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Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure. Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis was used to identify a signature associated with high risk of early clinical failure independent of IPI and COO. Further analysis revealed the signature was associated with metabolic reprogramming and identified cases with a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion of ARID1A mutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts. This novel and integrative approach is the first to identify a signature at diagnosis, in a real-world cohort of DLBCL, that identifies patients at high risk for early clinical failure and may have significant implications for design of therapeutic options., (© 2024. The Author(s).)

RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival. From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892). Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL. CLINICAL TRIAL REGISTRATION: NCT04697160 (January 6, 2021)., (© 2023. The Author(s).)

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL)., Patients and Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes., Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003)., Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908., (©2022 The Authors; Published by the American Association for Cancer Research.)

The molecular classification of diffuse large B cell lymphoma has paved the way for precision medicine that targets oncogenic driver pathways and actionable mutations. In this issue of Cancer Cell, Wilson et al. execute a massive genomic analysis in order to identify putative molecular signatures linked to a differential response to ibrutinib plus R-CHOP., Competing Interests: Declaration of interests P.M. reports no conflicts of interest. S.M.A. receives research funding (to his institution) for clinical trials from Bristol Myers Squibb, Takeda, SeaGen, Affimed, Regeneron, Trillium, and ADC Therapeutics., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Although methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.

Purpose of Review: Recent years have seen the development of gene expression profiling and next-generation sequencing in diffuse large B cell lymphoma (DLBCL), leading to a more defined characterization of this disease into distinct subentities. The genomic era has ushered in the possibility of using precision guided therapy, in part based on targeting genes with somatic mutations. Such precision-targeted therapies will ultimately reduce the need for chemotherapy, induce fewer adverse events, and likely enhance the cure rate for these patients. Here, we discuss emerging therapeutic strategies that have been recently developed for the upfront and relapse setting of DLBCL., Recent Findings: Clinical trials exploring precision medicine have showed promising results; however, attempts to enhance frontline immunochemotherapy by adding targeted agents to the R-CHOP backbone did not confirm the expected benefit. The last decade has also seen a revolutionary development of immunotherapy in B cell lymphomas. While cellular immunotherapy demonstrated a striking success of CAR T cells in DLBCL, checkpoint inhibitors have lacked success in B cell lymphomas. A parallel therapeutic expansion has involved bispecific monoclonal antibodies as a powerful tool for redirected T cell therapy independently from costimulatory molecules and major-histocompatibility complex. The landscape of drugs for the treatment of DLBCL has become overwhelmed by the increasing number of targeted and immunological therapies; however, none have enhanced efficacy of frontline therapy. Future direction should focus to redefine therapeutic paradigm and develop mechanism-based combinatorial regimens specifically tailored for DLBCL genetic subgroups.

Although the majority of patients with diffuse large B-cell lymphoma (DLBCL) can be cured with the standard immunochemotherapy R-CHOP, one-third of them relapses with a dismal outcome in most cases. In the recent years, remarkable advances have been achieved based on the discovery of molecular genetics in DLBCL. In addition to the major cell-of-origin designations of germinal center B-cell and activated B-cell subtypes, next-generation sequencing has unveiled the remarkable complexity of DLBCL and identified potential molecular targets for tailored therapies. Despite these findings, the current standard of care for DLBCL patients is still R-CHOP, and optimization of frontline therapy remains an important goal. In this review, we summarize recent updates on the evolution of frontline therapies for DLBCL., (© 2019 John Wiley & Sons, Ltd.)

Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL., Competing Interests: Conflict of interest statement: A.Y. has potential conflicts of interest; funds for research came from Servier and for clinical trials from Servier and Novartis., (Copyright © 2018 the Author(s). Published by PNAS.)

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase β (GSK3β) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3β S9 inhibitory phosphorylation, resulting in increased β-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3β S9 phosphorylation levels and β-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3β S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3β regulation, providing a mechanistic rationale for combination strategies., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib. We demonstrate that HDAC inhibitor regulation of MyD88 expression is mediated by STAT3. In turn, STAT3 silencing caused a decrease in MyD88 mRNA and protein levels, and enhanced the ibrutinib antilymphoma effect in MyD88 mutant DLBCL cells. Induced mutations in the STAT3 binding site in the MyD88 promotor region was associated with a decrease in MyD88 transcriptional activity. We also demonstrate that treatment with the HDAC inhibitor panobinostat decreased phosphorylated STAT3 binding to the MyD88 promotor. Accordingly, combined treatment with panobinostat and ibrutinib resulted in enhanced inhibition of NF-κB activity and caused regression of DLBCL xenografts. Our data provide a mechanistic rationale for combining HDAC inhibitors and ibrutinib for the treatment of DLBCL., Competing Interests: Conflict of interest: The authors have declared that no conflict of interest exists.

