Identification, risk factors, and clinical course of CNS relapse in DLBCL patients across 19 prospective phase 2 and 3 trials-a LYSA and GLA/ DSHNHL collaboration.

Progression or relapse in the central nervous system (CNS) remains a rare but mostly fatal event for patients with diffuse large B-cell lymphoma (DLBCL). In a retrospective analysis of 5189 patients treated within 19 prospective German and French phase 2/3 trials, we identified 159 patients experiencing a CNS event (relapse: 62%, progression: 38%). Intracerebral, meningeal, intraspinal, or combined involvement was reported in 44%, 31%, 3%, and 22% of patients, respectively. 62 of 155 evaluable patients (40%) showed concurrent systemic progression/ relapse. 82% of all CNS events occurred within two years after study inclusion or randomization. 87% of patients showed extranodal involvement outside the CNS. Patients generally had poor outcomes with a median overall survival (OS) of 3.4 months (95% CI 2.9-4.2) and a 2-year OS of 15% (10-22%). Outcomes did not differ depending on the site or time point of CNS events. Patients with isolated CNS events demonstrated significantly better OS (p = 0.023). Twenty-five patients were consolidated with autologous or allogeneic stem cell transplantation and achieved a 3-year OS of 36% (20-66%). This large study including more than 5000 DLBCL patients highlights the unmet medical need to improve the outcome of DLBCL patients suffering from CNS relapse.

Quality of life assessment in diffuse large B-cell lymphoma (DLBCL) in REFLECT: a prospective, non-interventional, multicenter, German study, assessing Sandoz rituximab in combination with CHOP.

Health-related quality of life (HRQoL) data are important indicators of health status in patients with lymphoma. The objective of this analysis was to assess the impact of treatment with Sandoz rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) on HRQoL in treatment-naïve adult patients with diffuse large B-cell lymphoma (DLBCL) included in the prospective, real-world REFLECT study. REFLECT is the first prospective study to assess HRQoL in patients with DLBCL treated with a rituximab biosimilar. HRQoL was assessed via the patient-reported European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire at baseline, mid-treatment (month 3), end of treatment (month 6), and follow-up (months 9 and 12). Subgroup analyses were performed to evaluate the influence of baseline characteristics on HRQoL, and associations between baseline HRQoL and treatment response. HRQoL was assessed in 169 patients. Mean global health status score remained stable from baseline (54.8) to mid-treatment (month 3; 54.7), before steadily improving through to end of treatment (month 6; 61.4), and follow-up month 9 (64.9) and month 12 (68.8). Similar trends were observed across most functional and symptom subscales. Higher cognitive, physical, or role functioning, and less appetite loss, diarrhea, fatigue, or pain at baseline, were all associated with an improved likelihood of reaching a complete versus partial response at the end of treatment. Overall, these findings confirm the HRQoL benefits of R-CHOP therapy in treatment-naïve adult patients with DLBCL, and suggest that baseline HRQoL may be predictive of treatment response.

Early blast clearance during sequential conditioning prior to allogeneic stem cell transplantation in patients with acute myeloid leukaemia.

For patients with relapsed or refractory AML, sequential conditioning prior to allogeneic stem cell transplantation (alloSCT) is an established and potentially curative treatment option. Early response to treatment during conditioning indicates chemotherapy-responsive disease and may have prognostic value. We retrospectively evaluated blast clearance on day 5 after melphalan, administered 11 days prior to alloSCT as part of a sequential conditioning in 176 patients with active AML. Overall survival (OS) was 52% (95% confidence interval [CI] 45%-60%), and relapse-free survival (RFS) was 47% (95% CI 40%-55%) at 3 years. Patients who achieved early blast clearance did not show a significant improvement in OS and RFS (OS, hazard ratio [HR] HR 0.75, p 0.19; RFS, HR 0.71, p 0.09, respectively), but had a significantly lower non-relapse mortality rate (HR 0.46, p 0.017). HLA-mismatched donor, older age, adverse genetic risk and higher comorbidity scores were associated with inferior survival outcomes. A high initial blast count was only associated with inferior prognosis in patients receiving chemotherapy-only compared to total body irradiation containing conditioning therapy. These results indicate that for patients transplanted with active AML, sensitivity to chemotherapy might be of less importance, compared to other disease- and transplant-related factors.

