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Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma.We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed.Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group.Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

We aimed to assess HKII expression and its prognostic significance in diffuse large B-cell lymphoma (DLBCL) patients. The HKII protein level was determined by immunohistochemistry in 159 newly diagnosed DLBCL patients, and its relationship with overall response rate, progression-free survival (PFS), and overall survival (OS) was analyzed. HKII was expressed in 95 DLBCL patients (59.7%). HKII-positive patients had poorer outcomes than negative patients for 5-y PFS (68% vs. 84%, p = 0.029) and 5-y OS (78% vs. 94%, p = 0.05). When only patients without no bulky disease, B symptoms, or extranodal involvement who had low IPI scores were considered, those with positive HKII had worse 5y-PFS and 5y-OS (p 0.05). Multivariate analysis indicated that HKII status was an independent prognostic factor of OS. In subgroup analysis, HKII expression was associated with inferior OS in the CHOP group (p = 0.017). In CHOP group patients without bulky disease or extranodal involvement who had low LDH and low IPI scores (p 0.05), positive HKII was associated with worse PFS and OS. No differences in PFS and OS, or any independent prognostic factors, were found in the RCHOP group. In DLBCL, HKII is valuable as a prognostic biomarker and may be useful as a tool for assessing disease risk.

Supplemental Methods S1 contained the complete inclusion and exclusion criteria.

Supplementary Table 1 PDF file 55K, Cut-points for protein markers used in different analyses. Cut-points selected for pair-wise comparisons were chosen to reduce the total number of comparisons that would be done. Cut-points for the discovery/confirmation analyses (see Supplementary Methods) were optimized based on enrichment of responders versus non-responders and reasonable population size

Supplementary Figure 1 PDF file 77K, Biomarker sample collection from the LYM-3001 intent-to-treat population

Supplementary Table 4 PDF file 69K, OS, ORR, CR rate, and TTNT in all patients in the cross-validation model (see Supplementary Methods) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Among all biomarker-positive patients there was a significantly longer OS with bortezomib-rituximab versus rituximab, a significantly higher ORR, a higher CR rate, and a significantly longer TTNT. No significant differences were seen for biomarker-negative patients

Supplementary Table 3 PDF file 70K, Median PFS for patients in the discovery and confirmation sets, and in all patients, in the cross-validation model (see Supplementary Materials) who were positive or negative for the biomarker pair PSMB1 P11A (G allele) and low CD68 expression (≤50 CD68-positive cells). Presence of the biomarker pair was associated with a significant PFS benefit in patients treated with bortezomib-rituximab versus rituximab in the discovery set, a positive trend in the smaller confirmation sets, and a significant benefit among all patients. No significant differences were seen for biomarker-negative patients

Kaplan-Meier curves for progression-free survival (A) and overall survival (B) of the initial 43 patients and the subsequent 123 patients enrolled.

Purpose: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib–rituximab versus rituximab in the phase III LYM-3001 study.Experimental Design: A total of 676 patients were randomized to five 5-week cycles of bortezomib–rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.Results: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib–rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib–rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib–rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.Conclusions: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib–rituximab versus rituximab. Clin Cancer Res; 19(9); 2551–61. ©2013 AACR.

Supplementary Figure 2 PDF file 135K, Forest plot for single marker (A) protein and (B) germ-line DNA biomarker analyses

Supplementary Methods PDF file 64K, TaqMan SNP Genoytping Assays and Ligation-based Multiplexed Genotyping Assays

Supplementary Table 2 PDF file 78K, Evaluation of PFS and OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

Purpose: The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies.Patients and Methods: Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR12 weeks).Results: A total of 166 patients were included in the final analysis. Overall, the PFR12 weeks was 68%, and objective response rate was 13% (95% confidence interval, 7.6%–18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR12 weeks, median PFS and OS were: 58%, 4.1 and 11 months for UPS (n = 19); 63%, 5.6 and 13 months for LPS (n = 13); 75%, 11 and 15 months for LMS (n = 26); 75%, 7.7 and 12 months for SS (n = 47); 81%, 5.6 and 12 months for FS (n = 18); 77%, 21 and not reached for ASPS (n = 13); 54%, 11 and 16 months for CCS (n = 7); and 44%, 2.8 and 8.8 months for other sarcoma (n = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred.Conclusions: Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. Clin Cancer Res; 24(21); 5233–8. ©2018 AACR.

