Clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma.

The clinical implications of CSF-ctDNA positivity in newly diagnosed diffuse large B cell lymphoma (ND-DLBCL) remains largely unexplored. One hundred ND-DLBCL patients were consecutively enrolled as training cohort and another 26 ND-DLBCL patients were prospectively enrolled in validation cohort. CSF-ctDNA positivity (CSF(+)) was identified in 25 patients (25.0%) in the training cohort and 7 patients (26.9%) in the validation cohort, extremely higher than CNS involvement rate detected by conventional methods. Patients with mutations of CARD11, JAK2, ID3, and PLCG2 were more predominant with CSF(+) while FAT4 mutations were negatively correlated with CSF(+). The downregulation of PI3K-AKT signaling, focal adhesion, actin cytoskeleton, and tight junction pathways were enriched in CSF(+) ND-DLBCL. Furthermore, pretreatment CSF(+) was significantly associated with poor outcomes. Three risk factors, including high CSF protein level, high plasma ctDNA burden, and involvement of high-risk sites were used to predict the risk of CSF(+) in ND-DLBCL. The sensitivity and specificity of pretreatment CSF-ctDNA to predict CNS relapse were 100% and 77.3%. Taken together, we firstly present the prevalence and the genomic and transcriptomic landscape for CSF-ctDNA(+) DLBCL and highlight the importance of CSF-ctDNA as a noninvasive biomarker in detecting and monitoring of CSF infiltration and predicting CNS relapse in DLBCL.

PRMT5 activates lipid metabolic reprogramming via MYC contributing to the growth and survival of mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable and aggressive subtype of non-Hodgkin B-cell lymphoma. Increased lipid uptake, storage, and lipogenesis occur in a variety of cancers and contribute to rapid tumor growth. However, no data has been explored for the roles of lipid metabolism reprogramming in MCL. Here, we identified aberrant lipid metabolism reprogramming and PRMT5 as a key regulator of cholesterol and fatty acid metabolism reprogramming in MCL patients. High PRMT5 expression predicts adverse outcome prognosis in 105 patients with MCL and GEO database (GSE93291). PRMT5 deficiency resulted in proliferation defects and cell death by CRISPR/Cas9 editing. Moreover, PRMT5 inhibitors including SH3765 and EPZ015666 worked through blocking SREBP1/2 and FASN expression in MCL. Furthermore, PRMT5 was significantly associated with MYC expression in 105 MCL samples and the GEO database (GSE93291). CRISPR MYC knockout indicated PRMT5 can promote MCL outgrowth by inducing SREBP1/2 and FASN expression through the MYC pathway.

Cause-specific mortality in a population-level cohort of diffuse large B-cell lymphoma following chemotherapy in the early 21st century.

Diffuse large B-cell lymphoma (DLBCL) is a severe non-Hodgkin's lymphoma. Life expectancy has improved with rituximab, but cause-specific mortality data is lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database to study 27,449 individuals aged 20-74 years diagnosed with primary DLBCL who received chemotherapy between 2000 and 2019, we calculated standardized mortality rate (SMR) and excess absolute risk (EAR) and examined the connection between age, sex, time after diagnosis, and cause of death. Based on 12,205 deaths, 68.7% were due to lymphoma, 20.1% non-cancer causes, and 11.2% other cancers. Non-cancer mortality rates (SMR 1.2; EAR, 21.5) increased with DLBCL compared to the general population. The leading non-cancer death causes were cardiovascular (EAR, 22.6; SMR, 1.6) and infectious (EAR, 9.0; SMR, 2.9) diseases with DLBCL. Risks for non-cancer death and solid neoplasms are highest within the first diagnosis year, then decrease. Among socioeconomic factors, being white, being married, and having a higher income were favorable factors for reducing non-cancer mortality. To improve survival, close surveillance, assessment of risk factors, and early intervention are needed.

CD30 protects EBV-positive diffuse large B-cell lymphoma cells against mitochondrial dysfunction through BNIP3-mediated mitophagy.