Background: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease. Prospective clinical trials have demonstrated that lenalidomide is an effective and safe treatment option, especially for non-germinal center B-cell (non-GCB) DLBCL. However, routine clinical data are lacking, which is why we provide the results of the so-far largest relapsed/refractory (R/R) DLBCL real-life analysis., Methods: We retrospectively assessed 123 R/R DLBCL patients who received either 15 or 25 mg/day of lenalidomide from January 2006 to January 2015., Results: During a median follow-up period of 4.5 years, complete remission was achieved in 32% and a partial remission in 33% non-GCB patients compared with 0% and 3% in the GCB group (p < .001 and .001, respectively), with median response durations of 15 and 5 months, respectively (p < .001). Lenalidomide at 25 mg was superior to 15 mg in terms of response (complete remission 21% and partial remission 23% vs. 0% and 8%; p = .007 and .05) and median response duration (10 vs. 4 months; p = .03). Toxicity was limited and reversible. Median progression-free survival differed between non-GCB and GCB patients (37 vs. 30 months; p < .001) and between the two dosages (24 vs. 34 months; p = .002). However, overall survival was similar between the subgroups (38-42 months)., Conclusion: We provide evidence that lenalidomide is a valid treatment option for R/R DLBCL, with limited and reversible toxicity, and is more efficient in non-GCB DLBCL and at higher doses., Implications for Practice: Despite the advent of new treatment strategies, many patients with diffuse large B-cell lymphoma (DLBCL) relapse or die of the disease; hence, novel therapeutic approaches are urgently needed. This study confirms that lenalidomide is a valid and well-tolerated treatment option for relapsed/refractory (R/R) DLBCL. Superior outcomes were observed in non-germinal center B-cell (GCB) DLBCL, probably because of inhibition of the nuclear factor-κB pathway. Similarly, high drug doses resulted in greater clinical benefits. Overall, lenalidomide is a suitable therapeutic option for R/R DLBCL, especially in non-GCB DLBCL, and 25 mg/day dosing should be preferred., Competing Interests: of potential conflicts of interest may be found at the end of this article., (©AlphaMed Press.)

Y-ibritumomab tiuxetan (90Y-IT) combines the benefits of a monoclonal antibody with the efficacy of radiation in the treatment of B-cell non-Hodgkin lymphoma (NHL), a remarkably radiosensitive hematologic malignancy. 90Y-IT activity has been well established in the indolent setting, being approved in front-line treatment of follicular lymphoma (FL) patients as well as salvage therapy. However, no advantage in OS was observed with respect to standard treatment. Promising data are available also for aggressive B-cell lymphoma. In particular, the addition of RIT to short-course first line chemotherapy enables reduction of chemotherapy while maintaining cure rates in elderly, untreated diffuse large B-cell lymphoma (DLBCL) patients. Furthermore, 90Y-IT improves response rate and outcomes of relapsed/refractory DLBCL patients, eligible and ineligible for autologous stem cell transplantation (ASCT). Clinical results have shown a role of 90Y-IT even in mantle cell lymphoma (MCL). RIT might improve responses and treat minimal residual disease when used as consolidation after first-line chemotherapy in MCL. Moreover, 90Y-IT has demonstrated its efficacy in combination with high-dose chemotherapies as conditioning regimen for ASCT, with evidence suggesting the ability to overcome chemotherapy resistance. Herein, we review the available evidence for this approved drug and examine the recently published and ongoing trials for potential novel indication in aggressive B-cell NHL.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma in western countries. Despite the addition of rituximab to chemotherapy, the prognosis is still poor and almost one-third of patients fail or relapse after first-line treatment. Gene expression profiling has identified three main signatures related to subgroups with different biological characteristics and responses to treatment. Novel agents targeting the oncogenic drivers of these subsets are currently under investigation with the aim of providing a tailored approach and avoiding unnecessary toxicity. Herein, we review the emerging therapies for DLBCL with a focus on preclinical and early clinical trials as well as future directions.

Background: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL)., Patients and Methods: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria., Results: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases., Conclusions: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The first-line standard treatment for diffuse large B-cell lymphoma (DLBCL) is the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). It is associated with cardiotoxicity, which is why new treatment strategies are needed. Liposomial doxorubicin has been proven to reduce these side-effects, but until now a direct comparison regarding efficacy has not yet been published. We retrospectively assessed 364 consecutive DLBCL patients who underwent either R-CHOP (218; 60%) or R-COMP (doxorubicin replaced by non-pegylated liposomal doxorubicin; 146; 40%) in first line and compared outcome and survival. We provide evidence that both regimens induce a high and comparable number of complete remissions and that both are able to cure patients with DLBCL. Confirmatory data are needed., (Copyright © 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma entity whose prognosis for high-risk patients is poor. Aggressive salvage treatments to improve patient outcome have been unsatisfactory. Therefore, we evaluated the efficacy of yttrium-90-ibritumomab tiuxetan (Zevalin®; (90)Y-IT) consolidation after early salvage chemotherapy with autologous stem cell transplantation. Thirty-seven patients with intermediate-high risk DLBCL not in complete remission (CR) after three cycles of rituximab, cyclophosphomide, doxorubicin, vincristine and prednisone (R-CHOP) were assessed retrospectively. After early salvage treatment, 70% achieved CR and 30% partial remission. Twenty patients underwent additional consolidation with (90)Y-IT. During the 3-year follow-up, 50% in the (90)Y-IT-treated group experienced relapse compared to 82.3% in the other cohort (p=0.002). Progression- and disease-free survival were significantly longer in the (90)Y-IT group. However, probably due to the relatively short follow-up period, no difference in overall survival was observed. (90)Y-IT consolidation after early salvage chemotherapy improves treatment responses and reduces the percentage of relapses without significant additional toxicities., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)