BCL2 translocation

This study reports a rare case of TdT positive "double hit" HGBL following the treatment of concurrent FL/DLBCL and highlights the mutation characteristics. Collectively, this study will help enrich the knowledge of TdT positive "double hit" HGBL transformed from FL/DLBCL.

BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls.

P=N/A, N=64, Recruiting, Swiss Group for Clinical Cancer Research | Not yet recruiting --> Recruiting

P=N/A, N=64, Not yet recruiting, Swiss Group for Clinical Cancer Research | Initiation date: Dec 2023 --> Mar 2024

Accordingly, this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations. Moreover, the results of clinical trials are summarized, with a particular focus on treating nodal and gastrointestinal FLs.

DFL with 1p36 deletion is a rare subtype of FL, with some overlaps with other types of FL or indolent B-cell lymphomas in their pathologic features. An accurate diagnosis requires comprehensive considerations based on their clinical, pathologic, immunohistochemical, and molecular features.

Three patients deceased and the 2-year overall survival achieved 88%. Follicular lymphoma affecting the oral cavity is uncommon, usually affects the palate as a non-ulcerated swelling and the presence of a systemic disease most always be ruled out.

© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

P2/3, N=363, Active, not recruiting, National Cancer Institute (NCI) | Suspended --> Active, not recruiting

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

PTFL is mainly characterized by adolescent male onset, with early clinical manifestations and pathological manifestations of high-level histological status, high proliferation index, and lack of t (14; 18)/Bcl-2 translocation and Bcl-2 expression. It is mainly treated by localized surgical excision and has a good prognosis.

In preclinical pharmacology studies, the mantle cell lymphoma (MCL) xenograft tumor mouse model derived from JeKo-1, which has mutated TP53 and checkpoint kinase 2 (CHEK2), an HRD score of 46, and was refractory to ibrutinib and bortezomib, showed near complete response after LP-284 treatment. Overall, based on its impressive preclinical anti-tumor efficacy profile, low drug-drug interaction liability, and findings from toxicological studies, a Phase 1 study is currently planned with LP-284 to assess its safety, tolerability, pharmacokinetics, and clinical activity in patients with relapsed or refractory B-cell lymphoma. Clinical development will be informed by an emphasis on patient selection strategy based on DDR/HR biomarkers.

ConclusionsIncorporating genetic signatures associated with radiosensitivity, and specifically alterations involving BCL2 and CREBBP, may independently improve patient selection for RT. CREBBP HAT domain mutations are potentially targetable and may have important implications for augmenting radiosensitivity to VLDRT.

In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.

Both divergent evolution, either from clonally related or unrelated precursors, and linear evolution processes are involved in the development of relapses in patients with an early-stage FL following complete remission, with the former being more frequent. The above findings, together with the evidence of divergent evolution of tFL in the majority of cases, challenge the current therapeutic strategy of early-stage FL, which does not target the premalignant cell population that underpins lymphoma recurrence in the majority of cases. Additionally, the routine diagnostic workup, which includes IG gene clonality and BCL2 translocation analyses, cannot address the evolutionary path in clonally related lymphomas.

DLBCL is a family of aggressive B-cell neoplasms with marked variation in pathogenesis and clinical features. Gene expression profiling (GEP) more than 20 years ago identified the cell of origin (COO) as a key discriminator, but more recently high throughput sequencing has identified highly varied mutational profiles that should point the way in the future towards improvements in targeted therapy and patient outcome.

Six patients with localized disease were treated with radiotherapy and 37 with rituximab associated with ciclophosphamide, doxorubicin, vincristine, and prednisone. In PD-L1 positive patients the better response to the first line therapy may be related with the prevalence of early stages and a reduced MTV at the diagnosis. In conclusion, our data suggest that , grade III FLs have a more intense expression of PD-L1 and may be candidate to test efficacy of PDL1 inhibitors.

P1, N=18, Recruiting, He Huang

Genetically, this lymphoma group is characterised by a high rate of either STAT6 or SOCS1 mutations.The ICC classification took this development into account by introducing the provisional entity CD23 positive, BCL2 rearrangement-negative germinal centre lymphoma. Further studies must now show how exactly this entity can be defined (combination of morphology, immunohistochemical phenotype, focus on genetic alterations) in order to pave the way towards a uniform classification and a better clinical characterisation of these cases - especially with regard to possible new therapeutic treatment options.

Older adults with aggressive NHL often experience improvement in QOL and other PROs with treatment, even across age and frailty categories. VES-13 score and CGA identify patient groups at high risk for early death and poor QOL trajectory, for whom novel therapies and supportive care interventions are warranted. Higher VES-13 score is also associated with higher risk of unplanned hospitalization.

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.

In this cohort of older adults receiving treatment for DLBCL or double hit lymphoma, the vast majority felt it was important to know prognostic information over time and found that this information was helpful for decision making. Our finding that the majority estimated their likelihood of cure to exceed 75% despite most having aa-IPI scores indicating average cure rates < 60 suggests that older adults with newly diagnosed DLBCL hold overly optimistic views of their prognosis.