Supplementary Figure 3 PDF file 78K, Kaplan-Meier distributions of A) PFS and B) OS under the G-dominant genetic model for PSMB1 P11A among all patients evaluable for the biomarker pair of PSMB1 P11A genotype and CD68 expression who had low (≤50 CD68-positive cells) CD68 expression

GALLIUM is a global phase III study that demonstrated significant improvements in progression-free survival (PFS) for obinutuzumab plus chemotherapy (G-chemo) vs. rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). This study aimed to report the results of a subgroup of patients in China.Patients were randomized to G-chemo or R-chemo. Responders received maintenance therapy for 2 years or until disease progression. The primary endpoint was investigator (INV)-assessed PFS. Secondary endpoints included the overall response rate (ORR) and complete response rate (CRR) at the end of induction chemotherapy, overall survival (OS), and safety.Overall, 58 patients with FL were randomized to the G-chemo (n = 25) and R-chemo arms (n = 33). The INV-assessed PFS rate at 3 years was 81.8% in the G-chemo arm, vs. 70.2% in the R-chemo arm (hazard ratio 0.35; 95% confidence interval: 0.09-1.34; P = 0.1120). The INV-assessed CRRs (without positron emission tomography [PET]) in these arms were 24.0% and 21.2%, respectively, whereas the ORRs were 80.0% and 90.9%, respectively. INV-assessed CRR-PET was 52.6% in the G-chemo, vs. 60.9% in the R-chemo. Median OS was not reached in either arm. Grade 3 to 5 adverse events were more frequent in the R-chemo arm (97.0% vs. 88.0%).The results of this subgroup analysis were consistent with those of the global population, and they suggest that G-chemo has a positive benefit-risk profile in patients from China with FL.ClinicalTrials.gov, No. NCT01332968.

Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor contributing to lymphocyte homing, adhesion and activation. The prognostic significance of the protein is unknown in diffuse large B-cell lymphoma (DLBCL) in post-rituximab era. We detected expression of ICAM-1 immunohistochemically in 102 DLBCL tissue samples. Overexpression of ICAM-1 was found in 28 (27.5%) cases. In patients with low ICAM-1 expression levels, the addition of rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy resulted in an improved overall response rate, progression-free survival (PFS) and overall survival (OS) (P=0.019, 0.01, 0.02). In pre-clinical models, we found that chronic exposure of cell lines to rituximab led to downregulation of ICAM-1 and acquirement of a rituximab resistant phenotype. In vitro exposure of rituximab resulted in rapid aggregation of B-cells regardless of the ICAM-1 expression levels. MTT assay showed knockdown of ICAM-1 could cause rituximab resistance. Neutralization of ICAM-1 did not affect rituximab activity in vitro and in vivo. Our data illustrated that in post-rituximab era, R-CHOP significantly improved the ORR, PFS and OS in ICAM-1 negative subset patients. Downregulation of ICAM-1 may contribute to rituximab resistance, and that rituximab, by promoting cell-cell aggregation, may sensitize cells to the cytotoxic effects of chemotherapy agents.

This study aimed to evaluate the prognostic value of interim positron emission tomography (iPET) in diffuse large B-cell lymphoma (DLBCL). Among 53 enrolled patients, 39 had iPET-negative (iPET−) and 14 had iPET-positive (iPET+) scans. The objective response rate was 94.3%. The 3-year progression-free survival was 65.7% and the 3-year overall survival was 79.9%. The iPET− patients had significantly higher 3-year PFS rate (78.1% vs. 34.3%) and improved OS (87.1% vs. 62.3%) than iPET+ patients. In the univariate analysis, iPET− was the sole independent prognostic factor for PFS. In conclusion, PET/CT has a good prognostic value in patients with advanced-stage DLBCL. Trial registration: ClinicalTrials.gov, NCT 01804127. Registered on March 5th, 2013, https://www.clinicaltrials.gov/ct2/show/NCT01804127?term=01804127&rank=1 .

