BCL2 amplification

We identified a distinct high-risk DLBCL subgroup, characterized by MYC and BCL2 aberrations, beyond conventional DHL-BCL2 and DEL, and irrespective of cell-of-origin, thereby expanding the poor-prognosis group.

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.

After the first induction cycle with the 7+3 scheme (cytarabine + idarubicin), refractoriness was observed, in addition to the appearance of 6% of nuclei with BCL2 amplification by FISH, while maintaining the TP53 variant (confirmed by PCR). A new therapeutic scheme was initiated with decitabine 10- venetoclax... Clonal evolution of the leukemia was evidenced by the acquisition of BCL2 amplification alongside changes in the karyotype after antineoplastic treatment, and particularly following venetoclax administration, while maintaining the primary TP53 pathogenic variant.The increasing use of targeted therapies is improving remission and survival rates in most hematologic neoplasms, but it is also leading to the emergence of therapy-related clonal selections, as seen in this case, which could cause resistant relapses or even refractoriness. Understanding the mechanisms responsible for these phenomena would help to understand their relevance in the evolution of these patients.

Taken together, we refined existing Myd88 p.L252p and BCL2-driven MCD/C5 DLBCL mouse models by co-expressing the Cd79b p.Y195H mutation. Cd79b-mutant murine lymphomas exhibited increased BCR activation levels, resulting in an increased sensitivity towards BTK inhibition, when compared to Cd79b wt control tumors. These findings indicate that patients with CD79B ITAM mutations might be particularly sensitive to BTK inhibitor treatment.

Our results demonstrate that olverembatinib and BCL-2 inhibitor lisaftoclax have additive antitumor effects in imatinib-resistant GIST. This novel dual approach may have the potential for treating patients with GISTs whose disease has progressed after treatment with TKIs.

P2, N=30, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

There was difference in profiling of altered genes and signaling pathways between the DEL group and the non-DEL group. The presence of DEL alone should not be considered as an adverse prognostic indicator, and BCL2 alteration could define a subset of patients with poor prognosis within DEL.

While linkage to the IgH 3' RR mostly yielded expression in GC B-cells, the Igκ-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.

These high-grade lymphomas are a newly emerging entity; they have been found to have novel cytogenetic and molecular mutations distinct from lower-grade follicular lymphomas and a more aggressive clinical course and worse prognosis than grade 3a follicular lymphomas. Grade 3 follicular lymphomas are unusual in pediatric patients, although they have been found in patients with abnormal immune states, including autoimmune lymphoproliferative disorder.

These high-grade lymphomas are a newly emerging entity; they have been found to have novel cytogenetic and molecular mutations distinct from lower-grade follicular lymphomas and a more aggressive clinical course and worse prognosis than grade 3a follicular lymphomas. Grade 3 follicular lymphomas are unusual in pediatric patients, although they have been found in patients with abnormal immune states, including autoimmune lymphoproliferative disorder.

P2, N=30, Not yet recruiting, M.D. Anderson Cancer Center

Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.

This study showed that DLBCL patients treated with R-CHOP, BCL2 alterations, especially BCL2 and TP53 mutations were significantly associated with inferior outcomes, which were independent of the IPI. The novel prognostic models we proposed predicted outcomes for DLBCL patients treated with R-CHOP, but further validation of the prognostic models is still warranted.

We found in a Swiss DLBCL cohort that ~15% of patients are projected to respond to the venetoclax/ibrutinib combination based on their high Bcl-2 expression and nuclear NF-κB localization. Our data show that drug sensitivities exposed by drug response profiling can be attributed to specific mutational signatures and immunohistochemical biomarkers, and point to combined Bcl-2/BTK inhibition as a promising therapeutic strategy in DLBCL.

This study demonstrated that, in patients treated with R-CHOP, the presence of BCL2 alteration, especially BCL2GA/AMP, and TP53 mutation were significantly associated with inferior outcomes independent of IPI . The novel prognostic models we proposed could aid in individual risk prediction for DLBCL patients treated with R-CHOP . Further validation of this prognostic model is warranted.