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In the search for treatment schemes of COVID-19, we start by examining the general weakness of coronaviruses and then identify approved drugs attacking that weakness. The approach, if successful, should identify drugs with a specific mechanism that is at least as effective as the best drugs proposed and are ready for clinical trials. All coronaviruses translate their non-structural proteins (∼16) in concatenation, resulting in a very large super-protein. Homo-harringtonine (HHT), which has been approved for the treatment of leukemia, blocks protein elongation very effectively. Hence, HHT can repress the replication of many coronaviruses at the nano-molar concentration. In two mouse models, HHT clears SARS-CoV-2 in 3 days, especially by nasal dripping of 40 ug per day. We also use dogs to confirm the safety of HHT delivered by nebulization. The nebulization scheme could be ready for large-scale applications at the onset of the next epidemics. For the current COVID-19, a clinical trial has been approved by the Ditan hospital of Beijing but could not be implemented for want of patients. The protocol is available to qualified medical facilities.

Peri-engraftment respiratory distress syndrome (PERDS) is a kind of potentially life-threatening complication of autologous stem cell transplantation (ASCT). PERDS is characterized by fever, dyspnea, and hypoxemia during neutrophil engraftment. In order to identify the high-risk factors for PERDS, we retrospectively analyzed 260 patients with lymphoma undergoing ASCT in recent five years. The conditioning regimen was BuCyE (busulfan, cyclophosphamide, and etoposide). There were 16 patients (6.1%) diagnosed as PERDS. In multivariate analysis, prior anti-programmed death-1 (PD-1) therapy (hazard ratio [HR] = 8.852, 95% confidence interval [CI]: 2.954-26.527, P 0.001) and history of pulmonary disease (HR = 3.718, 95% CI: 1.197-11.545, P = 0.023) were independent risk factors for PERDS. Patients with prior anti-PD-1 therapy (n = 31) had higher incidence of engraftment syndrome (77.4% vs. 33.4%, P 0.001), PERDS (25.8% vs. 3.5%, P 0.001), and transplant-related mortality (9.7% vs. 0.4%, P 0.001), compared with those without prior anti-PD-1 therapy (n = 229). Subgroup analysis showed that sintilimab seemed to be associated with higher incidence of PERDS (42.9% vs. 11.8%, P = 0.06) compared with non-sintilimab group (pembrolizumab or toripalimab). C-reactive protein might be a feasible early predictor for PERDS. In conclusion, our study suggests that prior anti-PD-1 therapy may be a strong risk factor for life-threatening PERDS in patients with lymphoma undergoing ASCT.

To evaluate the safety and efficacy of rapid rituximab infusion (RRI) plus chemotherapy in patients with CD20(+) non-Hodgkin's lymphoma (NHL).A total of 177 patients received 4 - 6 cycles of rituximab-based chemotherapy. The first cycle was given with standard schedule. In the second and subsequent cycles, RRI was initiated. Rituximab was administered as 20% of the dose infused in the first 30 min and the remaining 80% was given over 60 min. Benadryl and dexamethasone were given before infusions. Vital signs were measured at baseline and during infusion.In the first cycle, 48 patients experienced grade I - II infusion reactions and two patients showed grade III - IV infusion reactions. Six patients experienced infusion reactions during RRI. Two patients showed grade III infusion reactions to RRI and dropped out of the study. With a median follow up of 37.5 months, the 3-year overall survival and progression-free survival rates of the whole cohort were 93.1 and 81.1%, respectively.Our preliminary observations suggested that RRI may be safe and feasible for patients with CD20(+) NHL.

