- Koji Izutsu (Chuo-ku, Japan)
- Wojciech Jurczak (Krakow, Poland)
255O - Genetic mutations of Tim-3 ligand, and exhausted Tim-3+CD8+ T cells and survival in diffuse large B cell lymphoma (ID 331)
- Tingting Zhang (Tianjin, China)
Abstract
Background
Tim-3 is emerging as a promising target for antitumor immunotherapy. A number of clinical trials are ongoing to evaluate anti-Tim-3 therapies as a single agent or combinations in solid tumors and hematologic malignancies. However, there remains a considerable lack of data related to the information of Tim-3 signaling in diffuse large B-cell lymphoma (DLBCL), especially the genetic characteristics and immune microenvironment.
Methods
Here, next-generation sequencing was utilized to identify DLBCLs harboring genetic mutations of Tim-3 ligand, and multiple immunofluorescence staining and quantitative pathological analysis techniques were applied to determine the immune microenvironment.
Results
Three genetic mutations of galectin-9, which is a major ligand of Tim-3, were identified in six DLBCL patients (6/188, 3.2%). And these mutations had never been reported in DLBCL according to the COSMIC database. We further found that the Tim-3 mRNA level was significantly higher in DLBCL compared to that of normal B cells through the Oncomine database. Using multiplexed immunofluorescence staining, we found that patients with Tim-3 expression on tumor-infiltrating lymphocytes (Tim-3+ TILs) experienced significantly poorer outcomes than those with Tim-3- TILs (p = 0.041), and the median survival times were 65.0 months (95% CI: 71.2–88.6) and 79.9 months (95% CI: 54.4–75.6), respectively. Furthermore, we defined a novel subtype of exhausted T cells, named as exhausted Tim-3+ CD8+ T cells, and also found that patients with exhausted Tim-3+CD8+ T cells (median survival, 62.8 months, 95% CI: 50.0–75.6) had a significantly shorter survival than those with non-exhausted Tim-3-CD8+ T cells (median survival, 82.5 months, 95% CI: 72.0–92.9) (p = 0.034).
Conclusions
Overall, our findings provid an important addition to the genetic information of Tim-3 ligand in DLBCL. And we uncovered that patients with Tim-3+ TILs and exhausted Tim-3+ CD8+ T cells exhibited inferior survival, supporting potential strategies to block Tim-3 alone or in combination with other immune checkpoints as treatment options for DLBCL patients.
Editorial acknowledgement
The authors thank the Marvel Medical Laboratory, Tianjin Marvelbio Technology Co.,Ltd (Tianjin, China) for the support of next-generation sequencing.
Funding
This study was supported by the Natural Science Foundation of Tianjin (19JCYBJC26500, 18JCZDJC45100), the National Natural Science Foundation of China (81770213, 81670184), the National Key New Drug Creation Special Programs (2017ZX09304-021, 2018ZX09201015), the Clinical Oncology Research Fund of CSCO (Y-XD2019-162), the Projects of Tianjin Municipal Health Bureau (15KG145), the National Human Genetic Resources Sharing Service Platform (2005DKA21300)/Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital.
Disclosure
All authors have declared no conflicts of interest.
256O - Associations of OX40 and tumour microenvironment with outcomes in diffuse large B-cell lymphoma (ID 332)
- Xian-Huo Wang (Tianjin, China)
Abstract
Background
OX40, a novel costimulatory molecule expressed on activated T cells, plays an important role in enhancing the anti-tumor immune response. However, little is known about how OX40 functions in microenvironment in diffuse large B-cell lymphoma (DLBCL). The aims of this study were to determine the OX40 expression in DLBCL microenvironment and the relationship with the prognosis of patients.
Methods
The OX40 mRNA expression between DLBCL tissues and normal tissues, and its associated with survival were analyzed through Oncomine. The CD4, CD8, Pax-5, OX40 and Foxp3 multiplexed immunofluorescence staining, and quantitative analyses of OX40+ tumor-infiltrating T-lymphocytes were performed in DLBCL biopsy samples.
Results
We found that the OX40 mRNA expression was significantly upregulated in DLBCL patients through Oncomine (p<0.001) and high OX40 mRNA expression was significantly correlated with the favorable prognosis (p=0.018). The total OX40+ cells expression level in patients was significantly associated with Ann Arbor stage (p=0.039) and IPI score (p=0.047). The expression of OX40, compared with that in stable disease (SD)/progressive disease (PD) patients, was significantly increased in complete response (CR) or partial response (PR) patients (p=0.002; p=0.002, respectively). A higher total expression of OX40 and a greater number of CD8+/OX40+ T-cells were significantly correlated with longer overall survival (OS) (p=0.008; p=0.004, respectively). The expression of CD8+/OX40+ T-cells maintained prognostic value for OS in multivariate analysis (p=0.030; p=0.024, respectively).
