirtobrutinib demonstrated clinically meaningful efficacy in Chinese patients with cBTKi pretreated R/R MCL, preliminary antitumor activity in Chinese patients with cBTKi pretreated R/R CLL/SLL and was generally well-tolerated with no new safety signals observed.

Primary vitreoretinal lymphoma (PVRL), a rare subtype of primary central nervous system lymphoma (PCNSL), can lead to permanent vision loss and central nervous system (CNS) involvement, resulting in a poor prognosis. PVRL often masquerades as uveitis, and its partial response to topical corticosteroids further complicates the diagnosis. The gold standard for diagnosis is cytological analysis; however, owing to its low sensitivity, cytokine profiling and genetic testing may serve as supplementary diagnostic tools. There is no universally accepted consensus regarding PVRL treatment protocols. Combined systemic high-dose intravenous methotrexate (MTX) and intravitreal therapy may help manage bilateral ocular lesions, although this combination's ability to delay CNS relapse remains controversial. For relapsed or refractory (R/R) PVRL patients aged <60 years, intensive consolidation chemotherapy followed by autologous stem cell transplantation may be considered. Novel targeted therapies such as ibrutinib and lenalidomide have demonstrated efficacy in R/R cases. Large-scale multicenter prospective studies are urgently needed to determine optimal treatment strategies.

In this phase-2a study (NCT01994382), patients aged ≥18 years with relapsed/refractory peripheral T-cell lymphoma (PTCL; angioimmunoblastic T-cell lymphoma/T follicular helper [AITL/TFH], n = 29); PTCL-not otherwise specified [NOS], n = 11; and Other, n = 25) received 30 mg oral cerdulatinib, a reversible dual inhibitor of spleen tyrosine kinase and Janus kinase, twice daily in 28-day cycles until disease progression or unacceptable toxicity. Overall response rate (ORR) was 36.2% (12 complete responses [CR],9 partial responses [PR], and 14 stable disease); median time to response was 1.9 months. ORR was 51.9% for AITL/TFH (10 CR, 4 PR) and 31.8% for Other (2 CR, 5 PR); median duration of response was 12.9 and 5.3 months, respectively. The most common grade ≥3 treatment-emergent adverse events were asymptomatic amylase elevation (23.1%), anemia (20.0%), and asymptomatic lipase elevation (18.5%). These data suggest clinical activity and acceptable tolerability for cerdulatinib in patients with relapsed/refractory PTCL.

Posttransplant lymphoproliferative disorder (PTLD) is a complication of pediatric solid organ transplantation. Benign adenotonsillar lymphoid hyperplasia confounds the ability to diagnose PTLD. Our aim was to identify factors that predict the presence of PTLD to inform decision-making regarding adenotonsillectomy.

The electronic medical records at a quaternary children's hospital were queried over a 23-year period (2000-2023) for solid organ transplant patients that underwent tonsillectomy and/or adenoidectomy. Demographics, clinical presentation, and EBV serologies were analyzed to determine factors associated with presence of PTLD on final pathology.

A total of 114 patients met inclusion criteria for analysis. Thirty-two of the 114 patients (28.1%) who underwent tonsillectomy and/or adenoidectomy had PTLD. Age at transplant, age at biopsy, sex, race, and type of organ transplanted were not found to be associated with development of PTLD. Patients with PTLD were more likely to have smaller tonsils, sore throat, fever, and tonsillar exudate; they were less likely to experience sleep disordered breathing. The immunosuppression agent used for induction and the number of maintenance immunosuppressive medications were not associated with the development of PTLD. Increased Epstein-Barr Virus (EBV) PCR copy number correlated to increased risk of developing PTLD (p < 0.003).

Tonsillar hypertrophy and sleep disordered breathing are not necessarily indicative of the presence of PTLD. Suspicion for adenotonsillar PTLD should be based on symptomatology, clinical exam, EBV serologies, and degree of EBV PCR positivity. Sore throat, fever, tonsillar exudates, and significant elevation in EBV PCR copy number are particularly concerning for PTLD.