Background The optimal treatment strategies for extranodal natural killer/ T‐cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open‐label, phase II, single‐center study aimed to explore the efficacy and safety of radiotherapy followed by DICEP (Dexamethasone, ifosfamide, cisplatin, etoposide, and pegaspargase) regimen in the treatment of patients with untreated, stage IE/IIE, extranodal NK/T‐cell lymphoma. Methods Thirty eligible patients were enrolled in this study, receiving radiotherapy of 50Gy/25fx, and followed by chemotherapy with DICEP regimen for 3 cycles if tolerated. Median follow‐up time of this study was 70.8 months. We constructed Kaplan‐Meier survival curves for survival analyses. Results The most common manifestations at the onset of disease were nasal obstruction (80%), with or without fever, and pharyngalgia (20%). The overall response rate (ORR) was 96.7% (29/30). Four patients (13.3%) had progression of the disease (PD), the estimated 5‐year progression‐free survival (PFS) rate was 86%. Four patients (13.3%) died of disease, and the estimated 5‐year cumulative overall survival (OS) was 87%. The most common hematological toxicity was grade 3 or grade 4 neutropenia, which could be successfully managed via using growth‐stimulating factors or dose modifications. Hypoalbuminemia and decreased fibrinogen are the top two nonhematologic toxicities. No treatment‐related death occurred in this study. Conclusions Our present study showed that radiotherapy followed by DICEP chemotherapy could be an effective and tolerable treatment modality for newly diagnosed, stage IE/IIE ENKTL patients. Adverse events were predictable and manageable. Trial registration ClinicalTrials.gov Identifier: NCT01667302. Registered: 1 July 2012, The current results indicated that radiotherapy followed by DICEP chemotherapy could be an effective and feasible treatment strategy for patients with stage IE/IIE ENKTL.

Objective Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is relatively rare, and risk factors of this disease are still not well understood. This study aims to identify clinical features and prognostic factors of PT-DLBCL patients. Methods Thirty-two patients were included in this retrospective study who were diagnosed as PT-DLBCL and treated in Fudan University Shanghai Cancer Center between November 2010 and May 2018. The demographic details, clinico-pathological characteristics of the patients were summarized, and the impact on progression-free survival (PFS) and overall survival (OS) was analyzed. Results The median age of the patients was 57 (range 36-76) years old. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 4-6 cycles and central nervous system (CNS) prophylaxis, with a CR rate 87.5% and an ORR 96.9%. Nineteen patients continued prophylactic contralateral testis radiation therapy (PCTRT) in our hospital. The 3-year PFS and OS rates were 79% and 92%, respectively. None of the 19 patients who received PCTRT experienced local recurrence. All three patients who suffered from CNS relapse were germinal center B-cell subtype. Kaplan-Meier analyses showed that PT-DLBCL patients with late-stage (Stage IV) (P =0.022), higher IPI score (IPI≥ 2) (P =0.017), B symptoms (P =0.004), and elevated LDH level (P =0.03) had a shorter PFS. More importantly, we found that patients with the ratio of the LDH level in serum to that in CSF ≥ 6.5 suffered from a worse PFS (P =0.028). Conclusion Our work revealed that staging IV, IPI score ≥2, having B symptoms and elevated LDH level were risk factors for PT-DLBCL patients. Significantly, the PT-DLBCL patients with a high ratio of LDH level in serum to that in CSF were indicated to have a worse PFS.

60th Annual Meeting of the American-Society-of-Hematology (ASH) -- DEC 01-04, 2018 -- San Diego, CA Jurczak, Wojciech/0000-0003-1879-8084; Johnson, Peter/0000-0003-2306-4974; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Leppa, Sirpa/0000-0002-8265-511X WOS: 000468868300004 PubMed: 30901302 PURPOSE Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted. (C) 2019 by American Society of Clinical Oncology Amer Soc Hematol Janssen Global Services; Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748] Supported by Janssen Global Services, which also provided writing and editorial support, and by Memorial Sloan Kettering Cancer Center Support Grant No. P30 CA008748 (A.Y.).

