MYC translocation

Anti-IL6 antibody tocilizumab improved the ADC's cytotoxic activity in CD37+ cells...Adding idelalisib or venetoclax overcame resistance in the resistant derivative and improved the cytotoxic activity in the parental cells. In conclusion, targeting B-cell lymphoma with the naratuximab emtansine showed vigorous anti-tumor activity as a single agent, which was also observed in models bearing genetic lesions associated with inferior outcomes, such as MYC translocations and TP53 inactivation or R-CHOP resistance. Resistant DLBCL models identified active combinations of naratuximab emtansine with drugs targeting IL6, PI3Kδ, and BCL2.

P1/2, N=170, Active, not recruiting, Cyteir Therapeutics, Inc. | Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Jul 2024 --> Dec 2024

We concluded that the U2932 and VAL cell-derived human IL6-expressing mouse models reproduced the clinical features of an aggressive DLBCL with a highly consistent pattern of tumor development. Based on these findings, NSG mice expressing human IL6 have the potential to serve as a new tool to develop DLBCL xenograft models to overcome the limitations of standard subcutaneous DLBCL xenografts.

Furthermore, comparing the prognosis between these two groups, AR-HGBL-11q showed a relatively favorable prognosis (P = 0.15), although the difference was not statistically significant. We analyzed this rare lymphoma entity in the HIV setting and highlighted the importance of integrating histomorphological and immunophenotypic features in its diagnosis and classification.

P3, N=302, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: May 2024 --> May 2025 | Trial primary completion date: May 2024 --> May 2025

P3, N=1033, Active, not recruiting, University College, London | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.

These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.

Here we demonstrate that EBV- BL comprises two subsets of cases based on SOX11 expression. The mutual exclusion of SOX11 and EBV, and the association of SOX11 with a specific genetic landscape suggest a role of SOX11 in the early pathogenesis of BL.

Treatment approaches are evolving, with chemoimmunotherapy remaining standard for many indolent cases while intensified regimens and targeted agents show promise for refractory or high-risk aggressive disease. Continued elucidation of the genetic and microenvironmental underpinnings of lymphomagenesis is critical for developing personalized therapeutic strategies.

P1, N=85, Recruiting, BeiGene

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

Due to small sample size and lower than expected relapse, we were unable to demonstrate conversion of dMRD to uMRD using MN. However, this pilot study did confirm high correlation of uMRD and dMRD status with disease free survival and clinical relapse within 4 months, respectively. If strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans.

P2, N=349, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Dec 2024

P1/2, N=280, Recruiting, Kronos Bio | N=170 --> 280

Finally, we have corroborated these findings in two human Burkitt lymphoma cell lines and we have found that the death of cancer cells was accompanied by chromosomal instability. Based on these findings, we propose PICH as a potential therapeutic target for Burkitt lymphoma and for other cancers where PICH is overexpressed.

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

Major deregulations are found in the lymphoid compartment as well, with skewing towards immune tolerant Th17 and Treg and inhibition of CD8+ cytotoxic and CD4+ activated effector T cells. In summary, this review will provide an overview of the complex cross-talk between MM plasma cells and immune cells in the microenvironment and the molecular mechanisms promoting progression from precursor states to full-blown myeloma.

Next-generation sequencing is increasingly being used to detect mutations and new FISH techniques such as by flow cytometry are in development and may address some of the current test limitations. Here we review the primary and secondary cytogenetic aberrations in myeloma and discuss the range of techniques available for their assessment.

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.

© 2024 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

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.

No pts with uMRD by ctDNA had clinical relapse on study during 2 year follow up, confirming uMRD correlates with disease free survival. If a strong negative predictive value is confirmed in a larger study, ctDNA MRD testing may be used to spare pts from imaging or to guide additional work up in pts with inconclusive findings on scans.