Although cisplatin combined with 5-fluorouracil is a common first-line regimen for advanced nasopharyngeal carcinoma (NPC), there are no standard regimens for refractory or relapsed patients. A study of DXD regimen [cisplatin (D), capecitabine (X) and docetaxel (D)] was conducted to evaluate the efficacy and toxicity for patients with refractory or relapsed NPC.The regimen was administered as follows: 50 mg/m(2) docetaxel and 50 mg/m(2) cisplatin on day 1 and 800 mg/m² capecitabine on days 1 - 14, repeated every 3 - 4 weeks.Thirty patients were enrolled. The overall response and complete remission rate was 46.4 and 21.4%. Median follow-up was 24 months; median overall survival (OS) and progression-free survival (PFS) were 14.0 and 8.0 months. Five-year OS and PFS rates were 14.8 and 13.3%, respectively. Four patients achieved long-term tumor-free survival (range, 53.8 - 125.3 months). Multivariate analysis demonstrated that Epstein-Barr virus DNA status (p = 0.003) and therapeutic effect (p0.001) were significant independent factors for OS and PFS. The main grade 3/4 toxicities included neutropenia (26.6%), anemia (13.3%) and thrombocytopenia (10.0%). There were no chemotherapy-related deaths.The DXD regimen appeared to be effective and well tolerated by patients with refractory or relapsed NPC. Further investigation is warranted.

Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. Although the International Prognostic Index (IPI) provides a clinical model for risk stratification of patients with DLBCL, notable variability in outcome is still observed within the same IPI category. Tumor-infiltrating macrophages (also called Tumor-associated macrophages) are the major component in the microenvironment of DLBCL. Their correlation with the prognosis of DLBCL remains controversial. Using a CD68 antibody in immunohistochemical analysis, we studied the expression of CD68 in 112 Chinese patients with DLBCL, with 65 patients (58%) categorized as low CD68 expression and 47 patients (42%) as high CD68 expression. The complete response (CR) rate of patients with low CD68 expression was higher than that with high CD68 expression (66.1% vs. 51.6%), but there was no statistical significance (P = 0.060). The median survival time of patients with low CD68 expression was not achieved and that of high expression was 41 months (P = 0.029). The results suggest that higher expression of CD68 tended to yield poor treatment outcome of DLBCL.

The genetic landscape of Natural killer/T-cell nasal-type lymphoma (NKTL) has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene but none has employed whole-genome sequencing (WGS). Whole-genome sequencing was performed for 11 pairs of tumor-blood samples to study the association between somatic mutations and response to pembrolizumab. Interestingly, recurrent PD-L1 SRs were validated in four of the seven complete responders (CR) cases. JAK3-activating (p.A573V) mutations were also validated in another two pembrolizumab-treated patients who have achieved CR. Lastly, we also found a homozygous 3 bp insertion (p.Q131_H132insQ) in the ARID1B gene, a chromatin remodeler gene and a subunit in the SWI/SNF complex in the last remaining CR case. A recent study has also reported PBRM1-deficient and ARID2-deficient tumors correlated with better response to anti-PD1/PD-L1 therapy renal cell carcinoma. There seems to be a relationship between truncating alterations in the subunits of the SWI/SNF complex and response to PD1/PD-L1 therapy. However, the exact mechanisms behind these associations remain to be elucidated for NKTL. Analysis of the WGS data from the four remaining progressive disease (PD) patients' tumors did not reveal similar alterations in the PD-L1 and JAK3 genes. A careful inspection was also carried out on the genes associated with major histocompatibility complex and interferon gamma pathways, which are known to associate with resistance to immune checkpoint blockade in melanoma, but no further mutation in these groups of genes was found in our cohort. Furthermore, a TP53 (p.W14X) stop-gain mutation, a hallmark tumor suppressor gene, was detected in a patient who had progressive disease after given pembrolizumab. We went on to check if PD-L1 IHC staining could explain the response of these NKTL patients to pembrolizumab. In this study, tumors were stained and assessed for PD-L1 positivity by the same pathologist. All cases, except two cases, have greater than 20% of tumor cells stained positive for PD-L1. Interesting, both cases are CR. In addition, all four PD cases were strongly stained for PD-L1 with an average of 69% PD-L1 positive cells (range, 50% - 90%) but their outcomes were dismal. This suggests that there could be a companion biomarker that could be added to PD-L1 IHC positivity for better predictive power of response to PD1 blockade therapy. Here we report retrospectively, for the first time, the genomic mutational profiles of anti-PD1 blockade in 11 relapsed/refractory NKTL patients using WGS data, which provide proof-of-concept data that the response to anti-PD1 is relevant and correlates with recurrent PD-L1 and JAK3 genomic alterations in this malignancy. Disclosures No relevant conflicts of interest to declare.