Epstein-Barr virus (EBV) positive diffuse large B-cell lymphoma (EBV+ DLBCL) predicts poor prognosis and CD30 expression aggravates the worse consequences. Here, we reported that CD30 positivity was an independent prognostic indicator in EBV+ DLBCL patients in a retrospective cohort study. We harnessed CRISPR/Cas9 editing to engineer the first loss-of-function models of CD30 deficiency to identify that CD30 was critical for EBV+ DLBCL growth and survival. We established a pathway that EBV infection mediated CD30 expression through EBV-encoded latent membrane protein 1 (LMP1), which involved NF-κB signaling. CRISPR CD30 knockout significantly repressed BCL2 interacting protein 3 (BNIP3) expression and co-IP assay indicated a binding between CD30 and BNIP3. Moreover, silencing of CD30 induced mitochondrial dysfunction and suppressed mitophagy, resulting in the accumulation of damaged mitochondria by depressing BNIP3 expression. Additionally, CRISPR BNIP3 knockout caused proliferation defects and increased sensitivity to apoptosis. All the findings reveal a strong relationship between mitophagy and adverse prognosis of EBV+ DLBCL and discover a new regulatory mechanism of BNIP3-mediated mitophagy, which may help develop effective treatment regimens with anti-CD30 antibody brentuximab vedotin to improve the prognosis of CD30+ EBV+ DLBCL patients.

25-Hydroxy vitamin D deficiency is an inferior predictor of peripheral T-cell lymphomas.

The aim of the study was to explore the significance and prognostic value of 25-hydroxy vitamin D (25-(OH) D) deficiency in peripheral T-cell lymphomas (PTCLs). One hundred fifty-six patients of newly diagnosed PTCLs were enrolled in the study. Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curves were plotted, and corresponding areas under the curve (AUC) were calculated to estimate the accuracy of International Prognostic Index (IPI) plus 25-(OH) D deficiency and Prognostic Index for T-cell lymphoma (PIT) plus 25-(OH) D deficiency respectively in PTCL risk stratification. Our results showed that the 25-(OH) D deficiency was an independent inferior prognostic factor for both PFS (P = 0.0019) and OS (P = 0.005) for PTCLs, especially for AITL and PTCL-not otherwise specified (PTCL-NOS). Additionally, adding 25-(OH) D deficiency to PIT indeed has a superior prognostic significance than PIT alone for PFS (P = 0.043) and OS (P = 0.036). Multivariate COX regression analysis revealed that PIT 2‒4, albumin (ALB) ≤ 35 g/L, and 25-(OH) D deficiency were regarded as independent risk factors of PFS and OS. Our results showed that 25-(OH) D deficiency was associated with inferior survival outcome of PTCLs, especially for AITL and PTCL-NOS. PIT plus 25-(OH) D deficiency could better indicate the prognosis for PFS and OS of PTCLs than PIT.

Prognostic value of POD18 combined with improved IELSG in primary central nervous system lymphoma.

PURPOSE: The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations. MATERIALS AND METHODS: A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan-Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor. RESULTS: The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54 years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828). CONCLUSIONS: In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model.

NOTCH pathway mutation contributes to inferior prognosis in HBV-infected chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) patients with hepatitis B virus (HBV) infection have a poor prognosis, underlying mechanism remains unclear. NOTCH mutations are frequent in CLL and associated with disease progression and drug resistance. It is also reported to be associated with hepatitis infection in lymphoid malignancies. In order to investigate the relation between the NOTCH pathway and HBV-associated CLL, we studied 98 previously untreated HBV-positive CLL patients and 244 HBV-negative CLL. NOTCH mutations were more frequent in HBV-positive CLL subgroup (p = 0.033). By survival analysis, HBV infection was associated with disease progression and poor survival (p = 0.0099 for overall survival (OS) and p = 0.0446 for time-to-treatment (TTT)). Any lesions of the NOTCH pathway (NOTCH1, NOTCH2, and SPEN) aggravated prognosis. In multivariate analysis, NOTCH mutation retained an independent significance for HBV-infected patients (p = 0.016 for OS and p = 0.023 for TTT). However, HBV positive with NOTCH unmutated had no statistical difference in prognosis compared with HBV-negative patients (p = 0.1706 for OS and p = 0.2387 for TTT), which indicated that NOTCH pathway mutation contributed to inferior prognosis in HBV-infected CLL. In conclusion, a cohort of CLL patients with HBV positive displayed a worse clinical outcome and the status of the NOTCH signaling pathway might play a crucial role.