Comparable outcomes for TBI-based versus treosulfan based conditioning prior to allogeneic hematopoietic stem cell transplantation in AML and MDS patients.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a standard treatment for patients with AML and MDS. The combination of fractionated total body irradiation(8GyTBI/Flu) with fludarabine is an established conditioning regimen, but fludarabine/treosulfan(Flu/Treo) constitutes an alternative in older/comorbid patients. We conducted a retrospective analysis of 215 AML(in CR) and 96 MDS patients undergoing their first allo-HCT between 2011 and 2022, identifying 53 matched Flu/Treo and 8GyTBI/Flu patients through propensity score matching. Median follow-up of survivors was 3.3 years and 4.1 years. For the Flu/Treo group, 1-year non-relapse mortality (2% vs. 10%, p = 0.03) was lower, while 1-year relapse incidence (16% vs. 13%, p = 0.81) was similar. Three-year outcomes, including relapse-free survival and graft-versus-host disease incidence, were comparable (OS: 81% vs. 74%, p = 0.70; RFS: 78% vs. 66%, p = 0.28; chronic GvHD: 34% vs. 36%, p = 0.97; acute GvHD (100 days): 11% vs. 23%, p = 0.11). Multivariable analysis, considering age, ECOG, HCT-CI, and MRD status, revealed no associations with main outcomes. Dose-reduced conditioning with Flu/Treo or 8GyTBI/Flu demonstrated favorable and comparable survival rates exceeding 70% at 3 years with 1-year NRM rates below 10% and low relapse rates in the matched cohort. These data underline the need for further evaluation of TBI and Treo-based conditionings in prospective trials.

Outcomes of pirtobrutinib for relapsed/refractory mantle cell lymphoma in compassionate use program in Europe.

BACKGROUND: Mantle cell lymphoma (MCL) is a type of B-cell lymphoma that is currently incurable. Pirtobrutinib shows promising response rates in heavily pretreated MCL patients according to the approval study, but the real-world data are scarce. METHODS: In this study, we retrospectively analyzed the efficacy and safety profile of pirtobrutinib in 10 relapsed/refractory MCL patients from compassionate use program (CUP). RESULTS: On average, the patients underwent three lines of systemic therapy prior to pirtobrutinib and were predominantly BTKi exposed (9/10). The best overall response rate (BORR) was 67%. In a median follow-up of 8.6 months, the mean duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were not reached. No new safety signals were documented. CONCLUSIONS: In summary, pirtobrutinib represented a safe and effective treatment option in a small real-world population.

Chimeric antigen receptor-T cell therapy shows similar efficacy and toxicity in patients with diffuse large B-cell lymphoma aged 70 and older compared to younger patients: A multicenter cohort study.

CD19-directed chimeric antigen receptor (CAR)-T cell therapy has become a standard treatment for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). While the benefits of CAR-T cell treatment are clear in the general patient population, there remains a relative scarcity of real-world evidence regarding its efficacy and toxicity in patients (pts) aged ≥70 years with DLBCL. We conducted a multicenter retrospective analysis including 172 r/r DLBCL pts with CAR-T cell treatment, axicabtagene ciloleucel or tisagenlecleucel, between 2019 and 2023 at three tertiary centers. Pts were grouped by age at CAR-T infusion (<70 vs. ≥70 years). Subsequently, descriptive and survival analyses, including propensity score matching, were performed to compare outcomes between both age groups. We identified 109 pts aged <70 and 63 pts aged ≥70 years. Overall response rates for both age groups were comparable (77.7% vs. 78.3%; p = 0.63). With a median follow-up of 8.3 months, median progression-free survival was 10.2 months (95% confidence interval [CI]: 6.5-21.8) and 11.1 months (95% CI: 4.9-NR) (p = 0.93) for both cohorts. Median overall survival reached 21.8 months (95% CI: 11.8-NR) and 34.4 months (95% CI: 10.1-NR) (p = 0.97), respectively. No significant differences in the incidence of cytokine release syndrome (p = 0.53) or grade ≥3 neurotoxicity (p = 0.56) were observed. Relapse and nonrelapse mortality were not significantly different between both groups. Our findings provide additional support that CAR-T cell therapy is feasible and effective in patients with r/r DLBCL aged 70 years or older, demonstrating outcomes comparable to those observed in younger patients. CAR-T cell therapy should be not withheld for elderly patients with r/r DLBCL.