The role of temozolomide in untreated PCNSL patients has not yet been clearly defined. The purpose of this study was to compare the efficacy and toxicity of MT and MC chemotherapy in this population. A total of 41 consecutive patients were enrolled from March 2001 to July 2011. The ORR and CRR for MT vs. MC were 70% vs. 61.9% and 45% vs. 38.1% on ITT basis, (p = NS); 73.7% vs. 68.4% and 47.4% vs. 42.1% on PP basis, respectively (p = NS). Grade 3-4 hematological toxicities were more common in MC than in MT group (85.7% vs. 15%, p = 0.0001). One treatment-related death was observed in each group. The 5-year PFS and OS of MT (36% and 62.2%) were comparable to MC (32.6% and 46.7%), (p = NS). In summary, our preliminary results suggest that MT combination may be a simplified and effective regimen comparable to MC for newly diagnosed PCNSL.

This study sought to investigate the efficacy and tolerability of the regimen of low-dose gemcitabine combined with carboplatin in chemo-naïve patients with non-small cell lung cancer (NSCLC). The study involved 37 chemo-naive patients with unresectable stage IIIB or stage IV NSCLC. The predominant histological type was squamous carcinoma (22/37), and the performance status (PS) was 2 in 23 patients (62%). All received gemcitabine, 250 mg/m(2) in 6-hour infusion on days 1 and 8 plus carboplatin area under the curve (AUC) = 5 on day 1, every 28 days. The overall response rate (ORR) was 62·2% and disease stabilization was achieved in 21·6% of the patients. After a median follow-up duration of 13 months, the median overall survival (OS) time was 14·0 months (95% CI 13·3-16·6 months), and the median progression-free survival (PFS) time was 7·0 months (95% CI 6·1-8·9 months). Hematological toxicities were well-tolerated with the development of grade 3/4 neutropenia and thrombocytopenia in 10·3 and 10·3% of patients respectively, and the gastrointestinal toxicities were mild.

The role of (18)Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) in extranodal natural killer/T-cell lymphoma (ENKL) is not well established. This study aimed to investigate the prognostic role of the pretreatment maximum standardized uptake value (SUV(max)) on PET/CT in patients with newly diagnosed ENKL. Among 364 consecutive patients with newly diagnosed ENKL, 81 patients were included and reviewed. The impact of SUV(max) on survival and the relationship between SUV(max) and other clinicopathological parameters were analyzed. The median SUV(max) was 14.6 (range 2.0-45.4). The optimal cutoff value of SUV(max) to predict overall survival (OS) was 15. Patients with high SUV(max) (SUVmax15) were associated with bulky disease (P0.001), local invasion (P = 0.030), high score of Korean Prognostic Index (KPI, P = 0.046), resistance to primary treatment (P = 0.014), poor OS (P0.001), and unfavorable progression-free survival (P0.001). With a median follow-up of 25.0 months, the median OS was 63.0 months (range 2.0-99.0 months). Multivariate analyses revealed the following independent prognostic factors for OS: age60 years (P = 0.001), stage III-IV (P = 0.023), SUV(max)15 (P = 0.020), and bulky disease (5 cm) (P = 0.002). By using the SUV(max), patients in most subgroups stratified by the KPI or the International Prognostic Index (IPI) were further discriminated in OS with significant statistical difference. Our results suggest the pretreatment SUV(max) is predictive of prognosis in patients with newly diagnosed ENKL. The SUV(max) may provide additional prognostic information for IPI and KPI.