Risk of hepatitis B virus (HBV) reactivation was assessed in B-cell non-Hodgkin lymphoma (NHL) patients with resolved HBV infection (hepatitis B surface antigen negative, hepatitis B core antibody positive) who received obinutuzumab- or rituximab-containing immunochemotherapy in the phase 3 GOYA and GALLIUM studies. HBV DNA monitoring was undertaken monthly to 1 year after the last dose of study drug. In case of HBV reactivation (confirmed, HBV DNA ≥29 IU/mL), immunochemotherapy was withheld and nucleos(t)ide analog treatment (preemptive NAT) started. Immunochemotherapy was restarted if HBV DNA became undetectable or reactivation was not confirmed, and discontinued if HBV DNA exceeded 100 IU/mL on NAT. Prophylactic NAT was allowed by investigator discretion. Among 326 patients with resolved HBV infection, 27 (8.2%) had HBV reactivation, occurring a median of 125 days (interquartile range, 85-331 days) after the first dose. In 232 patients without prophylactic NAT, 25 (10.8%) had HBV reactivation; all received preemptive NAT. Ninety-four patients received prophylactic NAT; 2 (2.1%) had HBV reactivation. No patients developed HBV-related hepatitis. On multivariate Cox analysis, detectable HBV DNA at baseline was strongly associated with an increased risk of reactivation (adjusted hazard ratio [HR], 18.22; 95% confidence interval [CI], 6.04-54.93; P < .0001). Prophylactic NAT was strongly associated with a reduced risk (adjusted HR, 0.09; 95% CI, 0.02-0.41; P = .0018). HBV DNA monitoring–guided preemptive NAT was effective in preventing HBV-related hepatitis during anti–CD20-containing immunochemotherapy in B-cell NHL patients with resolved HBV infection. Antiviral prophylaxis was also effective and may be appropriate for high-risk patients. These trials were registered at www.clinicaltrials.gov as NCT01287741 (GOYA) and NCT01332968 (GALLIUM).

BACKGROUND: To explore a more effective treatment strategy for newly diagnosed stage I and II extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, we conducted a prospective phase II study of sequential chemoradiotherapy with the L-asparaginase, dexamethasone, ifosfamide, cisplatin, and etoposide (DICE-L) regimen. METHODS: Patients with newly diagnosed stage I and II ENKTL in the upper-aerodigestive tract were enrolled. Treatment was comprised of up to 4 cycles of DICE-L followed by 50 Gy of intensity modulated radiation therapy (IMRT) to the involved field. The primary endpoint was the complete response (CR) rate. The secondary endpoints were the objective response rate (ORR), the 5-year overall survival (OS) rate, the 5-year progression-free survival (PFS) rate, and safety. RESULTS: A total of 81 patients were enrolled from June 2009 to May 2012 in Shanghai Cancer Hospital. Among these patients, 68 patients achieved CR and 1 patient achieved partial response (PR). The CR rate was 84%, and the ORR was 85.2%. With a median follow up of 88.1 months, the 5-year OS and 5-year PFS rates were 82.4% and 63.4%, respectively. The most common adverse events were grade 3 to 4 neutropenia (73.5%) and febrile neutropenia (21%). CONCLUSIONS: Sequential chemoradiotherapy using DICE-L followed by radiotherapy is an effective treatment modality for stage I to IIE ENKTL and is safe with acceptable toxicity.

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)–based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n = 706) or rituximab (n = 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-d-glucose–PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee–assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P < .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P < .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point. This trial was registered at www.clinicaltrials.gov as #NCT01287741.