3 Laryngoscope, 135:2182-2189, 2025.

Treatment strategies for early stage diffuse large B-cell lymphoma (ES-DLBCL) include R-CHOP, with a similar schedule to that used in advanced stage, or a reduced number of cycles followed by radiation therapy (RT). We retrospectively analyzed 179 ES-DLBCL patients, managed according to the clinical practice. Treatment regimens include chemoimmunotherapy 4-6 cycles +/- RT as consolidation. First-line therapy was R-CHOP/CHOP-like in 88.8% of cases. RT as consolidation was administered to 29.9% of cases. Complete response rate was 87.2%, median PFS and OS were not reached. IPI 2-3 and first-line regimen with 3-4 cycles of R-CHOP without RT were the 2 prognostic variables for OS in multivariate analysis. After a median follow-up of 48 months, 31 patients died (17.3%). We suggest that both R-CHOP 6 cycles and 3-4 cycles followed by RT as consolidation seem to be valid first-line regimens, while an abbreviated strategy without RT could be associated to inferior outcome.

High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (double hit [HGBL-DH] or triple hit [HGBL-TH]) or not otherwise specified (HGBL-NOS) are considered to be more aggressive diseases among large B-cell lymphomas (LBCLs). CD19-targeting chimeric antigen receptor (CAR) T cells have changed the prognosis of chemoresistant LBCL. Clinical and pathological data of patients treated for relapsed/refractory LBCL or HGBL in third line or more, all characterized by fluorescence in situ hybridization, were collected from the French DESCAR-T registry. Between January 2018 and November 2022, a total of 228 patients were included across 14 centers, 73 with HGBL (28 HGBL-DH MYC-BCL2, 14 HGBL-TH, 8 HGBL-DH MYC-BCL6, and 23 HGBL-NOS) and 155 with non-HGBL. The median follow-up was 18.5 months (95% confidence interval [CI], 14.3-23.4) from the date of infusion. Progression-free survival and overall survival (OS) were not significantly different between HGBL and non-HGBL, at 3.2 months (95% CI, 2.8-6.0) vs 4.5 months (95% CI, 3.1-8.7; P = .103) and 15.4 months (95% CI, 5.6-32.4) vs 18.3 months (95% CI, 8.5 to not reached), respectively. From the date of eligibility, the median OS was inferior for patients with HGBL-TH/DH MYC-BCL2 at 6.6 months vs 18.5 months for HGBL-NOS vs 13.6 months for HGBL-DH MYC-BCL6 vs 11.8 months for LBCL (P = .037). However, patients who received infusion presented the same outcome. CAR T-cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes, especially in HGBL-TH/DH MYC-BCL2. This observation supports considering the potential benefit of using CAR T cells earlier in disease course.

Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) is a rare and life-threatening disorder. While the prognostic nutritional index (PNI) has been recognized as an independent prognostic indicator in lymphoma studies, its specific role in LA-HLH has not yet been reported.

We retrospectively examined clinical characteristics and prognostic factors from 124 LA-HLH patients.

23 patients (18.5%) had B-cell lymphoma-associated HLH (B-LA-HLH), and 101 cases presented with T or natural killer (NK)-cell lymphoma-associated HLH (T/NK-LA-HLH). The median survival time for the entire group was two months, with T/NK-LA-HLH and B-LA-HLH showing median survival times of 1.6 months and 5.0 months, respectively, post-HLH diagnosis. The optimal threshold for the prognostic nutritional index (PNI) was 35.5. Analysis of prognostic factors indicated that the HLH onset at lymphoma relapse and a PNI below 35.5 were independent predictors of inferior overall survival. Patients with a PNI below 35.5 had a significantly shorter estimated survival duration than those with a PNI of 35.5 or higher (p = 0.003).

The onset of HLH at lymphoma relapse and a low PNI may be considered adverse prognostic indicators for LA-HLH, potentially aiding in risk stratification and informing clinical decisions.

There are multiple established risk factors for DLBCL; these risk factors share an underlying biology, which generally cause immune dysfunction, spanning immunosuppression to chronic inflammation. EBV is an established risk factor for DLBCL and approximately 10% of DLBCLs are EBV-positive. EBV is a ubiquitous infection, and it is thus among populations that are immunocompromised, by age or medically defined, where EBV-positive DLBCLs arise. In this chapter, we review the current classification, epidemiology, clinical, pathology, and molecular characteristics of EBV-positive DLBCL, and discuss the role of EBV in lymphoma tumorigenesis. We further discuss current and novel treatments aimed at the NFκB pathway and other targets.