The combination of gemcitabine (G), vinorelbine (V), and pegylated liposomal doxorubicin (D) has proved to be effective in relapsed Hodgkin's lymphoma (HL). Its efficacy in non-Hodgkin's lymphoma (NHL) remains to be discussed. We retrospectively evaluated the efficacy and toxicity of the dose-adjusted gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule in 35 heavily pretreated patients with relapsed and refractory aggressive NHL or HL. Treatment consisted of G: 800 mg/m(2) intravenous (i.v.) on day 1, V: 15 mg/m(2) i.v. on day 1; D: 20 mg/m(2) i.v. on day 1, repeated for 14 days. Patients responded to GVD proceeded to subsequent autologous stem cell transplantation. The objective response rate (ORR) was 48.6 %, with 31.4 % complete remission. A higher ORR was observed in patients with HL than in patients with NHL (80.0 vs. 36.0 %, P = 0.023). With a median follow-up of 26 months, the estimated median progression-free survival and overall survival were 5 (range 1-73 months) and 36 months (range 2-73 months), respectively. The estimated 5-year survival rate was 44.6 % (95 % confidence interval 28.1-61.1 %). Toxicities were mild (grade 3/4 neutropenia 34.3 %, thrombocytopenia 5.7 %). Our results suggest that the dose-adjusted GVD in 14-day schedule is effective and well tolerated in patients with refractory and relapsed HL and aggressive NHL. The potential long-term survival in NHL is promising.

Various studies on lymphoma microenvironment have demonstrated the prognostic impact of tumor-associated macrophages (TAMs) in patients with B-cell lymphoma. Little is known about the correlation between TAMs and treatment outcome in mature T- and natural killer (NK) cell lymphomas. We analyzed the prognostic relevance of CD68+ TAMs by immunohistochemical analysis in 64 Chinese patients with mature T- and NK-cell lymphomas. Higher number of infiltrated TAMs was significantly related to B symptoms and extranodal involvement (p < 0.05). The TAMs content did not differ significantly between pathological subtypes. Using the mean value of TAMs per high-power field (hpf) as the cutoff point (87/hpf), 36 cases (56.2 %) were categorized as low level of TAMs content and 28 cases (43.8%) as high level. Patients with high level of TAMs content had a worse 5-year overall survival compared to those with low level (28.1 vs. 44.3 %, p = 0.039). In multivariate analysis, TAMs content remained an independent biological variable for survival distinct from the International Prognostic Index (Cox multivariate model, p = 0.009). High TAMs content indicated an adverse overall outcome in mature T- and NK-cell lymphomas. Our results show that expression of stromal TAMs may become a useful marker for prognosis of mature T- and NK-cell lymphomas.