Conclusions
Here, for the first time, we describe the expression characteristics of OX40 and tumor microenvironment in DLBCL through multiple immunofluorescence staining and quantitative pathological analysis techniques, and the association between OX40 expression and outcomes, providing a theoretical foundation for the potential clinical transformational application value of OX40 agonists for DLBCL therapy.
Editorial acknowledgement
All authors thank the National Human Genetic Resources Sharing Service Platform/Cancer Biobank of Tianjin Medical University Cancer Institute and Hospital grant 2005DKA21300 for the support of patient tissues.
Legal entity responsible for the study
The Research Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (TMUCIH) approved the study, which was conducted in accordance with the Declaration of Helsinki.
Funding
This work was supported by Natural Science Foundation of Tianjin grants 19JCYBJC26500 and 18JCZDJC45100), National Natural Science Foundation of China grants 81770213 and 81670184, National Key New Drug Creation Special Programs grants 2017ZX09304-021 and 2018ZX09201015, Clinical Oncology Research Fund of CSCO grant Y-XD2019-162.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant abstracts 255O and 256O (ID 1119)
- Lorenz H. Truemper (Goettingen, Germany)
LIVE Q&A (ID 1121)
- Koji Izutsu (Chuo-ku, Japan)
257O - Intercontinental cooperative non-Hodgkin T-cell lymphoma prospective registry study in Asia: ICT study (ID 528)
- Sang Eun Yoon (Seoul, Korea, Republic of)
Abstract
Background
The peripheral T-cell lymphoma (PTCLs) are uncommon and regionally heterogeneous malignancies. However, most studies have been conducted individually in each country, there was no opportunity to analyze the incidence across Asia comprehensively. Besides, the consensus for the treatment of T-cell NHLs has not been established. Thus, we conducted an Asian-specific study to determine the incidence of T-cell NHLs and to assess treatments commonly agreed by the majority.
Methods
We performed a multinational-multicenter, prospective registry study for adult patients with PTCLs. Six countries and 32 institutes in the Republic of Korea, China, Taiwan, Singapore, and Indonesia participated in the ICT study between April. 2016, and February. 2019.
Results
A total of 486 cases were registered. Regardless of subtypes, the median age was 57 (range 19-89) years, and 60% of men had more than women. The patients in stage 3 or 4 were 57.4%. The most prevalent subtype was ENKTL (28.6%), with the second most common subtype being AITL (24.7%), followed by PTCL-NOS (20.8%). The median PFS and OS were 21.1 months and 83.6 months. The PFS and OS for ALK-positive ALCL were superior. In frontline treatment, localized ENKTL patients who received chemoradiotherapy demonstrated superior ORR and PFS (P-value = 0.03) compared to chemotherapy alone. Advanced stage ENKTL who received upfront Auto-SCT also achieved superior outcomes (P-value=0.04). Among patients with PTCL-NOS, AITL, and ALCL, they were treated dominantly with CHOP and CHOEP. However, there was no difference in the survival benefit depending on regimens (CHOP-like vs. CHOEP like, vs. others, P-value = 0.68). Patients who underwent Auto-SCT showed better survival outcomes (P-value= 0.02), but it was not the influence of upfront Auto-SCT (P-value=0.98). In the salvage setting, the efficacy of cytotoxic chemotherapy was disappointed, and none of the salvage strategies is showing superiority.
Conclusions
We identified the relative incidence of T-cell lymphoma and the survival outcomes across Asia. Although the registration of patients is likely to be biased due to the large number of patients registered in some countries, the ICT study was meaningful as a first PTCLs registry study in Asia.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
258O - A germline variant rs2736098 in the TERT gene is a novel predisposition allele associated with JAK2V617F-positive myeloproliferative neoplasms (ID 233)
- Md Abdullah Al Maruf (Kowloon, Hong Kong PRC)
Abstract
Background
Myeloproliferative neoplasms (MPN) are a group of blood malignancies proliferating clonally and driven by somatic mutations in JAK2, CALR or MPL gene, but the contribution of genetic polymorphisms is not well characterized. Several germline variations at the JAK2 and TERT genes have been identified to be associated with MPN in different ethnic populations. Based on the previous studies, it has been established that rs2736100, rs2853677 and rs7705526 of TERT gene have strong association with MPN. The aim of this study was to identify any novel single-nucleotide polymorphism (SNP) in the TERT gene that may have any association with JAK2V617F-positive MPN.
