Mediastinal B Cell Lymphoma

P2, N=30, Active, not recruiting, David Bond, MD | Trial completion date: Jul 2024 --> Dec 2024 | Trial primary completion date: Jul 2024 --> Dec 2024

P=N/A, N=540, Active, not recruiting, International Extranodal Lymphoma Study Group (IELSG) | Phase classification: P3 --> P=N/A

The 18F-FDG PET/CT performed during this episode of illness revealed a mild degree of 18F-FDG uptake along the pericardial lining [maximum standardized uptake value (SUVmax) =6.76] compared with the blood pool activity (SUVmax =3.17), which favors pericarditis over relapsed lymphoma. His symptoms subsided 2 weeks after treatment with an non-steroidal anti-inflammatory drug, and he had no sign of relapsed lymphoma on subsequent follow-ups.

According to a multivariate model integrating AID expression and BCR diversity, only HCD status was associated with outcome (PFS: HR=14.6 [2.46-86.8]; OS: HR=11.4 [1-128.8]). We confirmed this poorer prognosis in an independent cohort, in which 6/37 (16%) patients exhibited HCD (PFS: HR=12 [3-46]; OS: HR=17 [1.8-170]).

Recognizing patient-related factors that may influence response to ICIs is becoming critical to optimize the treatment pathway of heavily pretreated, young patients with a potentially long-life expectancy. These preliminary results indicate potential early GM signatures of ICIs response in lymphoma, which could pave the way for future research to improve patients prognosis with new adjuvant strategies.

P1, N=387, Completed, Juno Therapeutics, a Subsidiary of Celgene | Active, not recruiting --> Completed

P1, N=52, Not yet recruiting, Second Affiliated Hospital, School of Medicine, Zhejiang University

P1, N=30, Active, not recruiting, Malaghan Institute of Medical Research | Recruiting --> Active, not recruiting

P1/2, N=307, Completed, Kite, A Gilead Company | Trial primary completion date: Sep 2020 --> Jul 2023

P3, N=244, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2028 --> Sep 2027 | Trial primary completion date: Dec 2028 --> Sep 2027

These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.

P1, N=78, Recruiting, Adicet Bio, Inc | Trial completion date: Mar 2024 --> Dec 2027 | Trial primary completion date: Mar 2023 --> Dec 2025

Long term safety and efficacy data from these ongoing studies are eagerly awaited. In this comprehensive review, we discuss the mechanism of immune checkpoint inhibitors, the key takeaways from the reported results of completed and ongoing studies of these therapies in the context of hematological malignancies.

P=N/A, N=592, Completed, University Hospital Southampton NHS Foundation Trust | Active, not recruiting --> Completed

P2, N=35, Recruiting, Jennifer Crombie, MD | Not yet recruiting --> Recruiting

This large-scale genomic characterization of PMBCL identified novel treatment targets and genetic lesions for refined risk stratification. DUSP2 and CD58 mutation analyses may guide treatment decisions between rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab.

We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR=6.11 [1.61-23.2]). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poor outcomes from standard chemotherapy who might benefit from first-line anti-PD1 immunotherapy.

Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1. 4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle... Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

Like HIV associated DLBCL, these results show that PTLD is more genomically stable than IC-DLBCL, and that genomic stability is further enhanced in EBV(+)PTLD which have increased expression of UPS related genes. In contrast, EBV(-)PTLD have increased expression of DNA damage repair genes, including RAD51. In summary, monomorphic DLBCL PTLD tumors have enhanced genomic stability that appears to be mediated by two distinct mechanisms stratified by EBV status.

ConclusionAltogether, data suggests that ruxolitinib enhances immunogenicity primarily in 9p amplified cell lines and supports the hypothesis that ruxolitinib may prime for lymphoma cell death when combined with immunotherapy. These findings provide a foundation for in vivo assessment in humanized mouse models treated with combination anti-PDL-1 and JAK1/2 inhibitor, targeting tumorigenesis driven by 9p amplification.

