CARD11 mutation

To compare the safety and efficacy of zanubrutinib plus rituximab and lenalidomide (ZR2) and R-CHOP-like for elderly patients with newly diagnosed DLBCL, we conducted this single-center prospective study. Patients with gastrointestinal DLBCL have to be monitored closely by abdominal enhanced CT every cycle. Overall, ZR2 chemo-free regimen might be more appropriate for elderly DLBCL patients.

The application of rituximab has significantly enhanced the overall survival rates in patients with diffuse large B-cell lymphoma (DLBCL)...In addition, we revealed mutations in HIST2H2AB, BCL2, NRXN3, FOXO1, HIST1H1C, LYN and TBL1XR1 genes were only detected in initial diagnostic biopsies, mutations in the EBF1 gene were solely detected in the rrDLBCL patients. Collectively, this study elucidates some of the genetic mechanisms contributing to the progression of rrDLBCL and suggests that the presence of CD58 mutations might serve as a powerful predictive marker for relapse/refractory outcomes in primary DLBCL patients.

Immunophenotypically, the cases were predominantly GCB, in contrast to older adults (61%). In summary, we showed that molecular findings identified in the PCNSLs of the older patients were only sparingly present in pediatric and young adult patients.

Clinically significant findings, such as ABC COO (n = 16), TP53 loss (n = 13), DHITsig+ (n = 6), and CARD11 mutations associated with ibrutinib resistance (n = 3), were identified in 33 samples... Our results show the clinical utility and acceptable TAT of using a comprehensive WES and RNA-seq assay on a cohort of lymphoma patients. The produced BostonGene Tumor PortraitTM test reports included findings on significant alterations, LymphGen and LME subtypes, COOs, and potential clinical trial matches. These robust findings, coupled with the rapid TAT, demonstrate the feasibility of using integrated WES and RNA-seq to guide clinical decision-making in lymphoma patients.

Clinically significant findings, such as DHITsig+ (n = 4) and CARD11 mutations indicative of ibrutinib resistance (n = 3), were identified in 26 of the 39 patients ( Table 1), and an average of 8 clinical trials were identified for potential patient enrollment in each delivered report...This approach identified significant alterations and classified LBCL samples into previously reported lymphoma subtypes. The clinical reports included clinically relevant findings and matched clinical trials, demonstrating the feasibility of incorporating comprehensive molecular profiling in clinical practice for patients with lymphoma.

Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence but also directly increased the transcription of the antiapoptotic BCL2A1, leading to resistance against venetoclax and OAsIs combination...Consequently, MALT1 inhibition induced synergistic cell death in combination with BCL2 inhibition, irrespective of CARD11 mutational status, both in vitro and in vivo. Taken together our study identified mechanisms of resistance to targeted therapies and provided a novel strategy to overcome resistance in aggressive B-cell lymphoma.

He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine...Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4+ and CD8+ T cell malignancies.

The aaIPI staging combination with molecular biology markers is more conducive to accurately judging the prognosis of young DLBCL patients. TP53, POU2AF1 and CCND3 mutations predict worse survival in the patients with the aaIPI high-risk group.

QRICH1-deficient primary CD8+ T cells had increased proliferation and production of pro-inflammatory cytokines IFN-ɣ and TNF-α in response to ex vivo stimulation with anti-CD3/CD28, and QRICH1-deficient OT-1 CD8+ T cells also had increased cytokine production in response to antigen-specific stimulation with Ova peptide. Our findings reveal that QRICH1 negatively regulates T cell activation by modulating CARD11’s signaling output.

Our results reveal CARD11 as an important, cell-autonomous positive regulator of T, T and T cells. They highlight T cell-intrinsic effects of a GOF mutation in the CARD11 gene, which is recurrently mutated in T cell malignancies that are often aggressive and associated with variable clinical outcomes.

ETV6 and platelet-derived growth factor receptor (PDGFR)A/B gene mutations are supposed to be potential biomarkers for the prognosis of DLBCL patients via the statistical analysis of this small sample, and POD12 is also expected to be an effective endpoint for efficacy assessment.