Epigenetic control over the cell-intrinsic immune response antagonizes self-renewal in acute myeloid leukemia.

ABSTRACT: Epigenetic modulation of the cell-intrinsic immune response holds promise as a therapeutic approach for leukemia. However, current strategies designed for transcriptional activation of endogenous transposons and subsequent interferon type-I (IFN-I) response, show limited clinical efficacy. Histone lysine methylation is an epigenetic signature in IFN-I response associated with suppression of IFN-I and IFN-stimulated genes, suggesting histone demethylation as key mechanism of reactivation. In this study, we unveil the histone demethylase PHF8 as a direct initiator and regulator of cell-intrinsic immune response in acute myeloid leukemia (AML). Site-specific phosphorylation of PHF8 orchestrates epigenetic changes that upregulate cytosolic RNA sensors, particularly the TRIM25-RIG-I-IFIT5 axis, thereby triggering the cellular IFN-I response-differentiation-apoptosis network. This signaling cascade largely counteracts differentiation block and growth of human AML cells across various disease subtypes in vitro and in vivo. Through proteome analysis of over 200 primary AML bone marrow samples, we identify a distinct PHF8/IFN-I signature in half of the patient population, without significant associations with known clinically or genetically defined AML subgroups. This profile was absent in healthy CD34+ hematopoietic progenitor cells, suggesting therapeutic applicability in a large fraction of patients with AML. Pharmacological support of PHF8 phosphorylation significantly impairs the growth in samples from patients with primary AML. These findings provide novel opportunities for harnessing the cell-intrinsic immune response in the development of immunotherapeutic strategies against AML.

Radiotherapy in younger patients with advanced aggressive B-cell lymphoma-long-term results from the phase 3 R-MegaCHOEP trial.

The role of consolidative radiotherapy (RT) for patients with aggressive B-cell lymphoma has not been fully elucidated. The R-MegaCHOEP trial investigated the use of high-dose chemotherapy and rituximab with subsequent autologous stem cell transplantations compared to conventional immunochemotherapy (R-CHOEP) for high-risk patients up to 60 years. The study protocol included RT for patients with bulky (maximum diameter ≥7.5 cm) or extranodal disease. Two-hundred sixty-one patients were analyzed, 120 of whom underwent RT. The most frequently irradiated regions were mediastinum (n = 50) and paraaortic (n = 27). Median RT dose was 36 Gray in median fractions of 1.8 Gray. Acute toxicities were mostly mild to moderate, with only 24 and 8 grade 3 and 4 toxicities reported during RT. Patients with bulky disease who received RT showed significantly better 10-year EFS, PFS and OS (EFS: 64% vs. 35%; p < 0.001; PFS 68% vs. 47%; p = 0.003; OS: 72% vs. 59%; p = 0.011). There was no significant increase in secondary malignancies with the use of RT. RT administered for consolidation of bulky disease after immunochemotherapy improved the prognosis of young high-risk patients with aggressive B-cell lymphoma and should be considered part of first-line therapy. The trial was registered with ClinicalTrials.gov, number NCT00129090.