Primary cutaneous diffuse large B cell lymphoma, leg type (PCDLBCL-LT) is an aggressive B cell extranodal variant of lymphoma present in the skin, typically without evidence of extra cutaneous spread at the time of diagnosis. PCDLBCL-LT accounts for 20% of all primary cutaneous B cell lymphomas (CBCL) and 5% of all primary cutaneous lymphomas (PCL). It is more common in the elderly (median age 75 years). The disease commonly manifests as rapidly-growing red to bluish often ulcerating, nodular tumors, plaques or violaceous nodules on one or both lower extremities. Only 10% to 15% of lesions develop in other areas. A prognosis of PCDLBCL-LT is poor, with a 5-year survival rate of 40 to 50%. The first-line treatment of PCDLBCL-LT includes immunochemotherapy, most commonly R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone). In the case of a solitary lesion, excision or radiotherapy should be considered. Many patients demonstrate cutaneous relapses (70%) or systemic dissemination (50%). Recent studies have reported the use of Bruton's tyrosine-kinase (BTK) inhibitors, BCL2 inhibitors, immunomodulatory drugs and immune check-point inhibitors in treating relapsed or refractory patients. The study summarizes the current view of the pathogenesis, diagnosis and treatment of PCDLBCL-LT, including genetic abnormalities and novel targeted drugs.

Liquid biopsy through the analysis of circulating tumor DNA (ctDNA) is emerging as a powerful and non-invasive tool complementing tissue biopsy in lymphoma management. Whilst tissue biopsy remains the diagnostic gold standard, it fails to detect the molecular heterogeneity of the tumor's multiple compartments and poses challenges for sequential disease monitoring. In diffuse large-B-cell lymphoma (DLBCL), ctDNA facilitates non-invasive genotyping by identifying hallmark mutations (e.g., MYD88, CD79B, EZH2), enabling molecular cluster classification. Dynamic changes in ctDNA levels during DLBCL treatment correlate strongly with progression-free survival and overall survival, underscoring its value as a predictive and prognostic biomarker. In Hodgkin's lymphoma, characterized by a scarcity of malignant cells in tissue biopsies, ctDNA provides reliable molecular insights into tumor biology, response to therapy, and relapse risk. In primary central nervous system lymphoma, the detection of MYD88 L265P in ctDNA offers a highly sensitive, specific, and minimally invasive diagnostic option. Likewise, in aggressive T-cell lymphomas, ctDNA supports molecular profiling, aligns with tumor burden, and shows high concordance with tissue-based results. Ongoing and future clinical trials will be critical for validating and standardizing ctDNA applications, ultimately integrating liquid biopsy into routine clinical practice and enabling more personalized and dynamic lymphoma care.

First-line treatment balancing efficacy and safety is urgently needed for frail and elderly diffuse large B-cell lymphoma (DLBCL) patients. We designed a triplet chemo-light regimen, Pola-ZR, in previously untreated frail and elderly DLBCL patients to assess the efficacy and safety in a prospective DLBCL cohort (NCT06203652). Polatuzumab vedotin was given 1.8 mg/KG intravenously on day 1, zanubrutinib 160 mg twice a day orally from day 1 to day 21, and rituximab 375 mg/m2 intravenously on day 1. Twenty-one days were a cycle. If assessed complete response (CR) after 6 cycles, patients would receive zanubrutinib alone for another 6 cycles. PET/CT or contrast-enhanced CT scan was scheduled every 3 cycles. The primary end point was overall response rate (ORR) after 6 cycles. Twenty-four patients were enrolled from 01 Apr 2023 to 20 Dec 2023. Median age was 73. Sixteen (66.7%) patients had an international prognostic index score of 3 to 5. After a median follow-up of 10.2 months, the CR rate and ORR after 6 cycles was 83% and 83%. Non-responders had high total metabolic tumour volume. Lung infection was the major safety concern. PJP prophylaxis was recommended. Pola-ZR regimen showed rapid and deep response with manageable safety profiles in both GCB and non-GCB subtypes.

Lymphoma commonly presents in the head and neck. Studies on the sensitivity of core needle biopsy (CNB) in diagnosing subtypes of lymphoma are mixed. We performed a meta-analysis of the existing literature to uncover the sensitivity of CNB in diagnosing lymphoma subtypes.