High plasma levels of a 9-gene signature (BECN1, PRKCB, COPA, TSC22D3, MAP2K3, UQCRHL, PTMAP4, EHD1, NAP1L1 pseudogene) and a 5-gene signature (FTH1P7, PTMAP4, ATF4, FTH1P8, ARMC7) were significantly associated with inferior progression-free and overall survival in DLBCL patients, respectively, independent of the NCCN-IPI score. Total RNA sequencing of blood plasma samples allows the analysis of the cell-free transcriptome in DLBCL and PMBCL patients and demonstrates its unexplored potential in identifying diagnostic, cell-of-origin, and prognostic cfRNA biomarkers.

Mass spectrometry demonstrates that ZNF217 acts within a histone modifier complex containing LSD1, CoREST and HDAC and interferes with H3K4 methylation and H3K27 acetylation. Concluding, our data suggest non-catalytic activity of ZNF217, which directs histone modifier complex function and controls B cell differentiation-associated patterns of chromatin structure.

In this post hoc analysis of ZUMA-1 with up to 6 years of follow-up, axi-cel had long-term LREFS in a substantial proportion of patients, with a 5-year rate of 34% (57% among patients who achieved a CR). Additionally, a CR at 12 and 24 months may be predictive of extended OS. Among patients who achieved a CR, deaths due to axi-cel–related AEs mainly occurred before Month 24.

Twenty-three (79.3%) pts were treated with axicabtagene ciloleucel and 6 (20.7%) with tisagenlecleucel. Imaging features extracted from pre-infusion 18F-FDG PET/CT images in combination with several clinical features could predict survival and neurotoxicity in pts with DLBCL or PMBCL treated with CAR-T cell therapy. Quantitative features extracted from the PET/CT imaging exams may be useful for patient risk stratification and neurotoxicity prediction. Validation of these classifiers in independent datasets is warranted.

Lymphodepletion chemotherapy with fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day was administered on Days −5 to −3 prior to CAR T-cell infusion. Moreover, CART19/20 showed robust activity in patients with R/R NHL with durable responses seen. By utilizing a bispecific CAR and enriching for TN/MEM cells, this phase 1 trial of CART19/20 demonstrates the possibility of improving outcomes through targeting common mechanisms of CAR-T cell resistance.

Among them , stage III-IV accounted for 43/49 (87.8%) and GCB subtype 22/49 (44.9%),and received a median of 7 cycles(3-14)of prior treatment, previous radiotherapy was 8/49 (16.3%), and previous other target CART patients were 20/49 (40.8%).The disease status of patients before ASCT-CART was 23 patients in complete remission, 17 patients in partial remission, 3 patients with stable disease, and 6 patients with progressive disease.Patients were treated with BEAM and fludarabine before ASCT...Summary/Conclusion The ASCT-CART therapy could enhance its the remission rate and long-term efficacy in the treatment of advanced relapsed/refractory B-cell lymphoma with controllable safety. Patients who were in remission before ASCT-CART therapy achieved a longer term remission after ASCT-CART cell therapy.

Introduction Co-expression of C-MYC and BCL2 in diffuse large b-cell lymphomas (DLBCL), also termed double-expressor lymphomas (DEL), has been shown to be associated with poorer outcomes after standard R-CHOP induction therapy...Conclusion Co-expression of C-MYC/BCL2 was associated with inferior outcomes after ASCT in patients with R/R DLBCL. While ASCT has been the standard curative approach in the R/R setting, considerations for novel targeting therapies to achieve a deeper response prior to transplant or the upfront use of chimeric antigen receptor T-cell therapy at first relapse may be further explored in this high-risk subset of patients.

Moreover, analysis of serum proteins refines molecular classification. Altogether, joint analysis of serum proteins and ctDNA provides new tools to dismantle LBCL heterogeneity.

We found co-occurrence of inactivating events in A20 and XPO1 missense mutations impacting 15% of PMBCL evaluated cases, with consistent results seen across all studies (range: 13.8-20%). As expected, A20 mutations/del were more prevalent than XPO1 mutations across all studies (OR 2.46, 95% CI 0.84-7.18, p = 0.02). XPO1 mutated cases trended towards a greater likelihood of having co-occurring A20 mutations (OR 8.51, 95% CI 0.84-86.47, p = 0.08).