Yizhen Liu,1 Yumei Liu,2 Ping Zhao,3 Qunling Zhang,1 Xiaojian Liu,1 Fangfang Lv,1 Xiaonan Hong,1 Junning Cao,1 Kai Xue1,4 1Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 2Department of Endoscopy, Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Biology, University of North Alabama, Florence, AL 35632, USA; 4State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of ChinaCorrespondence: Kai XueDepartment of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 64175590Email xuekaishanghai@126.comBackground: Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common subtype of extranodal non-Hodgkin lymphoma (NHL), with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as the commonly used treatment regimen. However, full cycles of standard R-CHOP present the risk of severe bleeding or perforation, even leading to emergency surgery, especially for those with deep lesions in their first 1– 2 cycles of treatment. This study aims to explore the safety and efficacy of fractioned R-CHOP (rituximab d0, 50% dose of CHOP d1 and d5) followed by standard R-CHOP cycles in PG-DLBCL patients guided by endoscopic ultrasonography (EUS).Patients and Methods: Thirty-one PG-DLBCL patients were analyzed in this retrospective study. All patients had lesions infiltrated to at least the 3rd layer of the stomach under EUS at baseline. Patients switched to standard R-CHOP if they showed the reduced infiltrated layers and restricted lesions after fractioned R-CHOP cycles.Results: The overall response rate, 5-year progression-free survival (PFS) and overall survival (OS) of patients in our study were 93.5%, 75% and 84%, respectively. No treatment delay or dosage reduction from gastric adverse event was observed. None of the patients in our study suffered from severe bleeding or perforation during the treatment. Kaplan–Meier analyses showed that PG-DLBCL patients characterized by multiple localization, lesions ≥ 3cm, having B symptoms, lower serum albumin level, and elevated LDH level were associated with worse PFS and OS.Conclusion: Our data indicate that it might be an effective approach in treating deeply infiltrated PG-DLBCL patients by switching fractioned R-CHOP to standard R-CHOP cycles guided by EUS.Keywords: primary gastric diffuse large B-cell lymphoma, endoscopic ultrasonography, R-CHOP, prognosis

Rituximab in combination with chemotherapy has shown efficacy in patients with diffuse large B-cell lymphoma (DLBCL) for more than 15 years. HLX01 was developed as the rituximab biosimilar following a stepwise approach to demonstrate biosimilarity in analytical, pre-clinical, and clinical investigations to reference rituximab. With demonstrated pharmacokinetic similarity, a phase 3 multi-center, randomized, parallel, double-blind study (HLX01-NHL03) was subsequently conducted to compare efficacy and safety between HLX01 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (H-CHOP) and reference rituximab plus CHOP (R-CHOP) in a total of 407 treatment-naïve, CD20-positive DLBCL patients aged 18–80 years. The primary efficacy endpoint was best overall response rate (ORR) within six cycles of treatment in the per-protocol set (PPS). Secondary endpoints included 1-year efficacy outcomes, safety, and immunogenicity profile. The results showed difference in ORRs [H-CHOP 94.1%; R-CHOP 92.8%] between two treatment groups was 1.4% (95% confidence interval [CI], − 3.59 to 6.32, p = 0.608) which falls within the pre-defined equivalence margin of ± 12%. The safety profile was comparable between the treatment groups, with a similar overall incidence of treatment-emergent adverse events (H-CHOP 99.5%, R-CHOP 99.0%, p = 1.000) and serious adverse events (H-CHOP 34.0%, R-CHOP 32.5%, p = 0.752). This study established bioequivalence in efficacy and safety between HLX01 and reference rituximab. The trial was registered at http://www.chinadrugtrials.org.cn on 26 August 2015 [#CTR20150583].

Summary Background In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT00722137 , and is closed to new participants with follow-up completed. Findings Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding Janssen Research & Development.

Diffuse large B cell lymphoma is one of the predominant histological subtypes of primary gastric lymphomas. Factors that contribute to precise stratification and guide the treatment of this disease are still not well understood. We analyzed 73 primary gastric diffuse large B cell lymphoma patients retrospectively, and found that patients characterized by late stage, multiple localization, B symptoms, lower serum albumin level and elevated LDH level had a shorter overall survival through Univariate Cox regression analysis. Multivariate Cox regression analysis demonstrated that ALB ≤ 35g/L, staging ≥ IIE and multiple sites localization were independent adverse prognostic factors. Significantly, in 35 patients who received endoscopy at diagnosis, Kaplan-Meier analyses indicated that patients with large (≥3 cm) and deep lesions (≥11 mm) had an inferior OS (p = .01 and .039). These findings implicated that tumor size and depth are two indicators of prognosis under ultrasonography. Further randomized studies with large number of cases are needed.

