BCL6 translocation

P2, N=184, Recruiting, Genmab | Trial primary completion date: Aug 2027 --> May 2029

In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

The rare, but difficult, diagnostic classification HGBL (NOS) remains a diagnosis of exclusion with limited data on an optimal clinical approach. The days of talking loosely of double and triple hit lymphoma are numbered as this review synergises the current data on biology, prognosis, and therapies in HGBL.

TP53 and KMT2C mutations conferred inferior outcome (3-year EFS P < 0.05). Overall, MYC-R lymphomas in CAYA have a molecular profile similar to BL regardless of their high-grade or DLBCL morphology, whereas MYC-non-R has more heterogeneous genetic alterations closer to that of DLBCL.

P=N/A, N=140, Not yet recruiting, Beijing GoBroad Hospital; Beijing GoBroad Hospital

P1, N=68, Recruiting, University of Washington | Suspended --> Recruiting

P1, N=50, Suspended, University of Washington | Recruiting --> Suspended

P1, N=49, Active, not recruiting, AbbVie | Phase classification: P1b/2 --> P1 | Trial completion date: Jan 2024 --> Dec 2024 | Trial primary completion date: Jan 2024 --> Dec 2024

P1/2, N=190, Active, not recruiting, ArQule, Inc., a subsidiary of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. (Rahway, NJ USA) | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Further, we report the formation of intramolecular parallel G4 and triplex DNA, at Cluster II. Taken together, our studies reveal that multiple non-canonical DNA structures exist at the BCL6 cluster II breakpoint region and contribute to the fragility leading to BCL6 translocation in DLBCL patients.

Among MYC+ patients, those who received intensive chemotherapy achieved a better outcome compared to patients who received non intensive treatment (complete remission 84% vs 52%, p 0,028; 5-year PFS 66% vs 36%, p 0,021). Our retrospective results suggest that HIV-associated LBCL with MYC rearrangement could be considered for an intensive therapeutic approach whenever possible, while (R)CHOP seems to give inferior results in this subset of patients in terms of complete remission and PFS.

Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment.

P=N/A, N=100, Recruiting, MorphoSys AG | N=1000 --> 100 | Trial completion date: Jul 2029 --> Aug 2026 | Trial primary completion date: Jul 2028 --> Oct 2025

To the best of our knowledge, this is the first study exploring the molecular genetics of bone marrow large B cell lymphoma with HLH. Our study suggesting bone marrow large B cell lymphoma with HLH showed frequent MYD88/CD79B and PD-L1 alterations. Our study provided clues for the pathogenesis of bone marrow large B cell lymphoma with HLH and identified potential druggable targets for future clinical trials.

This study comprehensively characterizes PB-DLBCL as a separate entity with distinct clinical and morpho-molecular features. These insights may aid in developing tailored therapeutic strategies and shed light on its pathogenesis.

On the other hand, HGBL-DH/TH displays aggressive features, including a high incidence of advanced disease at diagnosis, and inferior efficacy to standard-induced chemical immunotherapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). DHL-BCL2/THL exhibits similar clinical characteristics, prognostic outcomes, and molecular features that set it apart from DHL-BCL6. This implies the need for testing novel agents or therapeutic strategies to expedite treatment development for patients with DHL-BCL2/THL.

Introduction: In the POLARIX study, polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) vs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL; NCT03274492; Tilly et al. In this exploratory biomarker analysis, we recapitulated that pts with molecularly defined DLBCL subtypes, including EZB and MCD by LymphGen and DZsig+ by RNAseq, have poor outcomes with R-CHOP therapy. In pts with the EZB and MCD subtypes, Pola-R-CHP appeared to improve 2-year PFS compared with R-CHOP. Pts with GCB DLBCL who were DZsig+ significantly benefited from Pola-R-CHP vs R-CHOP.

Introduction: High grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangements (HGBCL MYC/BCL2 and/or BCL6-R) is a group of aggressive lymphomas associated with poor outcomes when treated with R-CHOP... In our series, pts with limited stage MYC/BCL2-R had poor outcomes while MYC/BCL6-R experienced favorable outcomes. There was no additional prognostic impact when BCL6-R is present with MYC/BCL2-R. This adds to the growing evidence that MYC/BCL6-R is not a poor prognostic factor in HGBCL.

Introduction: In the POLARIX study (NCT03274492), polatuzumab vedotin in combination with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) demonstrated prolonged progression-free survival (PFS) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL; Tilly et al. Our analyses demonstrated that the mutation landscape of ctDNA in DLBCL characterized by the AVENIO ctDNA NHL assay resembles that of tumor tissue determined by WES. Patients with molecular subtypes defined by WES or ctDNA had similar PFS outcomes. Overall, these findings support the use of plasma ctDNA as an alternative to tumor tissue for the genotyping of DLBCL.