Dynamic changes in circulating EBV-DNA load during treatment have prognostic values in EBV+ DLBCL-NOS: a Chinese cohort study.

EBV-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL-NOS), is an EBV-positive clonal B-cell lymphoid proliferation and circulating EBV-DNA is a great indicator for prognosis among EBV associated disease. In this retrospective study, we report 66 EBV+ DLBCL cases among 2137 DLBCL-NOS cases diagnosed from 2013 to 2021 (prevalence of 6.0%). After a median follow-up of 27 months, progression-free survival (PFS) and overall survival (OS) at 2 years were 39.5% ± 6.2% and 53.6% ± 6.4%, respectively. Multivariate analysis showed that only the biomarker of the positivity of post treatment EBV-DNA had a borderline correlation with shorter PFS and OS (PFS: P = 0.053; OS: P = 0.065). Patients were divided into three subgroups according to dynamic changes of EBV-DNA status: EBV-DNA persistently negative group, EBV-DNA persistently positive group, and EBV-DNA transformed from positive to negative group; among the three groups, patients of the persistently positive group had worst PFS and OS (P = 0.0527 and P = 0.0139, respectively). Decline in EBV copies correlated significantly with treatment response as well. In conclusion, circulating EBV-DNA level played a vital role in prognostic and monitoring marker for EBV+ DLBCL-NOS.

Prognostic significance of absolute monocyte count and lymphocyte to monocyte ratio in mucosa-associated lymphoid tissue (MALT) lymphoma.

To investigate the prognostic significance of peripheral blood absolute monocyte count (AMC) and lymphocyte to monocyte ratio (LMR) in mucosa-associated lymphoid tissue (MALT) lymphoma, we retrospectively analyzed 316 newly diagnosed patients with MALT lymphoma. The best cut-off value of AMC was 0.6 × 109/L and LMR was 1.8 by x-tile according to progression-free survival (PFS). Multivariate analysis showed that MALT-IPI (p < 0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) (p = 0.010), and LMR (p = 0.003) have independent prognostic significance for PFS, MALT-International Prognostic Index (MALT-IPI) (p = 0.018), ß2-microglobulin (ß2-MG) (p = 0.015), and LMR (p = 0.029) predicted poor overall survival (OS). Receiver-operator characteristic (ROC) curves were used to compare the prognostic prediction capability of MALT-IPI and MALT-IPI-M (MALT-IPI combined with LMR); area under the curves (AUCs) for MALT-IPI-M were larger than that for MALT-IPI both PFS (0.682 vs 0.654) and OS (0.804 vs 0.788). Our results indicated that that low level LMR at diagnosis was associated with inferior prognosis. The new prognostic index, MALT-IPI-M, enabled the risk stratification capability for MALT lymphoma survival.

Prognostic significance of serum immunoglobulin paraprotein in mucosa-associated lymphoid tissue (MALT) lymphoma.

To assess the prognostic significance of immunoglobulin (Ig) paraproteinaemia in mucosa-associated lymphoid tissue (MALT) lymphoma, 218 patients diagnosed with MALT lymphoma were enrolled in this study. Serum Ig paraprotein was detected in 42 of 218 patients (19.3%), mostly IgM-K (15, 35.7%), followed by IgM-L and IgG-L. Advanced age (p = 0.025), poor Eastern Cooperative Oncology Group performance status (p = 0.014), bone marrow involvement (p = 0.019), B symptoms (p = 0.039), advanced disease stage (III-IV) (p < 0.0001), elevated serum ß2-microglobulin level (p < 0.0001), multiple extranodal sites of involvement (p < 0.0001), nodal involvement (p < 0.0001), systemic therapy (p < 0.0001) and higher MALT-lymphoma International Prognostic Index (MALT-IPI) scores (p = 0.001) were significantly associated with the presence of serum Ig paraprotein. Multivariate Cox regression analysis showed that Ig paraproteinaemia was an independent prognostic predictor for inferior progression-free survival (PFS) and overall survival. A new prognostic index based on MALT-IPI and Ig paraproteinaemia, as assessed using receiver operating characteristic curves and the area under the curve statistics, showed better discriminative ability than MALT-IPI in predicting PFS. In conclusion, Ig paraproteinaemia was a promising prognostic predictor for MALT lymphoma. Ig paraproteinaemia together with MALT-IPI might contribute to optimising therapeutic management in clinical practice.