PubMed, Embase by Elsevier REVIEW METHODS: Articles included examined the sensitivity of CNB by lymphoma subtype. We excluded articles that did not use CNB and lacked sufficient data. A random effect logistic regression model was used to pool sensitivity data. Pooled sensitivity estimates and corresponding 95 % confidence intervals were obtained from model estimates and all analyses were conducted at a significance of 0.05.

Screening yielded 32 articles (15 including Head and Neck nodes) with 3,027 biopsies. Across all subtypes, estimated sensitivity was 86.4 % (CI:76.1-96.7). There was significant heterogeneity among disease subtypes (p < 0.001). Chronic Lymphocytic Leukemia (CLL), Mantle Cell (MCL) and Diffuse Large B Cell (DLBCL) lymphoma exhibited highest sensitivities at 97.8 % (CI:94.2-99.1), 97.0 % (CI:92.2-98.9), and 94.5 % (CI:91.44-96.5), respectively. Low Grade B Cell not otherwise specified, Natural Killer/T cell, and Angioimmunoblastic Lymphomas demonstrated lowest sensitivities at 71.0 % (CI:44.5-88.2), 75.4 % (CI:23.0-96.9), and 77.1 % (CI:54.2-90.5), respectively.

CNB is highly sensitive in the diagnosis of some lymphoma subtypes, particularly MCL, DLBCL and CLL. Knowledge of CNB performance relative to each subtype can aid in clinical decision making, as it pertains to treatment and the need for excisional biopsy.

The GAINED study was a randomized phase 3 trial comparing obinutuzumab (G) with rituximab (R) plus ACVBP (doxorubicin, cyclophosphamide, and prednisone, combined with either vindesine or bleomycin) or CHOP14 (cyclophosphamide, doxorubicin, vincristine, and prednisone, administered on a 14-day schedule) induction, followed by positron emission tomography (PET)-guided consolidation. This post hoc analysis aimed to detail the outcomes of patients with primary mediastinal B-cell lymphoma (PMBL), verified through expert pathological review and the use of gene expression profiling (GEP) and next-generation sequencing. Of 620 centrally reviewed patients, 138 (22.3%) confirmed PMBL cases were analyzed. Baseline characteristics included a median age of 33.5 years, 63.8% female, 55.1% stage III to IV, 90.6% elevated lactate dehydrogenase, 87.6% Eastern Cooperative Oncology Group performance status score of 0 to 1, 62.3% extranodal involvement, 52.6% age-adjusted International Prognostic Index (aaIPI) of 2% to 3%, and 53.6% bulk (>10 cm). Induction regimens were R/G-CHOP14 (56.9%) and R/G-ACVBP (43.1%). Postinduction treatments, based on interim PET results, included: standard consolidation chemotherapy (59.8%) if change in maximum standardized uptake value (ΔSUVmax) of >66% after cycle 2 and >70% after cycle 4 (PET2-/4-), intensive treatment and autologous transplantation (26.8%) if PET2+/4-, and salvage therapy (13.4%) if PET4+ (ΔSUVmax of ≤70%). Among patients with GEP data (n = 107), 38 (35.5%) were PDL1high/PDL2high. Key somatic mutations data (n = 87) included SOCS1 (70.1%), B2M (56.3%), STAT6 (49.4%), TNFAIP3 (47.1%), GNA13 (39.1%), CIITA (37.9%), CD58 (36.8%), and TP53 (29.9%). After a median follow-up of 39.5 months, 2-year progression-free survival (PFS) and overall survival (OS) rates were 86.2% and 93.2%, respectively. In a multivariate model including bulk, aaIPI, and ΔSUVmax PET2/PET4, only bulk and ΔSUVmax PET4 of ≤70% were associated with shorter PFS (hazard ratio, 4.39 [95% confidence interval (CI), 1.28-15.11] and 4.95 [95% CI, 1.71-14.3], respectively), whereas none were associated with OS. The ΔSUVmax-based interim PET4 response emerged as the strongest predictor of patient outcomes in this selected clinical trial population. This trial was registered at www.ClinicalTrials.gov as #NCT01659099.

