All times are listed in CEST (Central European Summer Time)
828MO - Exonic mutation profile of primary gastrointestinal diffuse large B-cell lymphoma
- Shan-Shan Li (Guangzhou, China)
Abstract
Background
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma, and about 10% of DLBCL cases primarily occur in the gastrointestinal tract. Previous reports have revealed that primary gastrointestinal-DLBCL (pGI-DLBCL) harbors different genetic mutations from other nodal or extranodal DLBCL. However, the exonic mutation profile of pGI-DLBCL has not been fully addressed.
Methods
We performed whole-exome sequencing of 53 matched tumor and normal samples from pGI-DLBCL patients. The exonic mutation profiles were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed.
Results
A total of 6848 protein-altering events were found in our pGI-DLBCL cohort, and among these identified recurrent genetic mutations, the five most frequent mutated genes were
Conclusions
Our study provides a comprehensive view of the exonic mutational landscape of pGI-DLBCL, within which a specific gene cluster was mutated relating to humoral immunity activation and
Legal entity responsible for the study
The authors.
Funding
Genetron Health, Inc., China.
Disclosure
All authors have declared no conflicts of interest.
829MO - A gene signature to predict risk of transformation in patients with follicular lymphoma
- Ismael Fernandez-Miranda (Majadahonda, Spain)
Abstract
Background
Follicular lymphoma (FL) is an indolent but mainly incurable disease. Histological transformation to diffuse large B cell lymphoma is associated with rapid progression, treatment resistance and poor prognosis. Prospective identification of transformation-potential would also serve for guiding treatment and monitoring of patients. We aimed to validate a prognostic signature previously identified by our group (González-Rincón
Methods
We conducted targeted massive parallel sequencing on new diagnostic samples from 21 pre-transformed (pre-tFL) and 30 non-transformed FL (ntFL) patients. Additionally, our previously published cohort of 42 samples (22 pre-tFL and 20 ntFL) was included to enable risk analysis. Cox proportional hazards regression and Kaplan-Meier analysis were performed joining both cohorts to develop risk models.
Results
Comparative analysis revealed that pre-tFL showed more mutations than ntFL samples (9.5 vs. 8). The variant allele frequency (VAF) in pre-tFL samples was lower than in ntFL (pre-tFL: 24% vs. ntFL: 30%; t-test p<0.001), resulting in a higher proportion of subclonal mutations (<20% VAF) per sample (pre-tFL: 38% vs. ntFL: 24%; t-test p=0.034). The detection of mutations in
Conclusions
In summary, genomic analysis on FL samples have enabled the association of mutated genes with higher risk of transformation. We have also demonstrated that mutations below 20% VAF in FL samples at diagnosis are associated with transformation. Integration of the mutational status with clinical risk factors into a predictive model improves the risk stratification and could be useful for identifying patients at higher risk of transformation.
Legal entity responsible for the study
Lymphoma Research Group of the Instituto de Investigación Sanitaria Puerta de Hierro-Segovia de Arana.
Funding
The ISCIII-MINECO AES-FEDER (Plan Estatal de I+D+I 2008-2011 and 2013-2016) (DTS17/00039, PI17/00272); GILEAD (GL18/00019) and Comunidad de Madrid (B2017/BMD-3778). Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) (CB16/12/00291).
Disclosure
All authors have declared no conflicts of interest.
830MO - Integrated driver mutations profile of Chinese NK/T cell lymphoma
- Ting-zhi Liu (Guangzhou, China)
Abstract
Background
Natural killer (NK)/T-cell lymphoma (NKTCL) is a rare type of non-Hodgkin’s lymphoma prevalent in East Asian countries. There is still a significant lack of effective therapeutic targets for the treatment of NKTCL. In this study, we investigated the driver mutation profile of 15 Chinese patients with NKTCL to determine its possible mechanisms of formation and identify therapeutic targets.
Methods
We performed whole-exome sequencing (WES) on paired tumor/normal samples from 15 Chinese patients diagnosed with NKTCL. We performed a K-Means prediction based on the mutation profiles of proto-oncogenes retrieved from the NCG database. The NKTCL mutation patterns were analyzed using the Bayesian non-negative matrix factorization (Bayesian-NMF) method.
Results
Among the 15 Chinese NKTCL patients, the primary site of the lymphomas was the colon (40%), followed by ileum (26.7%), and small intestine (26.7%), while one patient’s was the rectum. Furthermore, the mean tumor mutation burden (TMB) was 1.04 (0.29-2.55). The RETSAT gene showed the highest mutation frequency (26.7%), followed by SNRNP70 (20%), and ADGRL3 (13.3%). Among the oncogenes, the genes with the six highest gene mutation frequencies included ARID1B, ERBB3, KMT2D, POT1, TET2, and TP53 (13.3%). NMF analysis of 509 single-nucleotide variants (SNVs) from 15 NK T-cell lymphoma samples identified three mutational signatures; signature one (46.69% SNV) and signature three (32.09% SNV) were well known C > T transition at CpG sites. Similar to feature 22 in the COSMIC database, the second feature (21.23% SNV) was dominated by the T > A transition. Furthermore, most samples featured signatures one and three as their main mutation patterns.