PD-L1 on large extracellular vesicles is a predictive biomarker for therapy response in tissue PD-L1-low and -negative patients with non-small cell lung cancer.

Immunotherapy has revolutionized the treatment of patients with non-small cell lung cancer (NSCLC). High expression of tissue PD-L1 (tPD-L1) is currently the only approved biomarker for predicting treatment response. However, even tPD-L1 low (1-49%) and absent (<1%) patients might benefit from immunotherapy but, to date, there is no reliable biomarker, that can predict response in this particular patient subgroup. This study aimed to test whether tumour-associated extracellular vesicles (EVs) could fill this gap. Using NSCLC cell lines, we identified a panel of tumour-related antigens that were enriched on large EVs (lEVs) compared to smaller EVs. The levels of lEVs carrying these antigens were significantly elevated in plasma of NSCLC patients (n = 108) and discriminated them from controls (n = 77). Among the tested antigens, we focused on programmed cell death ligand 1 (PD-L1), which is a well-known direct target for immunotherapy. In plasma lEVs, PD-L1 was mainly found on a population of CD45- /CD62P+ lEVs and thus seemed to be associated with platelet-derived vesicles. Patients with high baseline levels of PD-L1+ lEVs in blood showed a significantly better response to immunotherapy and prolonged survival. This was particularly true in the subgroup of NSCLC patients with low or absent tPD-L1 expression, thus identifying PD-L1-positive lEVs in plasma as a novel predictive and prognostic marker for immunotherapy.

Prevalence and clinical impact of CD56 and T-cell marker expression in acute myeloid leukaemia: A single-centre retrospective analysis.

Flow cytometry-based immunophenotyping is a mainstay of diagnostics in acute myeloid leukaemia (AML). Aberrant CD56 and T-cell antigen expression is observed in a fraction subset of AML cases, but the clinical relevance remains incompletely understood. Here, we retrospectively investigated the association of CD56 and T-cell marker expression with disease-specific characteristics and outcome of 324 AML patients who received intensive induction therapy at our centre between 2011 and 2019. We found that CD2 expression was associated with abnormal non-complex karyotype, NPM1 wild-type status and TP53 mutation. CD2 also correlated with a lower complete remission (CR) rate (47.8% vs. 71.6%, p = 0.03). CyTdT and CD2 were associated with inferior 3-year event-free-survival (EFS) (5.3% vs. 33.5%, p = 0.003 and 17.4% vs. 33.1%, p = 0.02, respectively). CyTdT expression was also correlated with inferior relapse-free survival (27.3% vs. 48.8%, p = 0.04). In multivariable analyses CD2 positivity was an independent adverse factor for EFS (HR 1.72, p = 0.03). These results indicate a biological relevance of aberrant T-cell marker expression in AML and provide a rationale to further characterise the molecular origin in T-lineage-associated AML.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001-2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

Comparison of antibody-based immunotherapeutics for malignant hematological disease in an experimental murine model.

ABSTRACT: Antibody-based immunotherapies have revolutionized leukemia and lymphoma treatment, with animal studies being crucial in evaluating effectiveness and side effects. By targeting the evolutionary conserved Slamf7 immune receptor, which is naturally expressed by the murine multiple myeloma cell line MPC-11, we have developed a syngeneic mouse model for direct comparison of 3 immunotherapies: monoclonal antibodies (mAb), bispecific T-cell engagers (BiTE), and chimeric antigen receptor (CAR) T cells (CART), all targeting Slamf7. Slamf7-BiTE is a bispecific single-chain antibody consisting of α-Slamf7 and α-CD3 Fv fragments joined through a Gly-Ser linker, and Slamf7-CART comprises the α-Slamf7 Fv fragment fused to the msCD8α transmembrane and msCD28, 4-1BB, and CD3ζ intracellular signaling domains. Slamf7-BiTE and Slamf7-CART effectively killed MPC-11 cells in vitro, independently of Slamf7-mediated inhibitory signaling by self-ligation. After chimerizing the constant region of the rat-anti-mouse Slamf7 antibody to mouse Fc-immunoglobulin G2a for enhanced effector functions, Slamf7-mAb triggered antigen-specific antibody-dependent cellular cytotoxicity by binding to Fcγ receptor IV. In vivo, all 3 immunotherapies showed antitumor effects against Slamf7-expressing targets. Unlike Slamf7-mAb, Slamf7-BiTE led to considerable side effects in test animals, including weight loss and general malaise, which were also observed to a lesser extent after Slamf7-CART infusion. In allogeneic transplant, Slamf7-BiTE and Slamf7-CART maintained activity compared with the nontransplant setting, whereas Slamf7-mAb displayed enhanced antimyeloma activity. In summary, our model faithfully replicates treatment efficacy and side effects detected after human immunotherapy. It aids in developing and improving immunotherapies and may help devise novel approaches to mitigate undesired effects in steady state and allogeneic stem cell transplantation.