Though high dose chemo-therapy combined with autologous hematopoietic stem cell transplantation (AHSCT) has made great progress on the treatment of chemo-sensitive malignant tumors, the relapse rate remains high. Successful immune reconstitution after AHSCT may reduce recurrence; therefore this study was to explore the characteristics of immune reconstitution after AHSCT and assess its feasibility in clinical use.Twenty four cases after AHSCT were enrolled in our study. There were 19 Non-hodgkin Lymphoma (NHL), 3 Hodgkin Lymphoma (HD) and 2 rhabdomyosarcoma. Nineteen cases had achieved complete remission (CR) while 5 partial remission (PR) before AHSCT. All cases were administered Interleukin (IL)-2 and Interferon (IFN)-alpha after AHSCT. Some patients were given thymus factor and/or CIK infusion. Phenotypes of peripheral blood T, B, NK subsets and immunological profile of TH1/TH2 by intracellular staining of cytokines after PMA/ionomycin stimulation were evaluated.75% of the cases achieved CR while 4.17% were progression of disease (PD) and 16.67% were relapsed during the median follow-up time of 12 (2-60) months. The changes of immune parameters after AHSCT were as followed: (1) CD4+T cells (normal control 33.5+/-6.9%) started to decrease dramatically one month after AHSCT, which was 2.5-13% (median rate 5.6%)in the 2nd month; and then slowly increased to 10-20% in the 7th month, but did not return back to normal even after one year in all patients. In addition, reversed ratio of CD4/CD8 lasted for a long period of time. B cells also began to decrease 1 month after AHSCT, and recovered to normal in the 4th month. But B cells remained 0% in the 6th month and 1% in 12th month in patients treated by rituximab before receiving AHSCT. The ratio of NK cells was 10-20% (higher than normal controls) in the 2nd month, then returned to normal thereafter. (2) The cytokine secretion by T cell: there were 48.79% patients whose TH1 was lower than normal controls or at the lower limit of normal range. All the patients with normal TH1 were treated by IFN-alpha or CIK cell infusion. TH2 was much higher than normal level among 68.29% cases and this abnormality lasted at least for 1 year in some cases. TH2 at normal range was only observed in cases receiving IFN-alpha treatment. Furthermore, IFN-alpha could significantly decrease TH2 level. (3) Increasing tendency of CD4+CD25+/CD4+, CD4+CD69+/CD4+ ratio was observed in patients received additional thymus factor treatment compared to those did not.Administration of CIK cells, thymus factor, IL-2 and IFN-alpha after AHSCT could improve the immunologic function of patients, and TH1/TH2 ratio may virtually reflect the immune status of patients. However more information is required to make prognostic assessments of immune reconstruction and the long-term survival rate.

The prognostic value of dynamic monitoring C-reactive protein (CRP) serum levels in NK/T-cell lymphoma Background and Objective C-reactive protein (CRP) is a kind of acute phase protein against inflammatory reaction. CRP has been proved to be associated with prognosis in various malignancies. Yet, the prognostic value of CRP in natural killer/T-cell lymphoma (NK/TCL) remains to be discussed. In this study, we aimed to observe the dynamic change of CRP serum levels during anti-lymphoma treatment, and to evaluate the prognostic value of CRP as a simple and economical biomarker during the early stage of treatment in patients with NK/T-cell lymphoma. Patients and Methods Between January 2003 and December 2011, 161 patients with newly diagnosed NK/TCL at the Sun Yat-sen University Cancer Center (SYSUCC) were reviewed retrospectively. Clinical and laboratory information was collected and analyzed. The following CRP serum levels were evaluated: pretreatment CRP (CRP0), early-treatment CRP (CRP1, after one cycle of chemotherapy, or two or three weeks since beginning of radiation), and post-treatment CRP (CRP2, after first-line treatment, or failure of first-line treatment). Results Overall, 161 patients were reviewed and analyzed. The median age was 44 years (range, 11¨C74). The majority had localized disease (stage I/ II; 75.5%). The CRP serum levels (mean ± standard deviation) were as follows: CRP0, 17.2±23.1 mg/L; CRP1, 14.0±30.0 mg/L; CRP2, 14.1±27.0 mg/L. The pretreatment CRP serum levels correlated with others unfavorable factors, including serum lactate dehydrogenase (LDH) (P = 0.005), presence of bulky disease (P = 0.002), presence of B symptoms (P = 0.017), the International Prognostic Index (IPI) score (P = 0.001) and the Korean Prognostic Index (KPI) score (P = 0.001). By the time of the final follow up assessment (May 2013), the median follow-up time was 23.0 months (range, 1.0-106.0 months). The median overall survival (OS) and progression-free survival (PFS) were 45.0 months (range, 1.0-106.0 months) and 32.0 months (range, 1.0-74.0 months), respectively. The independent unfavorable prognostic factors for OS (P < 0.05) in multivariate analysis included: elevated CRP1 (P < 0.001), presence of bulky disease (P = 0.007), and elevated β2-microglobulin (β2-mg) serum levels (P = 0.004). The receiver operating characteristic analysis revealed a similar cut-off value of CRP (8.16 mg/L) to the default value of the biochemical analyzer (8.2 mg/L). In addition, the result suggested a satisfying capacity of CRP1 in predicting response to initial treatment (sensitivity 94%, specificity 74%) and 5-year OS (sensitivity 75%, specificity 90%), among different serum biomarkers, including EBV-DNA, LDH, β2-mg, CRP0, CRP1, and CRP2. In all groups of patients classified according to dynamic CRP values, the patients with CRP0 (+) /CRP1(-) presented the most favorable prognosis (5-year estimated OS: 72.5%). Conclusions Our study suggests that elevated early-treatment CRP is an independent unfavorable prognostic factor for patients with NK/TCL. Compared with the baseline CRP, the dynamic change of CRP levels may provide more important information for prognosis during treatment. Disclosures: No relevant conflicts of interest to declare.

