No abstract

No abstract

No abstract

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. Significance: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common variant of non-Hodgkin lymphoma (NHL) accounting for approximately 30% of the NHL cases worldwide. Previous reports have associated certain viral infections with the development of DLBCL such as HIV and EBV, both infections related with an aggressive clinical course and worse outcome. The human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus regarded as the pathogenic agent for adult T-cell lymphoma/leukemia. HTLV-1 is endemic in Japan, the Caribbean basin, South America, and parts of Africa. In Peru, up to 3% of the healthy adult population carries HTLV-1. As data on the impact of HTLV-1 infection in DLBCL outcomes is scarce, we aim to describe the clinical features and outcomes of HTLV-1-positive patients with a pathological diagnosis of DLBCL. Methods: We retrospectively reviewed medical records of patients diagnosed and managed for DLBCL at the National Institute of Neoplastic Diseases in Lima-Peru between 2007 and 2019. Patients were evaluated for HTLV-1 infection at the time of diagnosis. Positive HTLV-1 cases were matched to negative HTLV-1 controls based on age, sex, and cancer staging. Treatment responses were assessed according to the Lugano criteria. Overall survival (OS) and event-free survival (EFS) curves were estimated using the Kaplan-Meier method and compared with the Log-rank test to determine the impact of HTLV-1 infection. Multivariate Cox regression models were reported with adjusted Hazar Ratios (aHR) with a 95% confidence interval (95% CI). Results: A total of 192 patients with DLBCL were identified and had sufficient data for analysis. Seventy (37%) cases were positive for HTLV-1 infection and 122 (63%) were not. Table 1 summarizes the clinical features and outcomes of DLBCL patients according to HTLV-1 status. Overall, the majority of patients were ≥65 years (59%), had ECOG performance status ≤2 (95%) and were stage III-IV (51%) at diagnosis. One third (n=64) of patients had extranodal involvement with 71 affected sites of which bone marrow involvement was frequently found in HTLV-1-negative DLBCL cases (55% vs. 7%, p<0.001) and liver/gastrointestinal tract in HTLV-1-positive cases (48% vs. 9%, p<0.001). There was no difference among DLBCL groups regarding risk stratification based on NCCN-IPI score (p=0.394). With a median follow-up of 6.5 years, we found that in DLBCL patients, HTLV-1 infection had no significant impact in 5-year OS (HTLV-1-positive 40% versus HTLV-1-negative 42%, p=0.930) and EFS rates (HTLV-1-positive 33% versus HTLV-1-negative 32%; p=0.890) (Figure 1). Multivariate cox regression analysis could not identify HTLV-1 infection as a risk factor for higher mortality or disease progression (Figure 1). Conclusion: To the best of our knowledge, this is the largest case series describing the clinical characteristics and outcome of HTLV-1-positive DLBCL patients. A study from Japan on early stage localized (head and neck) B-cell-NHL (n=198, HTLV-1 seropositive n=21 and with DLBCL n=12) treated with radiotherapy and/or multi-agent chemotherapy found poorer prognosis on HTLV-1 carriers compared to non-carriers (5-year OS: HTLV-1-positive n=21, 49% vs. HTLV-1-negative n=177, 78%, p=0.007; Hiroaki et al BJH 2003). In this study, we included DLBCL patients with both early and advanced stage disease along with localized and extranodal involvement. We found that HTLV-1 infection had no significant impact on 5-year OS and EFS rates when using conventional therapy for DLBCL. Moreover, we did not find differences in relapsed and mortality rates. Further investigation is needed to confirm the potential impact of HTLV-1 infection in DLBCL outcome. Disclosures No relevant conflicts of interest to declare.

7012 Background: Acute Lymphoblastic Leukemia (ALL) in Latino countries is characterized by high incidence and worst outcomes compare to other ethnicities. However, the actual epidemiological characterization of ALL in South America remains unknown. The lack of registries, uniform treatment and prospective protocols have been pointed out for these disparities. Also, biological, and social aspects of this disease play an important role that has not been well examined. We aimed to evaluate the survival of patients with acute lymphoblastic leukemia according to demographic characteristics with emphasis in the place of residence. Methods: We performed an analytical retrospective cohort study with subjects diagnosed and treated for ALL during the period 2016-2018 at the Peruvian national cancer center (INEN, Instituto Nacional de Enfermedades Neoplasicas). INEN is currently the main center dedicated to diagnosing and treat acute leukemias for patients without social neither private insurance. Also, INEN is located at the capital city (Lima-Peru). The calculated sample size was 378 patients. Patient data were obtained from the epidemiological registry and corroborated with the national registry of mortality (RENIEC, Registro Nacional de Identificacion y Estado Civil Overall survival probabilities according to demographic characteristics were estimated using the Kaplan-Meier curve; in addition, the Log-rank test and Cox regression were used. Results: A sample of 378 patients were included during the study period (N = 588), of which 212 (56.8%) were male, 42% were between 0-10 years, 24% in 46-65 years. Regarding the characteristics at diagnosis, 80% were Ph(-) BCP-ALL and 69% corresponded to high-risk groups. At 42 months of follow-up, the median survival of the patients was 29 months (95% CI: 23.3-34.6), and the overall survival at three years was 44.8%. Overall survival in males (48.8%) was higher than in females (39.5%). According to the range of age, the highest survival was in the group of 0-10 years (70%), followed by 11-20 years (36.8%) and the lowest survival was in 46- 65 years (12.5%). Furthermore, overall survival in Lima (51.5%) was higher than in the country-side (39.7%). There was a statistically significant association (p < 0.05) between survival and sex (p = 0.042), age range (p = 0.000) and place of residence (p = 0.005); according to the Log-rank test. Conclusions: We report a lower survival among all age groups in ALL compared to international working groups. Living in a country-side region represents a significant factor for dismal survival in our cohort. Specialized health care access to diagnosis and treatment should be warranted for patients with geographical limitations and programs to ensure it must be implemented.

I has been observed that the majority of these cardiovascular risk factors are not well controlled. In this way, stringent measures of control should be considered in order to prevent the cardiovascular complications related to them.

No abstract