Background: Extranodal Natural killer (NK) /T-cell lymphoma, nasal type (NNKTL), a unique and aggressive neoplasm, is commonly observed in East Asia and Latin America. Even at early stages, NNKTL has a poor clinical outcome because intrinsic chemotherapy resistance, rapid local disease progression and distant metastasis. Despite the use of high dose radiation therapy with or without multiagent chemotherapy regimens, NNKTL has a high rate of relapse (25-40%). Moreover, the estimated 5-year survival on relapsed NNKTL is 52.3%. The identification and validation of readily available biomarkers that predict treatment outcomes can aid in the use of consolidation cellular therapy (i.e. allogeneic bone marrow transplant) and tailored surveillance programs. Elevated serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) had been associated with inferior outcomes in non-Hodgkin lymphoma, but their utility in NNKTL remains unidentified. Here, we examined sICAM-1 levels in patients of early-stage NNKTL and its correlation with clinical characteristics, response to the therapy and clinical outcomes. Material and Methods: This was a retrospective observation study conducted in patients diagnosed as Stage I/II NNKTL in the upper aerodigestive tract treated at Shanghai Cancer Hospital, Shanghai, China and for which biospecimens collected at diagnosis and at the end of therapy (EOT) (frozen serum) were available. The study was approved by the IRB (Protocol number). Baseline and EOT sICAM-1 levels were measured by ELISA (R&D systems, Minneapolis, MN, sensitivity =0.35ng/ml) according to the manufacture' s protocol. Differences of sICAM-1 expression between baseline and EOT were analyzed by paired t-test. Difference of sICAM-1 between complete response and non-complete response groups were determined by Mann-Whitney U-test. Comparing sICAM-1 among different clinical characteristics was determined by Chi square and Fisher's test. Differences in overall survival (OS) and progression-free survival (PFS) between patients with high and low sICAM-1 levels were analyzed by the Kaplan-Meier method. Results: A total of 74 patients were included in the study (18F/56M), the median age of the patients was 45.5 (19-73). Patients were treated with radiation therapy alone (N=34), or combined modality therapy (N=40). As previously noted in other studies, achievement of a complete response at the end of therapy was associated with a better PFS and OS (P The net change (EOT minus Baseline) of sICAM-1 levels (ΔsICAM-1) was significantly higher is patients with relapse disease (81.4+63.1 vs 33.5+81.2, p Conclusion: Higher sICAM-1 levels at diagnosis were associated with primary treatment failure in early stage NNKTL. In addition, an elevated ΔsICAM-1 in patients achieving a complete response to first like therapy were associated with relapse disease and shorter PFS. Together, our data suggests that sICAM-1 may be used as serological biomarker to monitor and predict clinical outcome of early stage NNKTL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: SCT400 is a recombinant, human-mouse chimeric anti-CD20 IgG1 monoclonal antibody and has the same variable regions and antigen-binding site as rituximab. SCT400 has the heavy and κ light chain constant regions of human IgG1 allotype G1m (1,17), which is common in Asians. There is only one amino acid difference between SCT400 and rituximab (V219A in the CH1 domain of the heavy chain). The phase Ⅱ study showed that pharmacokinetics, pharmacodynamics and safety of SCT400 are equivalent to rituximab in patients with CD20-positive non-Hodgkin lymphoma. Objectives: This phase III study aimed to evaluate the safety and efficacy of SCT400 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) compared with rituximab plus CHOP in patients with treatment-naïve diffuse large B-cell lymphoma (DLBCL) (ClinicalTrials.gov, identifier: NCT02772822). Methods: In this multicenter, randomized, single-blind, parallel active-controlled, non-inferiority, phase III study, patients were enrolled from 37 centers in China. Eligible patients were aged 18～75 years with histologically confirmed CD20-positive, treatment-naïve DLBCL; international prognostic index (IPI) 0～2; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0～2. Patients were randomly assigned in a 2:1 ratio to receive either SCT400 plus CHOP (S-CHOP) or rituximab plus CHOP (R-CHOP) every 21 days cycle treatment for six cycles. The primary endpoint was objective response rate (ORR) after six cycles of therapy, assessed by an independent review committee, with a non-inferiority margin of -12%. The secondary endpoints were complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between October 19, 2016 and July 13, 2018, 534 patients were screened and 364 eligible patients were randomized to either the S-CHOP group (n=243) or R-CHOP group (n=121). Patient demographics and disease characteristics at baseline were well balanced between the two treatment groups. In the per protocol set (PPS), the best ORRs within six cycles of treatment were 94.5% (95% confidence interval [CI], 90.8% to 97.0%) and 94.1% (95%CI, 88.2% to 97.6%) in the S-CHOP and R-CHOP groups respectively, with an intergroup difference of 0.4% (95%CI, -4.7% to 5.6%, P=0.6569) (Figure 1A). The 95%CI lay on the positive side of the prespecified non-inferiority margin of -12%, meeting the criterion for non-inferiority. The results of using the full analysis set (FAS) were consistent with the primary efficacy analysis in the PPS. No significant differences were observed in the secondary efficacy endpoints, in either the PPS or the FAS (Figure 1B and Figure 2). There were no significant differences were observed in ≥1 adverse event (AE, 97.9% vs. 99.2%), grade≥3 AE (85.2% vs. 86.0%), serious AE (35.4% vs. 38.8%), treatment discontinuation due to AE (7.8% vs.12.4%) between S-CHOP and R-CHOP groups, respectively (Table 1). AEs of special interest occurred in 63.8% of patients in the S-CHOP group and in 59.5% of patients in R-CHOP group, including infection (46.5% vs. 46.3%), infusion-related reaction (20.2% vs. 17.4%), cardiotoxicity (17.7% vs. 11.6%), hepatitis B virus reactivation (1.2% vs. 3.3%), ileus and enterobrosis (1.2% vs. 0.8%), tumor lysis syndrome (0.0% vs. 0.8%) (Table 1). A total of 51 deaths were reported in the S-CHOP group (n=35, 14.4%) and R-CHOP group (n=16, 13.2%), and 10 deaths were due to AE (S-CHOP group: n=7, 2.9%; R-CHOP group: n=3, 2.5%) (Table 1). After treatment, study-drug related anti-drug antibodies (ADAs) were detected in 11(10.9%) patients in S-CHOP group and in 8(16.0%) patients in R-CHOP group (Table 1). Conclusion: SCT400 plus CHOP showed non-inferiority of efficacy to rituximab plus CHOP in patients with treatment-naïve DLBCL. The safety and immunogenicity profiles of SCT400 were comparable with rituximab, with no new treatment-related AE occurred. SCT400 could be a therapeutic option for DLBCL. Funding source: This study was supported by the sponsor, Sinocelltech Ltd., and by grants from the China National Major Project for New Drug Innovation (No. 2018ZX09736002 and No. 2017ZX09304015). Conflicts of interest: Liangzhi Xie is an employee of Sinocelltech Ltd. and has ownership interests in the company. All other authors declare no conflicts of interest. Figure 1 Figure 1. Disclosures Hu: Astellas Pharma, Inc.: Research Funding. Xie: Sinocelltech Ltd.: Current Employment, Current equity holder in publicly-traded company.