CXCR4-targeted Theranostics in Hematooncology: Opportunities and Challenges.

C-X-C motif chemokine receptor 4 (CXCR4) is overexpressed in a multitude of cancers, including neoplasms of hematopoietic origin. This feature can be leveraged by a theranostic approach, which provides a read-out of the actual CXCR4 expression in vivo, followed by CXCR4-targeted radioligand therapy (RLT) exerting anti-cancer as well as myeloablative efficacy. In a recent meeting of hematooncology and nuclear medicine specialists, statements on the current clinical practice and future perspectives of this innovative concept were proposed and summarized in this opinion article. Experts concluded that i) CXCR4-directed [68Ga]Ga-PentixaFor PET/CT has the potential to improve imaging for patients with marginal zone lymphoma; ii) CXCR4-targeted RLT exerts anti-lymphoma efficacy and myeloablative effects in patients with advanced, treatment-refractory T-cell lymphomas; iii) prospective trials with CXCR4-based imaging and theranostics are warranted.

Inotuzumab Ozogamicin as Induction Therapy for Patients Older Than 55 Years With Philadelphia Chromosome-Negative B-Precursor ALL.

PURPOSE: Despite recent advances in adapting the intensity of treatment for older patients with ALL, current protocols are associated with high rates of early deaths, treatment-related toxicity, and dismal prognosis. We evaluated inotuzumab ozogamicin and dexamethasone (Dex) as induction therapy in older patients with ALL within the German Multicenter Study Group for Adult ALL (GMALL). PATIENTS AND METHODS: The open-label, multicenter, phase II, INITIAL-1 trial enrolled 45 patients older than 55 years with newly diagnosed, CD22-positive, BCR::ABL-negative B-precursor ALL (B-ALL). Patients received up to three cycles of inotuzumab ozogamicin/Dex and up to six cycles of age-adapted GMALL consolidation and maintenance therapy. RESULTS: Forty-three evaluable patients with common/pre-B (n = 38) and pro-B ALL (n = 5), with a median age of 64 years (range, 56-80), received at least two cycles of inotuzumab ozogamicin induction therapy. All patients achieved complete remission (CR/CR with incomplete hematologic recovery). Twenty-three (53%) and 30 (71%) patients had no evidence of molecularly assessed measurable residual disease (minimum 10e-4 threshold) after the second and third inductions, respectively. After a median follow-up of 2.7 years, event-free survival at one (primary end point) and 3 years was 88% (95% CI, 79 to 98) and 55% (95% CI, 40 to 71), while overall survival (OS) was 91% (95% CI, 82 to 99) and 73% (95% CI, 59 to 87), respectively. None of the patients died during 6 months after the start of induction. Most common adverse events having common toxicity criteria grade ≥3 during induction were leukocytopenia, neutropenia, thrombocytopenia, anemia, and elevated liver enzymes. One patient developed nonfatal veno-occlusive disease after induction II. CONCLUSION: Inotuzumab ozogamicin-based induction followed by age-adapted chemotherapy was well tolerated and resulted in high rates of remission and OS. These data provide a rationale for integrating inotuzumab ozogamicin into first-line regimens for older patients with B-ALL.