Blinatumomab is a bispecific T-cell engager approved for the treatment of relapse/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Most studies evaluating blinatumomab were conducted in Caucasian populations, with limited data available in Chinese patients. This retrospective study aims to evaluate the efficacy and safety of blinatumomab in Chinese patients with R/R B-ALL.

A total of 19 patients (10 males, 9 females) with a median age of 49 years (range: 9-66) who received blinatumomab treatment at the Aerospace Center Hospital between November 2021 and November 2024 were included. Rates of complete remission (CR) and minimal residual disease (MRD) response, 1-year overall survival (OS) and relapse-free survival (RFS), and adverse events were analyzed.

The median number of blinatumomab cycles administered was 1 (range: 1-6). Twelve (80.0%, 95% confidence interval [CI]: 51.9-95.7) of the 15 patients with overt marrow disease achieved CR, with 8 achieving MRD negativity. Four patients with < 5% blast but positive MRD all sustained CR and achieved MRD negativity. The overall MRD response rate was 63.2% (12/19, 95%CI: 38.4-83.7). The 1-year overall survival (OS) and relapse-free survival (RFS) rates were 64.2% ± 12.1% and 73.3% ± 11.4%, respectively. MRD responders had significantly better OS compared to MRD non-responders (log-rank test, P = 0.023). Of the 16 patients with CR, 62.5% proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The most frequent adverse event was cytokine release syndrome, which occurred in 11 patients (10 with grade 1-2 and 1 with grade 3 severity).

Blinatumomab is both effective and well-tolerated in Chinese patients with R/R B-ALL, achieving high rates of CR and MRD negativity and facilitating more patients' eligibility for allo-HSCT.

Histiocytic neoplasms are a diverse group of disorders arising from macrophages, dendritic cells, and monocytes of the mononuclear phagocyte system. These neoplasms encompass a clinical spectrum from indolent, self-limited, and localized conditions to highly aggressive malignancies. Since the publication of the Revised Fourth Edition of the World Health Organization (WHO) classification, advances in molecular diagnostics have improved our understanding of the pathogenesis and classification of these disorders. In contrast to the Revised Fourth Edition, the International Consensus Classification (ICC) now recognizes Rosai-Dorfman-Destombes disease as a neoplastic disorder and introduces ALK-positive histiocytosis as a distinct entity. This manuscript reviews the current concepts regarding histiocytic neoplasms, focusing on the diagnostic criteria recommended by the ICC based on histopathology, immunophenotype, molecular alterations, as well as clinical and imaging characteristics.

Adult T-cell leukaemia/lymphoma (ATLL) is a rare, aggressive haematological malignancy linked to human T-cell leukaemia virus type I (HTLV-1) and associated with poor outcomes. Despite its higher prevalence in HTLV-1-endemic regions, the relationship between clinical characteristics and patients' sociocultural background remains underexplored. We retrospectively analysed 79 ATLL patients treated at our institution (1993-2023). The median age at diagnosis was 47 years, and 72% of patients were of Caribbean origin. Median progression-free and overall survival were 10.2 and 16.2 months, respectively, with only five patients receiving allogeneic stem cell transplantation. Central nervous system (CNS) involvement at diagnosis occurred in 22% of patients and was associated with worse outcomes, while 14% experienced CNS relapse within a median of 4.9 months. Using the Ontario Marginalization Index, we found higher levels of material, household/dwelling and racialized/newcomer-related marginalization compared to the general Greater Toronto Area population, though these factors were not linked to poorer outcomes. Our findings reveal that ATLL patients in this cohort were predominantly of Caribbean descent, presented at a young age and faced significant CNS involvement and poor survival outcomes, underscoring ATLL as an unmet clinical need.

Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin's lymphoma. The applicability of circulating tumor DNA (ctDNA) for predicting treatment response and prognosis in MCL remains underexplored.

This study included 34 MCL patients receiving first-line chemoimmunotherapy. We assessed the ability of plasma ctDNA to detect tumor-specific genetic alterations and explored its potential as a noninvasive biomarker for treatment response and prognosis in MCL.