Strikingly, treating EZB cells with EZH2 inhibitor tazemetostat (taz) ex vivo reprogrammed them to re-express the full spectrum of T cell engagement genes such as ICOSL, ITGB7, 4-1BBL, and OX40L and rendered them highly immunogenic...Collectively, EZH2 inhibitors yield a potent boost to CART mediated anti-lymphoma effects by enhancing CART cell functions and B cell immunogenicity, which would likely yield a significant clinical benefit for these patients where CART cells are less active. These results prompted us to initiate a clinical trial evaluating the safety and efficacy of this combination in B cell lymphomas (NCT05934838).

Using actinomycin D chase experiments, we found that hnRNPU loss leads to reduced MYC transcript stability... HNRNPU mutations are novel recurrent driver mutations specifically within MYC translocated B-cell lymphomas. HNRNPU acts as a modulator of MYC expression, and the most common mutations are predicted to negatively impact this role. We propose a model where HNRNPU mutations moderate MYC expression, thus buffering MYC-induced apoptosis and proteotoxic stress.

Methods This ancillary study was carried out on patients included by French LYSA centers in RELEVANCE, a randomized phase III trial comparing the chemotherapy-free regimen R2 versus standard R-chemo followed by Rituximab maintenance in previously untreated patients with FL...When combined, PET+/MRD+ identified POD24 patients with a NPV and PPV of 91.5% and 85.7% respectively. Conclusion Combining the results of ctDNA and PET/CT at W24 post induction improves early prediction of POD24 in previously untreated patients with follicular lymphoma.

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.

All patients were treated with anthracycline based therapy, with 94% receiving RCHOP and 6% receiving DA-EPOCH-R... These data both demonstrate the feasibility and the prognostic utility of ctDNA-MRD during and after SOC induction therapy for DLBCL in a real-world population using an ultrasensitive ctDNA-MRD assay. The higher predictive value and accuracy of detectable ctDNA-MRD as compared with PET/CT suggest opportunities for integration of such assays in lymphoma response criteria, to potentially inform future clinical decision making.

P=N/A, N=64, Not yet recruiting, Swiss Group for Clinical Cancer Research

In BCL2 + FL mutations in KMT2D, BCL2, ABL2, IGLL5 and ARID1A were enriched, while STAT6 mutations more frequently occurred in BCL2- FL. Although the landscape of lFL and sFL showed overlapping features, molecular profiling revealed novel insights and identified gains in 18q21 as prognostic marker in lFL.

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.

Head and neck FL with MZ differentiation can develop in both nodular and extranodular sites and is characterized by BCL2 translocation t(14;18). Although the mechanism of MZ differentiation is unclear, the characterization of this rare histopathologic phenomenon might be clinically important.

The up-regulation of MYC expression in these cases suggests a possible role in B-cell lymphomagenesis. Clinicians should be aware that another biopsy is still necessary to rule out concurrent or secondary DLBCL when nodal and extranodal lesions are noted after nTFHL-AI treatment.

Based on the overall findings, the diagnosis was changed to a high-grade B-cell lymphoma with MYC and BCL2 rearrangements and focal TdT expression, and the treatment regimen was altered accordingly. Although the definitive differentiation of an HGBL with MYC and BCL2 rearrangements and TdT expression from a B-LBL with MYC and BCL2 dual translocations can be challenging, this case emphasizes the importance of this distinction.

Del(17p) was an independent predictor of survival in patients with DLBCL treated with first-line immunochemotherapy. As previously described, BCL2, MYC, and DH rearrangements were associated with poorer PFS. Larger studies are needed to confirm the prognostic value of the less prevalent alterations, MYC and del(17p).

CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with potential for discriminating subjects at risk of developing FL or monitoring residual disease.

Thus, it should not be considered as a reliable molecular marker in the follow up of the disease, unless it is found to be present at the initial diagnosis of FL. Alternative genetic aberrations exist in BCL2-negative cases.

Together, these unique cases and their accompanying molecular and cytogenetic data suggest potential mechanisms for and unusual patterns of transformation in B-cell lymphomas and indicate numerous opportunities for further study.

Meanwhile, flow-cytometric analysis of cell surface marker expression interestingly revealed that MBII deletion was associated with clear indications of physiological plasmablast differentiation, akin to the non-transduced populations, rather than the prolonged undifferentiated state of the wildtype MYC overexpressing cells. These results suggest distinct roles for MB0 and MBII within MYC-driven B-cell transformation, with the overexpression of MB0 and MBII deletion MYC variant protein resulting in attenuation of typical MYC overexpression phenotype.

All patients received two cycles of R-CHOP-21 with HD-Mtx on day 15 and depending on the biological risk factors (C-MYC translocation, C-MYC and BCL2 translocation (double hit), 17p/TP53 deletion, co-expression of MYC and BCL2, P53+ and/or CD5+) either four additional courses of R-CHOEP-14 (no biological risk factors) or four courses of dose-adjusted EPOCH-R (biological risk factors). In addition, one course of R-HD-cytarabine was given to all patients... Intensified immunochemotherapy results in a favorable outcome in patients with high-risk LBCL apart from those with 17p/TP53 deletion, TP53 mutations and/or high ctDNA burden. Our findings highlight the role of ctDNA as a noninvasive biomarker with a potential to improve risk stratification beyond biological and clinical factors and to guide treatment decisions in patients with high-risk LBCL.

P1, N=20, Recruiting, Lapo Alinari | Trial completion date: Dec 2025 --> Mar 2027 | Trial primary completion date: Dec 2024 --> Mar 2027

P1, N=20, Recruiting, Lapo Alinari | Not yet recruiting --> Recruiting