CARD11(E626K) and HBZ cooperatively activate the non-canonical NF-κB pathway, IRF4 targets, BATF3/IRF4/HBZ transcriptional network, MYC targets, and E2F targets. Most KEGG and HALLMARK gene sets enriched in acute-type ATL are also enriched in double transgenic mice, indicating that these genes cooperatively contribute to ATL development.

Ibrutinib, a first-in-class bruton's tyrosine kinase inhibitor (BTKi), demonstrated considerable efficacy combined with R-CHOP in patients aged < 65 years old with non-germinal center B-cell-like (non-GCB) DLBCL in the PHOENIX study...Zanubrutinib and orelabrutinib have better target selectivity... The BTKiR2 regimen demonstrates impressive response rates, survival and safety in elderly patients with newly diagnosed DLBCL compared with conventional chemotherapy, which may also provide protection of CNS against lymphoma infiltration. However, long-term efficacy of BTKiR2 remains unclear. The predictors of poor prognosis are B symptoms and LDH increased.

We previously reported that combinations targeting CD20 (obinutuzumab), BTK (ibrutinib) and BCL2 (venetoclax) counteracted both tumor intrinsic anomalies and dialogs within corrupted MCL ecosystems. Indeed, CARD11 GOF mutations led not only to BCR-independence and consequently ibrutinib resistance but also to BCL2A1-mediated venetoclax resistance. Nevertheless, our data show that targeting the CBM through MALT1 inhibition reverts this resistance and that MALT1 targeting appears as a promising therapeutic option for counteracting MCL resistance, especially in the context of acquired CARD11 mutation.

Covalent BTK inhibitors (BTKis), including ibrutinib and acalabrutinib, irreversibly bind to cysteine 481 in the kinase domain of BTK, inhibit growth, and induce loss of viability of MCL cells...In the present studies, we determined that in vitro exposure of human MCL cells, including MCL cell lines: REC1, Mino and JeKo-1, as well as patient-derived (PD) MCL cells, to NX-2127 (10 to 250 nM) for 2 to 24 hours markedly depleted BTK levels via proteasomal degradation, since co-treatment with the proteasome inhibitor carfilzomib restored BTK levels. NX-2127 but not NX-5948 treatment also degraded and depleted IKZF1 and IKZF3 levels...Co-treatment with NX-2127 (10 to 100 nM) and low nM levels of venetoclax or ABBV-744 was synergistically lethal against MCL cells (Delta synergy score above 1.0 by ZIP method). Collectively, these findings demonstrate that treatment with NX-2127 degrades and attenuates BTK and IKZF1/3 levels, as well as inhibits the downstream pro-growth and pro-survival signaling, resulting in loss of viability of MCL cells, including those resistant to covalent BTKi treatment. These findings also show promising anti-MCL activity of NX-2127-based combination with BCL2 or BET inhibitor which merits further in vivo validation.

Lower overall and progression-free survival rates were found for cases with MYD88, CD79B, and BTK mutations. These data confirm the biologic singularity of PE-DLBCLs and provide some suggestions for targeted therapies.

The improved workflow of CfDNA sequencing is of sound feasibility in a limited amount of vitreous humor. The logistic model based on the mutations could help to provide reliable clues for the diagnosis of VRL.

HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.

An exploratory analysis of the ibrutinib-treated rrMZL study showed mutations in genes regulating NF-kB signalling pathway: TNFAIP3 ( A20 ) and MYD88 predicted response, whereas KMT2D ( MLL2 ) and CARD11 were associated with primary resistance. Conclusion Mutations in genes associated with the NFkB pathway present at baseline are predictive of response to zanubrutinib in rrMZL patients. Detection of acquired BTK and PLCy2 mutations on therapy is feasible and may herald clinical disease progression.

We found that QRICH1-deficient CD4+ and CD8+ T cells produced higher levels of IL-2 and IFN-ɣ, respectively, following stimulation by anti-CD3/CD28. Our findings identify QRICH1 as a negative regulator of T cell activation that modulates the signaling output of CARD11.