Commonly mutated genes in MCL included CCND1 (93.5%), ATM (48.4%), KMT2D (25.8%), and TP53 (25.8%). Subgroup analysis of tissue samples showed that CDKN2A mutations (P = 0.028), along with alterations in BCR and TCR signaling (P = 0.004) and the PI3K pathway (P = 0.008), were enriched in the blastoid subtype. ATM mutations (P = 0.041) were more prevalent in MIPI-low patients, while epigenetic chromatin remodeling pathway alterations (P = 0.028) were more common in MIPI-high patients. Plasma ctDNA demonstrated high sensitivity for detecting structural variants (96.6%), followed by mutations (71.3%) and copy number variants (30.0%). 75% of patients exhibited moderate-to-high concordance in detecting genomic variants between plasma and tissue samples. Pretreatment ctDNA levels exhibited high specificity in predicting clinical efficacy but had a suboptimal sensitivity of 68.2%. Higher ctDNA levels were significantly associated with shorter progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.009). Additional ctDNA-based genetic features associated with shorter PFS included TP53 (P = 0.002), TRAF2 (P = 0.023), and SMARCA4 (P = 0.023) mutations, while TP53 (P = 0.006) and TERT (P = 0.031) mutations predicted shorter OS. Persistent positive ctDNA in post-treatment plasma samples indicated molecular relapse and poor prognosis, whereas undetectable ctDNA defined a subset of patients with favorable survival outcomes.

This study identified plasma ctDNA as a promising biomarker that noninvasively captures tumor-derived genetic variants associated with treatment response and survival outcomes in MCL, highlighting the clinical value of ctDNA for diagnosis, recurrence prediction, and surveillance monitoring.

Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.

Allogeneic hematopoietic cell transplantation (alloHCT) is an effective treatment for patients with relapsed/refractory peripheral T-cell lymphoma (PTCL), but the contribution of the conditioning regimen is still unclear. Here we present a retrospective single-center study using conditioning with intermediate-dose total body irradiation (TBI) and fludarabine for alloHCT in PTCL. Forty-seven patients underwent alloHCT for PTCL between 2010 and 2023 after conditioning with fludarabine and intermediate-dose TBI (8 Gy in 87% of the cases). In most patients alloHCT was administered as part of second-line therapy, in 22 (47%) patients after having been primary refractory, and 21 (45%) of the patients were chemoresistant at alloHCT. With a median follow-up of 5.5 years, 5-year progression-free survival (PFS), overall survival, relapse incidence, and non-relapse mortality were 61%, 65%, 24%, and 15%, respectively. The 5-year PFS of patients transplanted with stable disease and progressive disease was 57% and 26%, respectively. Of 11 relapses, only 2 (18%) occurred beyond 6 months post transplant, and no relapse was observed after onset of chronic graft-versus-host disease. AlloHCT with intermediate-dose TBI/fludarabine conditioning is associated with a favorable toxicity/efficacy profile and can provide durable survival in a substantial fraction of patients with PTCL including those with poorly controlled disease at transplant.

With the advent of new therapeutic approaches, there is hope that anticancer treatment will eventually be possible without the use of chemotherapy. Efficient immunotherapeutic options have recently emerged in many cancers, offering a less aggressive approach, with overall better tolerance, making them also suitable for frail patients. Response to immunotherapy relies on the availability, functionality, and efficacy of the host's immune effector mechanisms. One of the key factors determining the efficacy of immunotherapy is the tumor microenvironment, which encompasses various immune effectors, including macrophages, which play a crucial role in regulating immune responses through phagocytosis and antigen presentation. Macrophages are prototypically divided, according to their polarization, into either the pro-inflammatory M1 type or the anti-inflammatory M2 type. In the tumor microenvironment, M2-polarized macrophages, known as tumor-associated macrophages (TAMs), are the predominant phenotype and are associated with tumor progression. The M1/M2 paradigm contributes to the understanding of tumor progression. Due to the variable microenvironment, the mechanisms regulating TAMs can vary across different cancers. Variations in TAM polarization may account for the different treatment responses in patients with similar diseases. This paper investigates the connection between TAMs, disease progression, and treatment responses in the most frequent solid hematologic cancer, diffuse large B-cell lymphoma.