These results demonstrate that HIV pos DLBCL tumors are less aberrant than their HIV neg counterparts irrespective of COO subtype. However, the degree of genomic stability differs by COO, with HIV pos GCB tumors being more genomically stable than HIV pos ABC tumors. Although both have enhanced expression of UPS related SCF genes (RBX1, SKP1), only HIV pos GCB tumors have enhanced expression of key DNA repair genes as well including Fanconi Anemia (BRCA2/FANCD1, FANCL) and mismatch repair (MSH2, MSH6) genes (adjusted p-values of ≤ 0.0263).

Blood and tissue samples will be analyzed by multi-parameter flow cytometry and hiplex imaging assays (Phenocycler-Fusion/CODEX) to identify immune signatures of response and resistance to Lonca, and to assess CAR T-cell persistence; blood samples will be analyzed by CAPP-Seq to measure minimal residual disease. Finally, total metabolic tumor volume will be assessed on pre-treatment PET-CT scans, and association with response to consolidation therapy will be analyzed.

Dose-adjusted Etoposide, Prednisolone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (DA-EPOCH-R) without radiotherapy has demonstrated excellent activity in a small phase II study but with increased chemotherapy toxicity. Key secondary endpoints include response to window phase treatment, overall survival, requirement for radiotherapy and safety of treatment including rates of early discontinuation due to treatment toxicity. Several biomarkers are also being investigated for their predictive value for treatment response including minimal residual disease status (measured by Adaptive Immunoseq and CAPP-Seq), PET-CT parameters (e.g., Metabolic tumour volume), and PD-1/PD-L1 expression and 9q24 alterations.

We could not confirm an association between COO, as determined by Hans algorithm, and outcomes in R/R aNHLs who received axi-cel at our center. Prospective analyses on larger datasets and other types of CAR-T products are needed.

In this study cohort, 106 (77.9%) patients received R-CHOP-like regimens as induction therapies, 25 (18.4%) patients received an R-EPOCH regimen, two (1.5%) patients received an R-HyperCVAD regimen, and three (2.2%) patients died before completing the first cycle of chemoimmunotherapy... A low ratio of circulating CD8+ T lymphocytes to M-MDSCs (CD8MMR) serves as a poor prognostic factor for both PFS and OS in treatment-naïve DLBCL patients. This finding warrants further investigation and highlights the possibility of risk-adapted strategies when treating DLBCL patients.

P2, N=25, Recruiting, New York Medical College | Trial primary completion date: Dec 2023 --> Dec 2024

In this secondary analysis of a phase III randomized trial of chemotherapy alone for DLBCL, initial bulk was not shown to be significantly associated with outcomes. Prospective data comparing consolidative RT versus no RT are necessary to determine optimal treatment paradigms.

CRT may be omitted in patients with a negative end of treatment PET scans; however, careful observation may also obviate the need for CRT in PET positive patients.

P1/2, N=307, Completed, Kite, A Gilead Company | Active, not recruiting --> Completed

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.

STR AI in 9p24.1 and 16p13.13 and PD-L1 and HLA-DR expression are highly frequent though probably independent events relevant to immunotherapy response in PMBCL.

Standard approach (S-CIT) was defined as R-CHOP-21/CHOP-21, with or without RT...DI-CIT demonstrates a survival benefit, with significantly less radiation exposure, curtailing long-term toxicities associated with radiotherapy. As we await results of randomized prospective trials, our study supports the use of dose-intensive chemoimmunotherapy for the treatment of PMBCL.

According to data from the phase III IELSG37 trial, consolidation radiotherapy is unnecessary for patients with primary mediastinal B-cell lymphoma who respond completely to standard immunochemotherapy. Two other studies of peripheral T-cell lymphomas and adult T-cell leukemia/lymphoma, respectively, point to golidocitinib, an investigational JAK1 inhibitor, and mogamulizumab, which targets CCR4, as potential new treatment options.