P3, N=1033, Active, not recruiting, University College, London | Recruiting --> Active, not recruiting | Trial completion date: Jul 2023 --> Jul 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

Importantly, modulation of MYC levels directly correlates with EBV's ability of infection in BL cells. Altogether, in contrast to the widely accepted hypothesis for the correlation between EBV and BL, we propose an alternative hypothesis in which MYC dysregulation could be the first event leading to the subsequent EBV infection.

The separate probe for the MYC gene has some shortcomings and should be used together with dual fusion probe to improve the accuracy of diagnosis.

"One limitation of the recently presented IRMMa model was an absence of patients prescribed daratumumab-based quadruplet induction, (dara-quads; daratumumab, lenalidomide, dexamethasone with carfilzomib [DKRd] or bortezomib [DVRd]). Among 234 patients analyzed, 86 patients received DKRd and 148 DVRd. Overall median follow-up was 1.4 years (y); 4.2y with DKRd (IQR 1.9-4.7, max 5.7) and 1y with DVRd (IQR 0.5-1.4, max 3.4). 25 patients progressed following DKRd and 20 following DVRd, with 9 progressing during induction chemotherapy."

This is the first and largest meta-analysis to show that induction DI regimens, in general, and R-EPOCH and R-HyperCVAD/MA regimens, in particular, are associated with better PFS than R-CHOP-like regimens in patients with DTHL. However, this advantage did not translate into a survival benefit.

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.

To strengthen the application of this technology into clinical practice, further analysis is being conducted for weighting and assigning of scores for each predictor variable. This would assist clinicians in making a precise diagnosis, complementing existing diagnostic modalities for EBL, and reducing the rate of misdiagnosis arising from diagnosis based on clinical suspicion and tissue morphology without immunohistochemistry.

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 conclusion, our newly developed targeted sequencing panel correctly identified 96.3% (26/27) analyzed gene rearrangements in B-ALL, including alterations evading standard diagnostic methodologies such as IGH::DUX4 or IGH::EPOR. Importantly, the assay allows individual analysis in a single sample format, thereby representing a valuable tool for B-ALL diagnostics in small to medium-sized laboratories.

FISH identified a therapeutically actionable variant in 3 (13%) patients [venetoclax, n=3]...Our results support MGPP as a robust alternative to FISH in supporting risk-adapted treatment decisions. We will implement MGPP in additional large prospective cohorts over the next year, to better understand its prognostic utility and feasibility in routine clinical workflows.

Pts with RT occurring as large B-cell lymphoma who did not previously receive CIT (e.g., fludarabine, cyclophosphamide, bendamustine, chlorambucil) for their CLL/SLL were included...The remaining 14% had been treated with an anti-CD20 monoclonal antibody (MoAb), steroids, lenalidomide, radiation, or alemtuzumab... This is the largest cohort of pts who developed RT having received only SMI with no CIT for their CLL reported, thus reflecting the current treatment landscape. Despite being CIT-naïve, pts in our series who received tx for their CLL/SLL and then developed RT had a short OS, underscoring the need to develop better therapies for these pts. In contrast, as in other published analyses (Wang Haematologica 2020), pts w/o prior tx for CLL/SLL had more favorable outcomes, with a median OS of approximately 5 years.

BTK inhibitors, ibrutinib and acalabrutinib are immunomodulatory and may enhance CAR-T expansion, engraftment and tumor clearance while decreasing the frequency and severity of CRS in chronic lymphocytic leukemia (Qin, et al...Three (20%) patients had grade 3 ICANS which resolved with dexamethasone and anakinra or tocilizumab...Conclusions Acalabrutinib successfully bridged most patients in this trial when given concurrently with axi-cel and safely maintained high CR rates. CRP and ferritin levels were typically only modestly elevated after cell infusion. Severe CRS was not observed and high-grade ICANS was uncommon.

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.

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

P1/2, N=48, Active, not recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Sep 2023 --> Sep 2024

.MYC gain trended towards worse OS; patients with ≥7MYC copies had worse OS (p = 0.013), similar to patients with MYC translocations. We propose that MYC gain represents a dose-dependent prognostic factor for LBCLs.