Survival rates for patients with high-risk large B-cell lymphoma (LBCL), particularly those with biological risk factors, remain inadequate. We conducted a biomarker-driven phase II trial involving 123 high-risk patients aged 18-64 with LBCL. Based on their biological risk profiles, patients received either R-CHOEP-14 (without risk factors) or DA-EPOCH-R-based regimens (with risk factors). Biological high-risk factors included C-MYC translocation, C-MYC and BCL2 co-translocation, 17p/TP53 deletion, co-expression of MYC and BCL2, and P53 and/or CD5 immunopositivity. Additionally, we evaluated circulating tumor DNA (ctDNA) kinetics during therapy. Sixty-one patients (50%) were classified into biologically high-risk group. Three-year failure-free survival and overall survival rates for the entire study population were 79% and 88%, respectively. DA-EPOCH-R did not improve survival compared to our previous trial, where patients with the same biological risk factor criteria received R-CHOEP-14-based therapy. High pretreatment ctDNA levels, 17p/TP53 deletion, and TP53 mutations were associated with worse outcomes. In contrast, ctDNA negativity at the end of therapy (EOT) was indicative of a cure and effectively addressed false residual PET positivity. The findings demonstrate promising survival for high-risk LBCL patients, aside from those with TP53 aberrations, high ctDNA levels, and/or EOT ctDNA positivity.

Traditional B-cell mitogens often fail to promote effective cell division in vitro for mature B-cell neoplasms, hindering chromosome analysis. The combination of DSP30 and IL-2 (DSP30/IL-2) has been suggested as a better alternative. This review evaluates DSP30/IL-2 efficiency using a systematic review and meta-analysis of 20 studies. Studies comparing the successful culture rate (SCR) and/or abnormalities detection rate (ADR) of DSP30/IL-2 against traditional mitogens and/or fluorescence in situ hybridization (FISH) were included. Subgroup analyses were performed for cases of chronic lymphocytic leukemia (CCL) and other B-cell neoplasms (OBCN). The findings show no significant difference in SCR between DSP30/IL-2 and traditional mitogens, but DSP30/IL-2 significantly increases ADR. However, DSP30/IL-2's ADR is lower than that of FISH. Analyses by CLL and OBCN subgroups showed similar results. Overall, DSP30/IL-2 is a superior alternative for cytogenetic studies in mature B-cell neoplasms.

The development of new first-line treatments for patients with follicular lymphoma (FL) is becoming increasingly challenging due to already excellent survival outcomes. The present study investigated the outcomes of patients with FL who underwent contemporary first-line therapies but would not have been eligible for inclusion in recent trials and explored how commonly used in/exclusion criteria impacted their survival outcomes. This study included adult patients diagnosed with FL in the period 2000-2018 registered in the Danish Lymphoma Registry. Through searches on ClinicalTrials.gov, four recent 1st line phase 3 randomized controlled trials with R-Bendamustine, R-CVP, and/or R-CHOP as control or experimental arms were included. Inclusion and exclusion criteria for each trial were retrieved and categorized. Patients were then divided into trial-eligible and ineligible groups according to blood test results correlated to organ function and ECOG performance score (PS). Survival outcomes were significantly worse among trial-ineligible patients, with adjusted differences between trial-eligible and ineligible patients of 12%-20% in five-year overall survival (OS) overall. Inclusion criteria based on PS and renal function were the main drivers of OS differences. More inclusive trials will lead to faster recruitment and secure focus on developing medicines for the group of patients with the worst outcomes.

Large/aggressive B-cell lymphomas are diverse both in terms of clinical presentations and treatment response. Diagnostic pathologic evaluation typically begins with a CD20/CD3 immunohistochemical panel. Prebiopsy steroid treatment has been reported to delay diagnosis and subsequent treatment due to altering histomorphology and immunohistochemical staining patterns. This study investigates the impact of prebiopsy steroid use on morphology and immunohistochemical staining patterns in large B cell lymphoma and/or mature B cell lymphomas with high Ki67 expression. Fourteen cases of B cell lymphoma treated with prebiopsy steroids and 13 cases of treatment-naive large B cell lymphoma and/or mature B cell lymphomas with high Ki67 expression were included in this study. Clinicopathological parameters, including type, dose, and route of steroid administration, were documented. Histopathologic slides from both groups were examined to assess morphology and immunohistochemical staining patterns. Morphologically significant effects attributable to steroid administration included significant histiocytic infiltrate and lack of diffuse pattern of infiltration of the lymphoma cells. The CD20 staining pattern, characterized by cytoplasmic/granular distribution and extracellular spillage, showed a statistically significant increase in the steroid group compared with the control group ( P =0.011). This alteration was more prevalent among patients treated with intravenous dexamethasone, high-dose corticosteroids over a short term, and with shorter dosing intervals. Prebiopsy corticosteroid administration induces changes in histomorphology and immunohistochemical staining patterns, particularly affecting CD20, thereby posing diagnostic challenges. The extent of these effects varies depending on the type, route, dosage, and duration of steroid administration.

