MYC rearrangement + BCL2 rearrangement

Our study demonstrates that our local population has similar clinicopathological and prognostic characteristics of DLBCL as compared to global findings. It also highlights the limitations of R-CHOP(-like) regimens in contemporary DLBCL management and therefore an ongoing need for improved therapeutic strategies.

Individual genomic features of LBCL cases may predict for development of disease progression in newly diagnosed patients treated with standard therapies, as well occur at higher frequencies in cases of disease progression based upon geographic region and/or cell of origin status. These novel findings support efforts to evaluate genomic features as biomarkers for response to specific therapies in subsets of LBCL patients who experience disease progression, which may lead to discovery of more effective treatment options.

Furthermore, because one IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.

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.

In total, 169 patients were treated with R-CHOP, 10 with R-CHOP and intermediate-dose methotrexate, 19 with R-DA-EPOCH, and 16 with other regimens. The 5-year OS for DHL patients was 32.4% (95% CI 16.6-48.2%) while all three TH patients were deceased or lost to follow-up. Our analyses of real-life data disclose that the R-CHOP protocol with CNS prophylaxis is a successful and curative treatment for a substantial proportion of DEL patients.

P3, N=300, Recruiting, Nordic Lymphoma Group | N=200 --> 300 | Trial completion date: Feb 2026 --> Dec 2028 | Trial primary completion date: Feb 2023 --> Dec 2025

In conclusion, our results demonstrate an increased exhaustion in circulating T-cells of HGBL-MYC/BCL2 patients. Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance to investigate potential immune evasion in the microenvironment of MYC-rearranged lymphomas.

Similar results were obtained by combining Talazoparib and different PARP inhibitors with the alkylating agent cisplatin, indicating a class effect. Importantly, PBMC-derived T cells from healthy donors did not show any sign of DNA damage accumulation upon exposure to Lonca, Talazoparib and the combination. These data provide the rationale for future therapeutic strategies based on selective induction of DNA damage in neoplastic B cells in combination with DDR inhibition in aggressive MYC-positive B cell lymphoma.

Blood 2020, Varano et al. Nature 2017), which converge on a common phenotype and high-grade morphology (Figure 1B).

23 (38%) vs 45 (33%) were treated with Tisa-cel and 90 (67%) vs 37 (62%) were treated with Axi-cel. Figure 2 Conclusion : CAR-T cell therapy used in third line or more seems to overcome the poor prognosis of HGBL subtypes as compared to other LBCL subtypes, all characterized with FISH. This observation supports the interest to evaluate the potential benefit of CAR-T earlier in the course of the disease.

HGBL-MYC/BCL2 patients have a distinct peripheral T-cell and NK-cell phenotype from LBCL NOS patients without a MYC rearrangement, but show no apparent functional deficiencies in terms of proliferation, cytokine secretion or cytotoxic activity. These results are not contradicting the application of T-cell and NK-cell based immunotherapeutic approaches for patients with aggressive B-cell lymphoma. Simultaneously, it emphasize the need to investigate the potential immunomodulatory impact of lymphoma intrinsic MYC in the tumor microenvironment.

Whereas R-CHOP or polatuzumab vedotin + R-CHP are now both standard treatments for DLBCL, in primary mediastinal B-cell lymphoma, dose adjusted EPOCH-R has become the standard of care based on prospective trials demonstrating that this treatment can obviate the need for mediastinal radiation in most patients.12,13 In the case of traditional Burkitt lymphoma, the Magrath regimen of R-CODOX-M/IVAC is frequently used for young/fit patients although there are also prospective data supporting the use of dose adjusted EPOCH-R for Burkitt lymphoma.14,15 For double/triple hit lymphoma, more intensive chemotherapy regimens are frequently recommended for fit patients including dose adjusted R-EPOCH, R-hyperCVAD, and R-CODOX-M/R-IVAC based on prospective single-arm trials and/or retrospective experience.16,17 In the case of HGBL, NOS, it is generally assumed that one of these intensive regimens should be used, as outcomes with R-CHOP are generally unsatisfactory, but comparative data are lacking. In conclusion, as outlined in the 2016 WHO classification and carried forward to updated classifications, HGBL remains an imperfectly described disease with lack of consensus diagnostic or treatment recommendations. In general, aggressive treatment regimens are recommended, if feasible, and future research is needed to study a larger number of cases with advanced molecular techniques and to prospectively assess different treatment regimens to improve outcomes for patients with these high-risk lymphomas.

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).

Follow-up studies will be necessary to see if this has any treatment/prognostic implications. Additionally, new entities have been added to the WHO 5th edition which are not necessarily reflected in the ICC.

RT-DLBCL has distinctive morphological and immunophenotypic features, characterised by IB morphology and common expression of CD5, MUM1 and LEF1. Cell-of-origin does not seem to have prognostic implications in RT-DLBCL.

Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R versus R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Only 15 patients received immunochemotherapy: 8 were treated with R-CHOP and CNS prophylaxis, other 7 patients had more intensive therapy: GMALL, CODOX/IVAC or DAEPOCH-R...The outcomes is poor and less than 40% of patient are alive from one year from diagnosis. Intensive therapy has not improved treatment results.

With a median follow-up time of 61.5 months (range 7-123 months), 20 patients succumbed, yielding: 3-year and 5-year progression free survival (PFS) in all patients 84.5% και 82.5% respectively, and 3-year and 5-year OS in all patients 86.7%. Conclusion s : This extensive i-FISH investigation provides clinically meaningful information on the genetic profile of NHLs, raises new questions, and points to directions for further investigation within the field of childhood lymphoproliferation.