Conclusions
In this study, the genome-wide analysis of 15 Chinese NK/T-cell lymphoma patients revealed that RETSAT, and SNRNP70 were the genes with the highest mutation frequencies. In addition, NK/T-cell lymphoma patients showed higher mutation frequencies in ARID1B, and ERBB3 oncogenes. These findings suggested the presence of possible driver genes, along with therapeutic targets for NKTCL. Furthermore, they illustrate characteristic mutation patterns, which are valuable for guiding future NKTCL research.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Discussion 828MO, 829MO and 830MO
- Andrew J. Davies (Southampton, United Kingdom)
831MO - Geptanolimab in Chinese patients with relapsed or refractory primary mediastinal large B-cell lymphoma: Results from a multicenter, open-label, single-arm phase II trial
- Yuan-Kai Shi (Beijing, China)
Abstract
Background
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare aggressive B-cell non-Hodgkin lymphoma. Geptanolimab is a novel fully human anti-programmed cell death protein 1 (PD-1) mAb and exhibits favorable results in previous studies. This is a multi-center, open-label, single-arm phase II clinical trial aiming to evaluate the efficacy and safety of Geptanolimab in Chinese patients with relapsed or refractory PMBCL.
Methods
All patients enrolled received Geptanolimab 3mg/kg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. The primary endpoint was objective response rate (ORR) per Lugano 2014. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 5.0.
Results
From October 22nd, 2018 to October 27th, 2020, twenty-five patients with relapsed or refractory PMBCL were enrolled and treated. As of data cut-off on March 12th, 2021, patients received a median of 28 (2-56) cycles of treatment. At a median follow-up of 56 (3.86-112.14) weeks, overall response rate (ORR) was 64% (16/25, 95% confidence interval [CI]: 42.52%, 82.03%), including 6 patients (24%) with a complete response and 10 patients (40%) with a partial response. Median progression-free survival and duration of response have not reached yet. Treatment-related adverse events (TRAEs) of any grade occurred in 84% (21/25) patients. The most common grade 3-4 TRAEs were leucopenia (5/25, 20%), neutropenia (4/25, 16%) and lymphopenia (4/25, 16%).
Conclusions
Geptanolimab showed good anti-tumor activity with ORR of 64% and manageable safety profile in Chinese patients with relapsed or refractory PMBCL.
Clinical trial identification
NCT03639181.
Legal entity responsible for the study
Genor Biopharma Co., Ltd.
Funding
Genor Biopharma Co., Ltd.
Disclosure
All authors have declared no conflicts of interest.
832MO - Immune microenvironment in classical Hodgkin lymphoma: Composition and dynamics in patients with relapsed/refractory disease
- Liudmila Fedorova (Saint-Petersburg, Russian Federation)
Abstract
Background
Classical Hodgkin lymphoma (cHL) is characterized by the unique tumor microenvironment (TME) rich in immune cells. One of the explanations for the depressed antitumor response in cHL is hyperexpression of inhibitory immune checkpoint receptors on T cells as well as increased proportion of M2 macrophages (M2) in TME. The presence of high number of M2 has been demonstrated to worsen the prognosis of patients treated with standard chemotherapy, while data regarding the prognostic value of TME features in patients treated with PD-1 inhibitors is limited.
Methods
This retrospective study included 61 primary tumor samples from pts with r/r HL, treated with Nivo, and 15 repeated samples obtained during relapse or progression of disease after immunotherapy. The PFS and the best overall response (BOR) depending on the proportion of cells positive for CD68, CD163, PD-1, LAG-3, TIM-3, CTLA-4, TIGIT, c-MAF in the TME in primary and sequential biopsies were analyzed. Immunohistochemical staining was performed with Bond III (Leica Biosystems). The antibody cocktail (CD163/c-MAF) was used for identification of M2. The response to Nivo was assessed by PET-CT with LYRIC. ROC analysis established 8,5% cut-off value for CD163 expression and 11,5% for CD68 expression, dividing patients with high and low number of positive cells.
Results
In the CD163low group, 4-year PFS was 24,1% (95% CI 9,3%-42,6%) with a median PFS of 11,6 months (95% CI 7,2-24,8); in the CD163high group - 42,6% (95% CI 20,2%-63,4%) with a median of 24,8 months (95% CI 20,4 - NA), p = 0,0086. Complete remission (CR) achievement as BOR to Nivo was associated with a lower level of M2 in primary biopsies (p = 0.047). In the analysis of sequential samples, an increase of PD- 1+ and LAG-3+ T-cells and depletion of CD68+ and CD163+ cells in repeated biopsies was observed (median PD-1–1.0% vs 7.0%; LAG-3–5.0% vs 8.0%; CD68–10.0% vs 7.0%; CD163–9.0% vs 3.0%, p<0,05).
Conclusions
We found that low number of CD163+ cells in primary samples were associated with inferior PFS during Nivo therapy, while a lower level of M2 was correlated with achievement of CR. In repeated biopsies after Nivo therapy the cell profile in the TME changed: number of PD-1+ and Lag-3+ T-cells increased and number of CD68+ and CD163+ macrophages decreased.
Legal entity responsible for the study
Liudmila Fedorova.
Funding
The reported study was funded by RFBR, project number 20-31-70001 #20-315-90085.
Disclosure
All authors have declared no conflicts of interest.
Discussion 831MO and 832MO
- Ingrid Glimelius (Uppsala, Sweden)