Classic Hodgkin lymphoma (cHL) exhibits a bimodal age distribution with incidence peaks in adolescents and young adults (AYAs) aged 15-39 years and in older adults over 50 years. The unique biology of cHL, characterized by a tumor microenvironment (TME) composed predominantly of non-malignant immune and stromal cells, plays a pivotal role in supporting Hodgkin and Reed-Sternberg (HRS) cells, the malignant cells of cHL. Understanding the role of the TME in cHL and its age-related differences is crucial for deciphering differential disease etiologies and developing biomarker-driven targeted therapies. Recent technical advances in single-cell sequencing and multiplexed spatial imaging have revealed age-related differences in TME composition and function, including key cellular interactions, leading to the development of age-specific prognostic indicators. In addition, advances in our ability to isolate nucleic acids from HRS cells have accelerated our understanding of the molecular alterations in cHL, many of which drive interactions within the TME. Molecular differences in cHL between pediatric/AYA and older adult patients have also emerged. This review summarizes the unique biology of cHL and its TME in children, adolescents, and young adults, highlighting recent breakthroughs in our understanding of cHL biology, differences across the age spectrum, and advances in biomarker development.

Primary central nervous system lymphoma (PCNSL) exhibits substantial intratumoural and intertumoural heterogeneity, complicating the development of effective treatment methods. Existing in vitro models fail to simulate the cellular and mutational diversity of native tumours and require prolonged generation times. Therefore, we developed a culture method for patient-derived PCNSL organoids (CLOs) and evaluated the organoids through extensive molecular characterisation, histopathological analysis, single-nucleus RNA sequencing, bulk RNA sequencing and whole-exome sequencing. These CLOs accurately mimicked the histological attributes, gene expression landscapes and mutational profiles of their original tumours. Single-nucleus RNA sequencing also revealed that CLOs maintained cell-type heterogeneity and the molecular signatures of their original tumours. CLOs were generated within 2 weeks, demonstrating rapid development and reliability. Therapeutic profiling was performed on three selected CLOs treated with four standard drugs. The CLOs exhibited specific sensitivity to methotrexate, and resistance to dexamethasone, ibrutinib and rituximab, suggesting that CLOs may be valuable tools for reflecting drug sensitivities. Taken together, these results emphasise that CLOs effectively emulate the key characteristics of PCNSL, increasing the understanding of the genetic landscape of this complex disease. CLOs provide a rapid and reliable platform for exploring individualised treatment strategies, potentially accelerating the transition of research findings to clinical practice.

Waldenström Macroglobulinaemia (WM) is sometimes difficult to differentiate from marginal zone lymphoma (MZL), two entities with overlapping features for which no single marker assessed by multiparameter flow cytometry (MFC) is specific. The aim of this work was to establish a diagnostic phenotypic score for bone marrow (BM) and peripheral blood (PB) WM samples, to differentiate it from MZL and to improve the detection of small circulating WM clones. This study revealed a distinct phenotypic profile between WM and MZL B-cells. WM B-cells showed decreased expression of CD19, FMC7, CD22, CD27 and increased expression of CD79b and CD13. Supervised and unsupervised MFC analyses were used to define a phenotypic scoring system: a score of 3/6 or greater in BM or 4/7 or greater in PB samples supported the diagnosis of WM (sensitivity of 97.9% and 94.1% and specificity of 80.0% and 93.5%, respectively). These results were validated in a prospective cohort with very high sensitivity and specificity for the two scoring systems. Clinico-biological correlations showed that the absence or low expression of CD38 on BM WM B-cells was significantly associated with increased BM and PB infiltration (p < 0.0001 and p = 0.0024 respectively) and CXCR4 mutation (p < 0.0001). These results demonstrate that MFC can be used to differentiate WM from MZL with a scoring system that can be easily implemented in routine practice.