The B-cell receptor (BCR) is critical for mature B-cell lymphomas (BCL), serving as a therapeutic target. We show that high-grade BCLs with MYC and BCL2 rearrangements [HGBCL–double-hit (DH)–BCL2] predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) tumors differ from IGH+ counterparts in germinal center (GC) zone programs, MYC expression, and immune infiltrate. Whereas IGH+ HGBCL-DH-BCL2 tumors favor IGM/IG-κ expression, IGHUND counterparts complete IGH isotype switching and IG-λ rearrangements. IGHUND lymphomas retain productive IGHV rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/IGL::MYC translocations. IGHUND HGBCL-DH-BCL2 models exhibit reduced sensitivity to the CD79B-targeting antibody–drug conjugate polatuzumab vedotin. Collectively, HGBCL-DH-BCL2 commonly arises from isotype-switched t(14;18)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications. Significance: These findings link BCR silencing in IGH isotype-switched t(14;18)+ GC B cells to RAG1/2 expression, which triggers IG light chain editing and predisposes to IGL::MYC translocations, promoting HGBCL. In HGBCL with MYC and BCL2 rearrangements, BCR silencing protects from polatuzumab vedotin killing. See related commentary by Shevchenko and Hodson, p. 284

Background: This study aimed to evaluate whether baseline 2-deoxy-2-[18F]-fluoro-D-glucose (2-[ ¹⁸ F]FDG) positron emission tomography/computed tomography (PET/CT) features reflecting tumor burden (Metabolic Tumor Volume [MTV] and Total Lesion Glycolysis [TLG]) and disease dissemination (Dmax) can predict treatment response and prognosis in patients with Hodgkin Lymphoma (HL). Methods: A retrospective single-center study was conducted on 361 classical HL consecutively diagnosed and treated with ABVD from January 2007 to June 2023. All patients underwent baseline, interim (iPET), and end-of-treatment (eotPET) PET/CT scans. Baseline MTV, TLG, and Dmax were calculated using specialized software (LIFEx 7.7). Treatment response was evaluated using Deauville scores and corresponding Lugano criteria. The primary endpoint was to evaluate the role of PET features in predicting progression-free survival (PFS). PFS was analyzed using Kaplan-Meier and Cox proportional hazards models. Results: Baseline MTV, TLG, and Dmax were significantly higher in patients who failed to achieve a complete metabolic response at both interim and end-of-treatment assessments ( p < 0.001). Multivariate analysis identified iPET metabolic response, eotPET metabolic response and baseline MTV, TLG, and Dmax as independent prognostic factors for PFS. Combining MTV and Dmax allowed for better risk stratification; Patients with both low MTV(≤ 111 cm ³ ) and low Dmax (≤ 38 cm) had a median 5-year PFS of 90%, compared to 39% for those with both high MTV and high Dmax. Conclusions: Baseline 2-[18 F]FDG PET/CT metabolic parameters expressing tumor burden and dissemination are strong, independent predictors of treatment response and prognosis in HL. Integrating these features provides a robust method for early risk stratification.

Along with the fact that classical Hodgkin lymphoma (cHL) in older adults is frequently considered biologically different from cHL in younger patients, its most distinctive feature is its dismal clinical outcome due to the decreased effectiveness and greater toxicity of therapies. Although strategies to mitigate specific toxicities (e.g., cardiological and pulmonary) have obtained some results, in general, reduced-intensity schemes, proposed as an alternative to ABVD, have proved to be less effective. The addition of brentuximab vedotin (BV) to AVD, especially in a sequential scheme, has demonstrated good efficacy. However, the problem of toxicity persists even with this new therapeutic combination, with comorbidities remaining an important prognostic factor. The adequate stratification of functional status is necessary to distinguish between those patients who will benefit from full treatment and those who will benefit from alternative strategies. A simplified geriatric assessment based on the determination of ADL (activity of daily living), IADL (instrumental ADL), and CIRS-G (Cumulative Illness Rating Scale—Geriatric) scores is an easy-to-use tool that permits adequate patient stratification. Other factors of considerable impact on functional status such as sarcopenia and immunosenescence are currently being studied. A fitness-based treatment choice would also be very useful for relapsed or refractory patients, a more frequent and challenging situation than that is found in young cHL patients.

Background: Hematological patients have a high risk of developing severe COVID-19 (37%). Most mRNA vaccine trials in hematological patients showed a low immunogenicity after two doses, while long-term data are scarce. Methods: In this monocentric retrospective observational study, we evaluated humoral and T cell-mediated immune responses in 230 hematological patients after three doses of the Pfizer-BioNTech mRNA COVID-19 vaccine. Patients were stratified by age, disease type/state, prior COVID-19 infection, and treatment status and regimens (anti-CD20 monoclonal antibodies, BTK and BCL-2 inhibitors, and treatment line). Antibody titer to SARS-CoV-2 was assessed by electrochemiluminescence immunoassay and T cell response by QuantiFERON interferon-γ release assay (IGRA). Data were analyzed using univariate (Fisher’s exact test) and Firth’s bias-reduced penalized-likelihood logistic regression. Results: A robust humoral response was observed with 91.55% of patients developing anti-spike antibodies (GMT 988.83 U/mL). Anti-CD20-bendamustine treatment was associated with a significantly lower antibody positivity compared to untreated subjects. Prior COVID-19 infection significantly boosted both antibody positivity (95.9% vs. 85.2%) and GMT (847.02 U/mL vs. 258.79 U/mL). Conversely, T cell response was suboptimal (36.1% positive), particularly in anti-CD20-bendamustine-treated and multi-treated patients (27.1%), but highest in those treated with BTK inhibitors (50%). Multivariable logistic regression analysis linked multiple treatments to lower T cell response. Following vaccination, 29.1% of patients contracted SARS-CoV-2, but only 0.89% developed severe COVID-19. Conclusions: Three doses of mRNA vaccine elicit a strong humoral but a low T cell response, as detected by IGRA, in hematological patients. These findings underscore the importance of completing vaccination before initiating immunosuppressive therapies.

IGG transcript a protein analyses in HGBCL-DH-BCL2(-BCL6) cell lines and HEK293T cells before and after complementation with IG expression vectors

Supplementary Table S7 from B-cell Receptor Silencing Reveals the Origin and Dependencies of High-Grade B-cell Lymphomas with MYC and BCL2 Rearrangements