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Supplementary Figure S3. Relative mRNA expression of activating and inhibitory markers. (A) Relative mRNA expression (mean {plus minus} SD) of activating markers in the complete remission (CR) and partial remission (PR) group. (B) Relative mRNA expression (mean {plus minus} SD) of inhibitory markers in the CR and PR group. Student's t-test, one-way ANOVA, Wilcoxon signed-rank test or Friedman test was used, as appropriate. SD: Standard Deviation, IQR: interquartile range.

Supplementary Table S2: Amount and potency of CAR T cells

Purpose:Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest.Patients and Methods:A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 × 107(n = 3), 5 × 107(n = 4), and 1 × 108(n = 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day −6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected.Results:The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status.Conclusions:JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.

BACKGROUND: To assess the value of characteristic computed tomography (CT) findings in predicting the survival of patients with pulmonary B-cell non-Hodgkin’s lymphoma (NHL). METHODS: Eighty-four patients who were histopathologically confirmed with pulmonary B-cell NHL between 2004 and 2018 were retrospectively enrolled. All patients underwent chest CT scan at the time of initial diagnosis in our hospital. Characteristic CT findings and clinicopathological features of the patients were analyzed, and Cox regression models were used to determine the relationship of CT findings with overall survival (OS) and progression-free survival (PFS). RESULTS: Air bronchogram occurred more frequently in patients with early-stage disease, primary pulmonary lymphoma (PPL) and the indolent histological type of lymphoma than in patients with advanced-stage disease, secondary pulmonary lymphoma (SPL), and the aggressive histological type (all P

Background This study aimed to investigate the association of pre-treatment inflammatory status with survival time and to develop a prognostic nomogram incorporating inflammatory cytokines in non-Hodgkin's lymphoma. Methods A total of 228 patients with diffuse large B-cell lymphoma (DLBCL) received R-CHOP-based regimens from a prospective randomized study (NCT01852435) were included as a training cohort. Other cohorts of 886 lymphoma patients were served as validation cohorts. Lymphocyte-monocyte ratio (LMR), serum levels of soluble interleukin s(IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor-α (TNF-α), were assessed before treatment. Least absolute shrinkage and selection operator (LASSO) regression were used to select variables for nomogram of overall survival (OS). The predictive accuracy of the nomogram was determined by concordance index (C-index). Findings The nomogram included lactate dehydrogenase (LDH), sIL-2R, TNF-α and decreased LMR. The C-index of the nomogram for OS prediction were range from 0.61 to 0.86 for training cohort of DLBCL and validation cohorts of DLBCL, PTCL, NKTCL and ASCT, which were superior to the predictive power of International Prognostic Index (IPI, 0.67 to 0.84) or NCCN-IPI (0.59 to 0.78), but not in those of indolent lymphoma like FL and MALT. Interpretations The nomogram incorporating inflammatory cytokines provides a useful tool for risk stratification in aggressive non-Hodgkin's lymphomas. Fund National Natural Science Foundation of China, the Shanghai Commission of Science and Technology, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of SHDC, and Chang Jiang Scholars Program.

BackgroundElderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2).ResultsAmong 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52–79) and 83% (95% CI 68–91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferasesCREBBP/EP300mutations was also mitigated by CR-CHOP. Grade 3–4 neutropenia was reported in 171, grade 3–4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported.ConclusionCR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL.Trial registrationClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.

Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be combined with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in treating DLBCL. Methods: Elderly patients with newly diagnosed DLBCL (IPI≥2) received oral HDACI chidamide (20mg twice a week for two weeks) and R-CHOP every 21 days (CR-CHOP) for six cycles. The primary endpoint was complete response rate at the end of the treatment. Whole exome sequencing, targeted sequencing and RNA-sequencing were performed in patients with available tumor samples. Findings: Among 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. 2-year PFS and OS rate were 68% (95%CI 52-80) and 80% (95%CI 64-90), respectively. There was no difference in 2-year PFS (83% vs 65%, P=0.210) or OS (91% vs 81%, P=0.313) rate between double-expressor lymphoma (DEL) and non-DEL phenotype. However, 2-year PFS and OS rate of DEL patients was significantly improved by CR-CHOP, comparing with historical control (NCT01852435, P=0.030 and 0.036). Instead of histone acetyltransferases CREBBP / EP300 , histone methyltransferases KMT2D mutations were associated with inferior PFS and OS (P=0.043 and

Background Pulmonary lymphoma arises primarily from the lung, which is extremely rare, or be secondarily involved by lymphoma. The clinical features, management, and prognostic factors have not been clearly identified. Methods Sixty-three patients with primary pulmonary lymphoma (PPL) and 117 patients with secondary pulmonary lymphoma (SPL) treated in our institution between June 2003 and December 2017 were retrospectively reviewed. Results MALT (67%) was the most common pathological subtype of PPL, while DLBCL (48%) was the most common subtype of SPL. Compared to the patients with PPL, the presence of B symptoms, advanced disease stage, intermediate-high or high risks of IPI and NCCN-IPI, elevated inflammatory parameters, and elevated cytokine levels were all observed in patients with SPL. Consolidation was the most frequent radiological finding in PPL cases, while nodules were the most frequent finding in SPL. With a median follow-up of 35 months (range 2–176), the estimated 3-year OS rates were 95%, 100%, 70% and 50% in indolent PPL, indolent SPL, aggressive PPL, and aggressive SPL, respectively. In indolent pulmonary lymphoma, none of the prognostic factors we studied significantly influenced survival of the patients. In aggressive pulmonary lymphoma, univariate analysis showed that NCCN-IPI was related to OS in PPL. Multivariate analysis showed that β2-MG was an independent prognostic factor for OS in SPL. Conclusions Primary and secondary pulmonary lymphoma differ in their clinical features and outcome. Furthermore, β2-MG is the independent prognostic factor for OS in patients with aggressive SPL.

Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest. Patients and Methods: A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 × 107(n = 3), 5 × 107(n = 4), and 1 × 108(n = 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day −6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.

Background: Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin's lymphoma and is heterogeneous in clinical, immunophenotypic and genetic features. More than 50% of patients with DLBCL are older than 60 years at diagnosis. Among them, up to 40% of patients relapse or develop refractory disease upon R-CHOP treatment. Dose-dense R-CHOP14 failed to show superior efficacy or survival compared with standard R-CHOP21 in elderly patients and intensive chemotherapy followed by autologous stem cell transplantation was difficult due to toxicity. Therefore, development of new first-line therapy remains great interests to improve disease outcome in elderly patients with DLBCL. Perturbation of the epigenome plays a crucial role in lymphoma progression. Several histone deacetylase inhibitors (HDACIs) have been investigated in relapsed or refractory DLBCL as mono- or combination treatment, showing promising activities to suppress lymphoma growth and overcome resistance to immune-chemotherapies. This prospective phase II study was to evaluate the efficacy and safety of chidamide in combination with R-CHOP21 in elderly patients with newly diagnosed DLBCL (NCT02753647). Methods: Patients with newly diagnosed DLBCL, aged 61 to 75 years, Eastern Cooperative Oncology Group performance status of 0 to 2, IPI>1 were enrolled. The dose and administration schedule were as follows: rituximab 375 mg/m2 on day 0, cyclophosphamide 750mg/m2 on day 1, doxorubicin 50mg/m2 on day 1, vincristine 1.4 mg/m2 on day 1, prednisone 60 mg/m2 from day 1 to day 5, chidamide 20mg/d on days 1, 4, 8 and 11, every 21 days for 6 cycles. The primary endpoint was complete response (CR) rate assessed by PET-CT, and secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and main adverse events (AEs). Results: From March 2016 to April 2018, 49 patients were enrolled; 41 patients completed all treatment and 8 patients were still in the treatment cycles. Median age was 67 years (range, 61-75) and 28 patients (57.1%) were male. Thirty-eight patients (77.6%) presented advanced Ann Arbor stage, and 41 patients (83.7%) showed elevated serum LDH level. Thirty-one patients (63.3%) had multiple extra-nodal sites, mainly involving bone, gastrointestinal, liver, and bone marrow. Forty-one patients (83.7%) had IPI scores ≥3 at diagnosis. By immunohistochemistry, 12 (24.5%) patients were categorized as germinal center B-cell (GCB) subtype based on Hans algorithm, and 12 (25.5%) patients were defined as BCL-2 and MYC double expression. Among 41 patients available for evaluation, the CR rate was 85.4% (35/41), and the ORR was 90.3% (37/41). After a median follow-up of 18 months (range, 3-30), the 1-year PFS was 92.1% and 1-year OS was 94.7%. There were 2 deaths due to disease progression, of which 1 had triple-hit lymphoma. Regarding toxicity, grade 3-4 neutropenia was observed in 167 cycles (60.5%), grade 3-4 thrombocytopenia in 27 cycles (9.8%), and grade 3 anemia in 11 cycles (4.0%). However, febrile neutropenia was reported in significantly fewer cycles (6.1%) and was a maximum of grade 3. Grade 3 liver dysfunction was observed in 7 cycles (2.5%). No grade 4 non-hematological events were reported. Of note, 2 patients positive for EBER-ISH at diagnosis remained in EBV-DNA negative during treatment and follow-up. Conclusion: Chidamide with R-CHOP21 is effective and safe in elderly patients with newly diagnosed DLBCL. Disclosures No relevant conflicts of interest to declare.

The Charcot-Marie-Tooth disease (CMT) is one of the most common human inherited peripheral neuropathies. The most common pattern of inheritance is autosomal dominant, with less often occurrence autosomal recessive and X-linked dominant/recessive inheritance. CMT is generally divided into three forms: demyelinating forms (CMT1), axonal forms (CMT2) and intermediate forms (DI-CMT). The autosomal recessive form (AR-CMT1 or CMT4) is accompanied by progressive distal muscle weakness and atrophy of the limbs, pes cavus and claw-like hands. In addition, CMT4 is also characterized by early onset, rapid progression, and varying degrees of sensory loss and spinal deformities (e.g. scoliosis). Recently, 11 subtypes of CMT4 have been identified. Some of these subtypes were clear in pathogenic mechanisms, some had founder mutation, but some still had limited clinical description and mutation analysis. In this review, we summarize the latest research progresses of CMT4, including genotypes and phenotypes, pathogenic mechanisms and mouse models.