Deep learning predicts therapy-relevant genetics in acute myeloid leukemia from Pappenheim-stained bone marrow smears.

ABSTRACT: The detection of genetic aberrations is crucial for early therapy decisions in acute myeloid leukemia (AML) and recommended for all patients. Because genetic testing is expensive and time consuming, a need remains for cost-effective, fast, and broadly accessible tests to predict these aberrations in this aggressive malignancy. Here, we developed a novel fully automated end-to-end deep learning pipeline to predict genetic aberrations directly from single-cell images from scans of conventionally stained bone marrow smears already on the day of diagnosis. We used this pipeline to compile a multiterabyte data set of >2 000 000 single-cell images from diagnostic samples of 408 patients with AML. These images were then used to train convolutional neural networks for the prediction of various therapy-relevant genetic alterations. Moreover, we created a temporal test cohort data set of >444 000 single-cell images from further 71 patients with AML. We show that the models from our pipeline can significantly predict these subgroups with high areas under the curve of the receiver operating characteristic. Potential genotype-phenotype links were visualized with 2 different strategies. Our pipeline holds the potential to be used as a fast and inexpensive automated tool to screen patients with AML for therapy-relevant genetic aberrations directly from routine, conventionally stained bone marrow smears already on the day of diagnosis. It also creates a foundation to develop similar approaches for other bone marrow disorders in the future.

CAR-T Cell Therapy Shows Similar Efficacy and Toxicity in Patients With DLBCL Regardless of CNS Involvement.

Efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement remain understudied. Here we analyzed the outcomes of CAR-T cell therapy in r/r DLBCL patients with CNS involvement and compared them with patients without CNS disease. Retrospective and monocentric comparative analysis of patient cohort with r/r DLBCL treated with CAR-T cell therapy: 15 patients with CNS versus 65 patients without CNS involvement. Overall response rates (80% versus 80%; P = 1.0), progression-free survival (P = 0.157), and overall survival (P = 0.393) were comparable for both cohorts. The frequency of cytokine release syndrome was comparable in the CNS and non-CNS cohorts; 93% versus 80%; P = 1.0. Numerically, immune effector-cell-associated neurotoxicity syndrome (all grades) was more frequent in patients with CNS manifestation (53% versus 29%; P = 0.063), although no grade 4 events were documented. Our study suggests that CAR-T cell therapy is effective and feasible in patients with r/r DLBCL and CNS manifestation.

Involved-Site Radiation Therapy Enables Effective Disease Control in Parenchymal Low-Grade Primary Cerebral Lymphoma.

BACKGROUND: Primary lymphoma of the central nervous system (PCNSL) encompasses a variety of lymphoma subtypes, with the majority being diffuse large B-cell lymphomas, which require aggressive systemic treatment. In contrast, low-grade lymphomas are reported infrequently and are mostly limited to dural manifestations. Very rarely, parenchymal low-grade PCNSL is diagnosed, and the cases documented in the literature show a wide variety of treatment approaches. METHODS: We screened all cases of PCNSL treated at our department (a tertiary hematooncology and neurooncology center) in the last 15 years and conducted a comprehensive literature research in the PubMed database. RESULTS: Overall, two cases of low-grade primary parenchymal PCNSL treated with irradiation were identified. The dose prescriptions ranged from 30.6 to 36 Gy for the involved site, with sparing of the hippocampal structures. Both patients had an excellent response to the treatment with a mean follow-up of 20 months. No clinical or radiological signs of treatment toxicity were detected. CONCLUSIONS: Our analysis corroborates the results from the literature and demonstrates that parenchymal low-grade PCNSL shows a good response to localized radiation treatment, enabling a favorable outcome while avoiding long-term treatment toxicity.

Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination.

The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.

Transcriptional reprogramming by mutated IRF4 in lymphoma.

Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.