Among the SCDLBCL, only relapse and high expression of Ki67 are associated with shorter OS (Tab1).Discussion Our study emphasizes the clinico-pathological, cytogenetic and molecular similarities and differences between PCDLBCL and SCDLBCL, underlying the importance of properly staging CDLBCL pts at time of diagnosis . In the PCDLBCL setting, we confirmed the independent pathological entity of the NOS category highlighting the better prognostic outcome of this subtype.

The presence of CCND3 mutations tended to have negative prognostic effects on PFS (HR: 31.8, 95%CI: 2.7-371.5, P = 0.004) and OS (HR:18.6, 95%CI:2.6-133.9, P = 0.006), in patients with BCL2 translocations.Conclusion :In DLBCL patients harboring both BCL2 and MYC translocation are most likely resulting in aggressive clinical behavior, while BCL2 translocation alone has similar prognosis with DLBCL patients without BCL2 rearrangement. DLBCL patients contained BCL2 translocation (with or without MYC rearrangement) demonstrate a higher proportion of mutation associated with epigenetic modify, which may benefited from epigenetic therapy.

No abstract available

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.

While detection of a translocation in sequencing data can be limited by factors such as poor biopsy quality, a translocation partner was identified for the majority of tumors with LR and LG patterns, with all but 1 translocation preserving the MYC gene. These results support that LR and LG patterns should be interpreted as a positive MYC FISH result.

In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R‐CHOP (R‐CHOP‐I) did not improve the outcome for non‐germinal centre like DLBCL. Acalabrutinib is well tolerated in combination with R-CHOP chemotherapy and may be associated with improved efficacy. This is being explored in the randomised REMoDL-A (NCT04546620) and ESCALADE (NCT04529772) trials.

In this large RWE study, we demonstrate that the presence of comorbidity within the Severe4 composite index had prognostic significance for OS in CART recipients for r/r DLBCL. Importantly, Severe4 was validated in a separate cohort. Severe4 is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS.

Although the frequency of DLBCL in Johannesburg has not dropped significantly in the post-ART era, a slight improvement in survival is observed. However, outcomes remain poor, indicating a need for further improvements in care.

Outcomes among HGBCL patients managed at the University of Michigan were favorable, though interestingly, not all patients received true dose escalations. Future directions will involve assessing whether dose escalations of this regimen are truly instrumental in improving survival outcomes.

Context: Historically, high-grade B-cell lymphomas (HGBCL) have an inferior prognosis and respond poorly to standard upfront R-CHOP... Outcomes among HGBCL patients managed at the University of Michigan were favorable, though interestingly, not all patients received true dose escalations. Future directions will involve assessing whether dose escalations of this regimen are truly instrumental in improving survival outcomes.

High-grade “triple hit” B-cell lymphoma is associated with an aggressive clinical course and poor prognosis, as was observed in our case. Additionally, our case underscores the importance of testing for BCL2, BCL6, and MYC rearrangements, even with lower levels of MYC immunophenotype expression.

High-grade “triple hit” B-cell lymphoma is associated with an aggressive clinical course and poor prognosis, as was observed in our case. Additionally, our case underscores the importance of testing for BCL2, BCL6, and MYC rearrangements, even with lower levels of MYC immunophenotype expression.

Children with IG-MYC-r within that subgroup had 3-year EFS of 47% and OS of 60%, representing a high-risk BCP-ALL. To develop effective management strategies this patient group must be allowed access to contemporary, minimal residual disease adapted, prospective clinical trial protocols.

CGP appears more sensitive than FISH in detection of IGH-BCL2 and IGH-MYC rearrangements. FISH testing is superior for detection of non-IGH-MYC. Neither FISH nor CGP detect all DHLs.

This study elucidates a recurrent pattern of mutational events driving FL into MYC-driven BCL2 rearranged HGBL, unveiling the mutational pathogenesis of this provisional entity. Through this refinement of the molecular taxonomy for aggressive, germinal-center derived B-cell lymphomas, this calls into question the current WHO-classification system, especially regarding the status of MYC/BCL6 rearranged HGBL.

Prognostic analysis was performed using publicly available data from the Haematological Malignancy Research Network (HMRN) study of 648 patients treated with RCHOP chemotherapy for DLBCL (Lacy et al, Blood 2020)... CDKN2A deletions are specific to the MCD genomic subtype of DLBCL and indicate particularly poor prognosis within this class. Relative mutual exclusivity with TP53 mutations suggests that CDKN2A deletion may constitute an alternative, critical “hit” to a tumor suppressor gene in MCD DLBCL. Further research should examine the clinical relevance of CDKN2A deletions for refractoriness to standard therapy and its role in immune evasion that is characteristic of relapsed/refractory MCD DLBCL.

Of the 550 pts who received CAR-T, 71% (n=393) got axicabtagene ciloleucel, 22% (n=120) tisagenlecleucel, and 7% (n=37) lisocabtagene maraleucel. Given these results, CIRS evaluation and “Severe4” should be considered prior to CAR-T in DLBCL. GS & AK contributed equally

This entity has a dismal prognosis with resistance to most conventional chemotherapy regimens. The treatment options were discussed with the patient who had an Eastern Cooperative Oncology Group (ECOG) Performance Status 3 and agreed to hospice care.

We propose a highly sensitive screening strategy for detection of MYC/BCL2 rearrangement in high-grade B-cell lymphoma in a resource-limited setting (pending validation in a larger cohort).