Methods
Here we genotyped 4 TERT variants (rs2736100, rs2853677, rs7705526 and rs2736098) in 137 Hong Kong Chinese JAK2V617F-positive MPN patients and 480 ethnically matched healthy controls by unlabelled probe melting analysis technique.
Results
The genotyping analysis for these 4 SNPs with allelic model showed strong association (P < 0.05) with JAK2V617F-positive MPN. In addition, we found rs2736098, a novel SNP that also showed a strong association with JAK2V617F-positive MPN (P = 0.0006). We also observed a very strong association after performing allele association test with 50000 permutations in single marker analysis (Pemp = 0.003). For non-synonymous SNP rs2736098 the minor allele ‘T’ was found to be a risk allele (OR: 1.59, 95% CI: 1.22-2.09; P = 0.004) after adopting the logistic regression with age and sex adjustment.
Conclusions
Our findings suggest that the rs2736098 variant of TERT gene is associated with an increased risk of JAK2V617F-positive MPN in Hong Kong Chinese patients, indicating that rs2736098 might be a unique and potential signature for predicting the risk of JAK2V617F-positive MPN in Hong Kong Chinese population. To strengthen our findings worldwide, it is required to conduct similar studies in different ethnicity with a larger sample size.
Legal entity responsible for the study
The authors.
Funding
The Hong Kong Polytechnic University, Hong Kong SAR, China.
Disclosure
All authors have declared no conflicts of interest.
259O - Treatment patterns and outcomes in older patients with mantle cell lymphoma in an Asian population (ID 369)
- Xinyi Yang (Singapore, Singapore)
Abstract
Background
Significant progress have been made in the treatment outcomes of mantle cell lymphoma (MCL) since the introduction of cytarabine and rituximab in modern regimens. However, older patients may not readily tolerate these agents nor derive benefit. We investigated the impact of age on treatment patterns and clinical outcomes of MCL patients in an Asian population.
Methods
A retrospective study was conducted on patients (n=66) diagnosed with MCL at the National Cancer Centre Singapore between 1998 and 2018. The median follow-up duration was 40 months. Survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional models.
Results
The median age of the cohort was 59 years (range, 26-84), with a male predominance (73%). The majority (86%) had advanced stage 3-4 disease at diagnosis. Compared with younger patients, older patients aged ≥ 60 years (n=32; 48.5%) presented more frequently with B-symptoms (75% vs 38%, p=0.0028), anaemia (75% vs 35%, p=0.0013), and carried higher prognostic risk scores (sMIPI high risk 84% vs 56%, p=0.016). Non-cytarabine-based induction chemotherapy was more commonly administered in older patients (76% vs 32%, p=0.0012). The 5-year overall survival (OS) and progression-free survival (PFS) was 68% and 25% respectively. In a multivariable model, older age (HR 3.42, 95%CI 1.48-7.92, p=0.004) and anemia (HR 2.56, 95%CI 1.10-5.96, p=0.029) were independently associated with poorer OS while older age (HR 2.24, 95%CI 1.21-4.14, p=0.010) and hypoalbuminemia (HR 2.20, 95%CI 1.17-4.13, p=0.014) were independently associated with poorer PFS. In an exploratory analysis, maintenance rituximab following induction chemotherapy improved PFS in younger patients, with median PFS of 131 months and 45 months with and without maintenance therapy respectively (HR 0.39, 95%CI 0.16-0.93, p=0.0346). In contrast, no survival benefit was observed in older patients.
Conclusions
We demonstrated in an Asian cohort that older patients with MCL remain challenging to manage given their adverse clinical features and inability to derive benefit from contemporary treatment advances.
Legal entity responsible for the study
The authors.
Funding
National Medical Research Council of Singapore (TCR12DEC005) Tanoto Foundation Professorship in Medical Oncology New Century Foundation Limited Ling Foundation Singapore National Cancer Centre Research Fund SHF-Foundation SingHealth Duke-NUS Academic Medical Centre and Oncology ACP.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant abstracts 257O, 258O and 259O (ID 1120)
- Soon Thye Lim (Singapore, Singapore)
LIVE Q&A (ID 1122)
- Koji Izutsu (Chuo-ku, Japan)