P1b/2, N=49, Active, not recruiting, AbbVie | Recruiting --> Active, not recruiting

This study demonstrated different pathways based on cell-of-origin classification and highlighted different clinical outcomes. miR-125b, miR-155b and TP53 expression may also represent potential prognostic factors in nGC-DLBCL.

The main objective of this study was to assess the application of the immunohistochemistry- and interphase fluorescence in situ hybridization (FISH)-based molecular markers in the diagnosis of DLBCL and its prognostic value in patients treated with rituximab-based immunochemotherapy...We did not find any difference in survival by GCB vs. non-GCB subtypes. These findings may improve prognostication in DLBCL and can contribute to designing further research in the area.

Primary diffuse large B-cell lymphoma of the CNS (CNS-DLBCL) is an aggressive disease, with dismal prognosis despite the use of high dose methotrexate (MTX)-based polychemotherapy...MYD88 and CD79B predicted a longer survival in patients affected by CNS-DLBCL. Notably, we identified novel mutations that enrich the mutational landscape of CNS-DLBCL, suggest a role of PTEN-PI3K-AKT and RTK-RAS-MAPK signaling in a subset of CNS-DLBCL, and provide new potential therapeutic targets.

P3, N=552, Active, not recruiting, Genmab | Trial primary completion date: Apr 2028 --> Dec 2024

P2, N=184, Recruiting, AbbVie | N=80 --> 184

Even though no MYC inhibitor has received regulatory approval to date, substantial efforts have been made to investigate avenues to render MYC a druggable target. Here, we summarize the different classes of molecules currently under development, which mostly target MYC indirectly in aggressive B-cell lymphomas, paying special attention to subtypes with MYC/BCL2 or BCL6 translocations or overexpression.

P2, N=80, Recruiting, AbbVie | Trial completion date: Sep 2025 --> May 2029 | Trial primary completion date: Dec 2023 --> Aug 2027

P3, N=552, Active, not recruiting, Genmab | Recruiting --> Active, not recruiting | Trial completion date: Jun 2024 --> Apr 2028 | Trial primary completion date: Jun 2024 --> Apr 2028

Genetic alterations in genes involved in immune escape (HLA, CD274/PDL1LG2) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center re-entry, aSHM and immune escape.

This Ph 1 trial is determining the tolerability and preliminary clinical efficacy of odronextamab plus cemiplimab to treat pts with R/R aggressive B-NHL.

P3, N=552, Recruiting, Genmab | Trial primary completion date: Jun 2023 --> Jun 2024

Severe4 was also a significant predictor of grade ≥3 cytokine release syndrome in the LC (odds ratio &lsqb;OR]=2.43, p=0.042), while maintaining this trend in the VC (OR=2.05, p=0.114). Thus, our results indicate that adverse outcomes for patients with DLBCL meant to receive CART can be predicted using a simplified CIRS-derived comorbidity index.

P2, N=80, Recruiting, AbbVie | Trial primary completion date: Aug 2025 --> Dec 2023

Treatment with the anti-CD20 monoclonal antibody (mAb) rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone is the standard first-line therapy; however, 30-40% of patients experience relapsed or refractory (R/R) disease (Harris LJ, et al. Secondary endpoints include safety, IRC-assessed progression-free survival, and overall survival. It is planned to enroll 81 patients into the study.

While the first upper gastrointestinal endoscopy for routine surveillance purposes was uneventful, the second one after developing unexplained weight loss revealed two new neoplastic lesions in the stomach. The histological evaluation revealed a poorly differentiated adenocarcinoma infiltrating the muscularis propria forcing gastrectomy as well as a high-grade B-non-Hodgkin-lymphoma with detection of a MYC- and BCL6-translocation, necessitating chemotherapy with R-CHOP.This case emphasizes the necessity of high awareness for gastric neoplasia in patients with CVID and highlights the need of a standardized yet not established endoscopic surveillance protocol for this vulnerable group.

Top: Classification of samples according to MYC status, Lymphgen assignment, and cell of origin (COO). Right: Genomic alterations (copy number alterations, CNAs; mutations and translocations) enriched in NMF clusters C1 to C5.

Archival formalin-fixed paraffin-embedded biopsies with DLBCL morphology were selected from 146 R-CHOP treated patients, of which 35% had detectable low-grade lymphoma at some point in their disease course... These experiments suggest that LRs, when clonally related, usually arise via convergent evolution from a common precursor cell (CPC) population where the driver mutation profile at both diagnosis and relapse is constrained by the genetics of the CPC. The superior outcomes on salvage therapy and HSCT support the hypothesis that LRs generally represent new chemotherapy-naïve disease and have implications for optimal patient management in the era of CAR-T cell therapy.

DHL with immature features is associated with a poor clinical outcome. This patient died 10 months after diagnosis.

DHL with immature features is associated with a poor clinical outcome. This patient died 10 months after diagnosis.

P1/2, N=190, Active, not recruiting, ArQule, Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.) | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024

P2, N=80, Recruiting, AbbVie | Not yet recruiting --> Recruiting