Abstract 1609 Introduction: Salvage chemotherapy followed by autologous stem cell transplant (ASCT) remains to be the standard treatment for most patients with relapsed and refractory aggressive non- Hodgkin lymphoma(NHL) and Hodgkin lymphoma(HL). However, there are no standard salvage chemotherapy regimens for these patients especially for refractory patients. The combination of gemcitabine, vinorelbine and liposomal-doxorubicin (GVD regimen) had been reported to be effective in patients with relapsed HL (N.L.Bartlett et al. Ann Oncol. 2007).The overall response rate was 70% and the complete remission rate was 19%. The main toxicities were mucositis (23%) and febrile neutropenia (9%). Despite this encouraging result in relapsed HL, it was still unclear whether GVD regimen was effective in recurrent aggressive NHL. Objective: This study aimed to evaluate the efficacy and toxicity of GVD regimen in patients with refractory aggressive NHL and HL. Patients and methods: Patients with aggressive NHL and HL who were relapsed or refractory to at least one salvage chemotherapy regimen were enrolled. The GVD regimen was given as follows: gemcitabine: 1000 mg/m2 intravenous(i.v.)on day 1,vinorelbine: 15 mg/m2 i.v. on day 1≤⪢liposomal-doxorubicin: 25 mg/m2 i.v. on day 1, repeated for 14 days≤®Patients with complete response (CR)or partial response (PR) proceeded to autologous stem cell transplant (ASCT) as consolidation. Results: From 1 May 2006 to 30 August 2008, 35 patients (25 NHL and 10 HL) were enrolled and received 129 cycles of chemotherapy. Twenty patients (57.1%) had been treated with at least 3 chemotherapy regimens before enrollment, and 15 patients (42.9%) had been treated with 2 chemotherapy regimens before. The overall response rate (ORR)was 48.6%(95% CI: 32.0%∼65.1%), with 31.4% CR rate(95%CI: 16.0%∼46.8%)≤®The ORR was higher in patients with HL than in patients with NHL(80.0% vs. 36.0%,p=0.023). The ORR was higher in relapsed patients than in refractory patients(73.3% vs. 30.0%,p=0.013). Sixteen patients (9 NHL and 7 HL) were treated by high dose chemotherapy supported by ASCT. With median follow-up of 16 months (2∼61 months),the median progression free survival(PFS) was 5 months(1∼61 months) and the median survival time was 38 months (2∼61 months). 4-year PFS and 4-year overall survival was 28.1% and 58.2% respectively. The serum LDH level and the sequential ASCT were independent prognostic factors. The survival time in patients treated with subsequent ASCT was significantly longer than those without ASCT (median survival: not reached vs. 21 months, p=0.005). The major toxicity was myelosuppression. The incidence of grade ¢ó/¢ô neutropenia and thrombocytopenia was 34.3% and 5.7% respectively≤®Mobilization of hematopoietic progenitor cell was successful in all the 16 patients. There were no treatment-related deaths. Conclusion: GVD regimen is an effective and well-tolerated salvage regimen both for patients with HL and patients with aggressive NHL. GVD followed by AHST yields promising long-lime survival even in patients who are previously heavily treated. Disclosures: No relevant conflicts of interest to declare.