Background To evaluate the efficacy and safety of doxorubicin (ADM) combined with thalidomide (THA) as a first-line treatment for patients with refractory aggressive fibromatosis (AF). Patients and Methods Eligible patients were treated with ADM 30 mg/m2 on days 1-2 and THA 200 mg nightly on days 1-21 every 3 weeks for a maximum of six cycles. THA was then continued for a total of 1 year. The primary end point was response rate (RR). Results Fifteen patients were enrolled in the study. No patient had a complete response, but five patients had partial responses, resulting in a RR of 33%. Eight patients (53%) had stable disease and two patients (13%) had progressive disease, and the disease control rate was 87%. The median progression free survival (mPFS) was 20.6 months (95% confidence interval, 14.5-26.7 months). Patients with below normal baseline serum albumin levels had significantly inferior mPFS compared with those with normal baseline serum albumin (1.4 months versus 23.7 months, P = 0.045). Grade 3/4 toxicities included leukopenia (33%), neutropenia (60%), febrile neutropenia (7%), nausea (7%), and vomiting (6.6%). Conclusions ADM plus THA was well-tolerated and effective as a first-line treatment for patients with refractory AF. However, patients with hypoalbuminemia at baseline had inferior clinical outcomes, and further studies are needed to investigate this issue.

The pivotal LYM-3002 study compared frontline rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) with bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) in newly diagnosed mantle cell lymphoma (MCL) patients for whom stem cell transplantation was not an option. This post hoc subanalysis of the VR-CAP data from LYM-3002 evaluated the effect of bortezomib dose intensity on OS in patients who completed ≥6 cycles of treatment. From the end of cycle 6, patients receiving ≥4.6 mg/m2/cycle of bortezomib had significantly longer OS (but not PFS) compared with those receiving