Mantle cell lymphoma (MCL) is an aggressive form of NHL where frequent relapse following standard therapies remains a serious concern, even for promising new treatments such as combinations of a BTK inhibitor with the selective Bcl2 inhibitor venetoclax. Combination of AZD4573 with acalabrutinib resulted in greater anti-tumor activity than either monotherapy. Altogether, these data suggest that AZD4573, alone or in combination with acalabrutinib, could be an effective therapy for patients with r/r MCL.

Of note, EBVnegative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors related to EBV infection.

Following relapse after initial CHOP chemotherapy, the patient was successfully treated with cyclosporine A and has remained in remission since, with prophylactic TMP-SMX and no infections. After a poor response to multiple rounds of chemotherapy, she required autologous bone marrow transplant and has been in remission since, with no infectious complications. These cases illuminate an unusual pathological manifestation for BENTA disease, and further suggest that CARD11 GOF mutations can contribute to the development of cutaneous T cell dyscrasias and/or malignancies involving both CD4+ (Sézary syndrome) and CD8+ (SPTCL) lineages, or both (ALLP).

Taken together, the in vitro and in vivo data for JNJ‑67856633 and JNJ-64264681 suggest that combination therapy can increase the anti-tumor effect of the monotherapies and provide a more sustained response, offering strong support for clinical investigation of the combination of these two novel agents. A phase 1b combination study is scheduled to initiate.

No abstract available

This was associated with improved in vivo potency in a mechanistic model of B cell activation. The optimized compound led to tumor regression in a CARD11 mutant ABC-DLBCL lymphoma xenograft model.

CARD11 mutation is associated with longer OS and a better prognosis after ICI treatment. Therefore, the CARD11 gene can be used as a biomarker for predicting the efficacy of ICIs in SKCM patients.

He will further discuss the underlying molecular and pathophysiological mechanisms of these different mutations and their association with clinical phenotypes. Sponsor: Joint Session: Scientific Committee on Blood Disorders in Childhood & Scientific Committee on Immunology and Host Defense

Importantly, mouse-based mutant MyD88- and CARD11-derived signatures marked DLBCL subgroups exhibiting mirroring phenotypes with respect to the triad of senescence induction, macrophage attraction, and evasion of cytotoxic T-cell immunity. Complementing genomic subclassification approaches, our functional, cross-species investigation unveils pathogenic principles and therapeutic vulnerabilities applicable to and testable in human DLBCL subsets that may inform future personalized treatment strategies.

In summary, the novel, selective, small-molecule MALT1 inhibitor CTX-177 demonstrated preclinical efficacy along with target engagement in several lymphoma models with activated antigen receptor signaling and NF-κB pathway. Our results underscore the preclinical therapeutic potential of CTX-177 as a single-agent or in combination with other inhibitors like BTK inhibitor for the treatment of malignant lymphomas.

Among the 15 pts who progressed on acalabrutinib, 14 pts received systemic therapies for MCL [eight received ibrutinib based therapies (4 non responders, 3 achieved CR and 1 were PR and all pts progressed subsequently), 5 got chemo-immunotherapy, bortezomib, lenalidomide and progressed and one pt did not receive any treatment and was lost to follow up and died. In this small cohort, we did not observe BTK mutations associated with acalabrutinib resistance in MCL pts. Further studies are ongoing to determine acalabrutinib resistance mechanism in MCL.

The clonality assay using the TCR repertoires exhibited an oligoclonal pattern in 4 of 4 splenic CD4+ cells, and 2 of 2 LNs CD4+ cells from compound mice. These results suggest that CARD11 mutant-induced NFkB activation and constant HBZ expression may have similar effects, such as T-cell infiltration into organs and LN adenopathy, and that the simultaneous occurrence of both may have additive effects.

In addition to ABC-DLBCL, a MALT1 inhibitor is a promising treatment option for patients with CLL, MCL, WM, and FL whose tumors have been shown to be sensitive to inhibition of BTK. MALT lymphomas, characterized by MALT1 and BCL10 translocation, represent another attractive target for MALT1 inhibition.

He will further discuss the underlying molecular and pathophysiological mechanisms of these different mutations and their association with clinical phenotypes. Sponsor: Joint Session: Scientific Committee on Blood Disorders in Childhood & Scientific Committee on Immunology and Host Defense