Association of marital status with stage and survival in patients with mycosis fungoides: A population-based study.

BACKGROUND: Previous studies have shown that marital status was associated with stages and survival in patients with melanoma or Merkel cell carcinoma. To date, the impacts of marital status on stage and survival in patients with mycosis fungoides (MF) have not been determined yet. METHODS: A total of 3375 eligible cases diagnosed from 2004 to 2015 were included from the Surveillance, Epidemiology, and End Results (SEER) database. Association of marital status with stage and survival in patients with MF was analyzed. RESULTS: Married patients were more likely to be diagnosed at T1 stage (p = 0.041). And married patients were less likely to present with lymph node involvement (p = 0.007). More favorable overall survival (p < 0.001) and cancer-specific survival (p < 0.001) were demonstrated in married patients as compared with divorced patients or widowed patients. A clinically feasible prognostic model including marital status, age, sex, race, and stage at presentation was constructed. CONCLUSION: Married marital status was associated with earlier stage at diagnosis and longer survival compared with divorced or widowed marital status in patients with MF.

Prognostic nutritional index, a novel biomarker which predicts worse prognosis in diffuse large B cell lymphoma.

The prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is associated with survival in several types of lymphoma. The purpose of this study was to investigate the prognostic value of PNI in diffuse large B cell lymphoma (DLBCL). With three hundred and ten patients were enrolled, the median level of PNI was 45.90 (range 25.30-139.70). According to the receiver operating characteristic (ROC) curve, 44.85 was determined to be the best cutoff value to divide patients into two different groups. With a median follow-up of 33.3 months (range 3.5-118.5), compared with the high PNI group, the 3-year and adjusted 3-year progression-free survival (PFS) and overall survival (OS) were worse in the low PNI group (all P < 0.050). Multivariate Cox analysis suggested that low PNI was an independent risk factor for PFS (hazard ratio (HR) 2.196, 95 % CI 1.197-4.030, P = 0.011) and showed a tendency to predict inferior OS (HR 1.918, 95 % CI 0.932-3.948, P = 0.077). Furthermore, PNI combined with other significant prognostic factors to build a novel prognostic index, namely NPI, was more accurate than the National Comprehensive Cancer Network international prognostic index (NCCN-IPI) to predict worse PFS and had a similar effect on predicting OS. All these findings suggested that PNI, as a novel available biomarker, was of prognostic significance in DLBCL patients.

Pretreatment whole blood Epstein-Barr virus DNA predicts prognosis in Hodgkin lymphoma.

The study investigated pretreatment Epstein-Barr virus (EBV) DNA status and its prognostic values in 96 patients newly diagnosed Hodgkin lymphoma (HL). With 13.5 % patients in positive EBV DNA status before therapy, the positive group had inferior progression-free survival (PFS) (P = 0.023) as well as overall survival (OS) (P = 0.001). Pretreatment EBV DNA positivity was observed as an independent prognostic factor in OS (P = 0.036) while a trend to predict PFS (P = 0.064). By monitoring changes of EBV DNA copies in 13 patients with positive pretreatment EBV DNA status, 5 of 6 patients with complete response (CR) had their copies undetectable after 3 cycles of first-line treatment and 7 patients with progressive disease (PD) all had elevated EBV DNA copies during their relapsed period. Whole blood EBV DNA may be an adjunctive biomarker to reflect treatment response, risk of disease relapse as well as prognosis in HL patients.

25-Hydroxy vitamin D deficiency predicts inferior prognosis in Hodgkin lymphoma.

The study investigated serum 25-Hydroxy vitamin D (25-(OH)D) deficiency and its prognostic values of patients newly diagnosed Hodgkin lymphoma (HL). With seventy-seven patients enrolled, the median level of 25-(OH)D was 44.5 nmol/L (range, 15.5-100.9 nmol/L) and 16 (20.8 %) of them were considered as 25-(OH)D deficiency. With a median follow-up of 28 months (range, 4-56 months), the 2-year progression-free survival (PFS) and overall survival (OS) rate were 75.3 %±5.5 % and 94.7 %±3.0 %, respectively. Patients with deficient 25-(OH)D level had inferior PFS (P<0.001) as well as OS (P<0.001). In multivariate Cox analysis, 25-(OH)D deficiency was observed as an independent prognostic factor for both PFS (hazard ratio (HR) 3.323, 95 % CI 1.527-7.229, P = 0.002) and OS (HR 5.819, 95 % CI 1.322-25.622, P = 0.020). Receiver-operator characteristic (ROC) curve showed International Prognostic Score (IPS) plus 25-(OH)D deficiency (IPS-D) predicted more accurately than IPS in PFS (AUC: 0.735 (95 % CI 0.622-0.829) vs. 0.701 (95 % CI 0.586-0.800), P = 0.033) and OS (AUC: 0.864 (95 % CI 0.767-0.932) vs. 0.825 (95 % CI 0.722-0.902), P = 0.028). All these findings suggest that serum 25-(OH)D level may be an adjunctive indicator to predict prognosis in HL patient.

Low serum cholesterol levels predict inferior prognosis and improve prognostic index scoring for peripheral T-cell lymphoma, unspecified.

Peripheral T-cell lymphomas, unspecified (PTCL-U) is a heterogeneous group of non-Hodgkin lymphomas, arising from the transformation of mature, post-thymic T-cells. Prognostic index for PTCL-U (PIT) is based on Europeans and may not be applicable for Chinese PTCL-U patients. Besides, low circulating cholesterol concentration is associated with elevated cancer incidence and mortality. The purpose of our study was to assess the prognostic value of serum lipid levels in PTCL-U and improve PIT. We screened the prognostic factors associated with progression-free survival (PFS) and overall survival (OS) by multivariate Cox regression analysis in ninety-one enrolled patients. The results showed that low-level high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were associated with unfavorable OS. Furthermore, we developed a new risk model, PITC, based on low-level HDL-C, LDL-C and PIT. In Chinese PTCL-U, PITC was superior to PIT in PFS and OS. In conclusion, serum cholesterol levels may be good candidates for predicting prognosis in PTCL-U.

Gemcitabine, oxaliplatin and dexamethasone (GemDOx) as salvage therapy for relapsed or refractory diffuse large B-cell lymphoma and peripheral T-cell lymphoma.

Background Outcomes of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) remain poor. The objective of this study was to evaluate the efficacy and safety of gemcitabine, oxaliplatin and dexamethasone (GemDOx) with or without rituximab as salvage therapy in patients with relapsed or refractory DLBCL and PTCL. Materials and Methods: We retrospectively reviewed patients with relapsed or refractory DLBCL and PTCL receiving GemDOx as salvage therapy between Jul 1, 2011, and Aug 31, 2017. Results: Thirty-three (57.9%) patients with relapsed or refractory DLBCL and 24 (42.1%) with PTCL were included in this study. The median age was 57 years (inter-quartile range 46-67). The overall response rate (ORR) in DLBCL was 48.5% with 27.3% of complete remission (CR), and the 2-year progression-free survival (PFS) and 2-year overall survival (OS) was 21% and 44%. In patients with PTCL, ORR was 50.0% with CR rate of 29.2%; the 2-year PFS and 2-year OS was 28% and 49%, respectively. Common grade 3-4 hematological adverse events were thrombocytopenia (26.3%), anemia (15.7%) and neutropenia (15.7%). Conclusion: With acceptable efficacy and good tolerability, GemDOx might be a new therapeutic option for relapsed or refractory DLBCL and PTCL.

The prognostic roles of hypogammaglobulinemia and hypocomplementemia in newly diagnosed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of lymphoma. Our retrospective study included 553 newly diagnosed DLBCL patients from May 2009 to October 2019. The relationships between hypogammaglobulinemia, hypocomplementemia and progression-free survival (PFS) and overall survival (OS) were assessed. In our center, 19.0% of patients had hypogammaglobulinemia, and 7.7% had hypocomplementemia at diagnosis. Immunoglobulin and complement deficiencies were associated with advanced disease and displayed inferior PFS and OS. Then, we designed a new immunization cumulative prognostic score (ICPS) model to comprehensively clarify the effect of these two variables on prognosis. Multivariate analysis showed that ICPS was an independent prognostic indicator for inferior clinical outcomes (PFS: p = 0.007, OS: p = 0.003). Furthermore, the predictive effect of ICPS combined with the International Prognostic Index (IPI) was superior to that of IPI alone (PFS: p = 0.016, OS: p = 0.037). In conclusion, hypogammaglobulinemia and hypocomplementemia could be regarded as adverse prognostic indicators in DLBCL.

Prognostic value of 25-hydroxy vitamin D in extranodal NK/T cell lymphoma.

25-hydroxy vitamin D [25-(OH)D] is widely used to determine vitamin D status in clinic. The aim of our study was to evaluate the prognostic value of 25-(OH)D in extranodal NK/T cell lymphoma (ENKTL). Ninety-three (93) ENKTL patients with available serum 25-(OH)D values were enrolled in our study. Vitamin D deficiency is defined as a 25-(OH)D below 50 nmol/L (20 ng/ml). Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves were plotted, and corresponding areas under the curves (AUC) were calculated to estimate the accuracy of PINK-E (prognostic index of natural killer lymphoma added with Epstein-Barr virus-DNA status) and 25-(OH)D deficiency in ENKTL risk-stratification. Our results suggested that the vitamin D deficiency was an independent inferior prognostic factor for both PFS [hazard ratio (HR), 2.869; 95% confidence interval (CI), 1.540 to 5.346; P = 0.003] and OS (HR, 3.204; 95% CI, 1.559 to 6.583; P = 0.006) in patients with ENKTL. Additionally, we demonstrated that adding 25-(OH)D deficiency to PINK-E score system indeed has a superior prognostic significance than PINK-E alone for PFS [AUC: 0.796 (95% CI: 0.699 to 0.872) vs. 0.759 (95% CI: 0.659 to 0.841), P = 0.020] and OS [AUC: 0.755 (95% CI: 0.655 to 0.838) vs. 0.721 (95% CI: 0.618 to 0.809), P = 0.040]. In conclusion, our study proved that 25-(OH)D deficiency was associated with inferior survival outcome of ENKTL patients.

Chidamide, a histone deacetylase inhibitor, inhibits autophagy and exhibits therapeutic implication in chronic lymphocytic leukemia.

Novel agents have made the management of chronic lymphocytic leukemia (CLL) more promising and personalized. However, long-term treatment is still warranted which may result in toxicity and resistance. Thus, new combination therapy may help achieve deeper remission and limited-duration therapy. Histone deacetylase inhibitors (HDACi) can affect many tumors by modulating key biological functions including autophagy. Studies have shown that some novel targeted agents including ibrutinib induce autophagy. This study aimed to explore the effect of oral HDAC inhibitor, chidamide, on CLL cells as well as the role of autophagy in this process. Here, we showed that autophagy flux in CLL cells was inhibited by chidamide via post-transcriptional modulation and chidamide had cytostatic and cytotoxic effects on CLL cells. Besides, the pro-survival role of autophagy in CLL cells was validated by using autophagy inhibitor and knocking down critical autophagy gene. Notably, a combination of chidamide and ibrutinib showed significant synergism and downregulated ibrutinib-induced autophagy. This work highlights the therapeutic potential of chidamide via its effect on autophagy, especially in combination with ibrutinib.