Zhitao Ying

Safety and efficacy of bevacizumab combined with R-CHOP regimen in seven Chinese patients with untreated diffuse large B-cell lymphoma.

BackgroundRituximab plus CHOP (R-CHOP) significantly improved the outcome of diffuse large B cell lymphoma (DLBCL), a common sub-type of non-Hodgkin lymphoma. But 40% – 50% of DLBCL patients cannot be cured by this regimen. Some clinical trials showed that bevacizumab might be useful in the treatment of DLBCL. This study evaluated the safety and efficacy of bevacizumab combined with the R-CHOP (A-R-CHOP) regimen in Chinese patients with previously untreated DLBCL.MethodsPatients with previously untreated DLBCL received A-R-CHOP regimen therapy. All patients with complete response (CR)/ unconfirmed complete response(CRu) after 8 cycles of A-R-CHOP received the bevacizumab maintenance therapy once every 3 weeks. The remained bulky disease was treated with radiotherapy.ResultsSeven Chinese patients were treated. All of them had bulky diseases. One patient had progressive disease after 4 cycles of A-R-CHOP therapy. The rest six patients completed 8 cycles of A-R-CHOP treatment. All of these six patients reached CR/CRu (5 CR, 1 CRu). Bevacizumab maintenance therapy was given to 4 CR patients. All 7 patients experienced Grade 3/4 hematologic adverse events; additionally, one had Grade 3 gastrointestinal toxicity and one had Grade 1 epistaxis. During bevacizumab maintenance therapy, one patient had Grade 1 gingival bleeding, another experienced Grade 1 proteinuria and then Grade 3 congestive heart failure 4 months after completion of maintenance therapy. At the end of July 2013, the patient who had progressive disease after 4 cycles of A-R-CHOP died of progressive disease, the other six remained CR response.ConclusionsThe A-R-CHOP regimen is effective for untreated DLBCL, but may cause bevacizumab-specific toxicities, which should be monitored.

The mTOR kinase inhibitor everolimus synergistically enhances the anti-tumor effect of the Bruton's tyrosine kinase (BTK) inhibitor PLS-123 on Mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive and incurable malignant disease. Despite of general chemotherapy, relapse and mortality are common, highlighting the need for the development of novel targeted drugs or combination of therapeutic regimens. Recently, several drugs that target the B‐cell receptor (BCR) signaling pathway, especially the Brutons tyrosine kinase (BTK) inhibitor ibrutinib, have demonstrated notable therapeutic effects in relapsed/refractory patients, which indicate that pharmacological inhibition of BCR pathway holds promise in MCL treatment. Here, we have developed a novel irreversible BTK inhibitor, PLS‐123, that has more potent and selective anti‐tumor activity than ibrutinib in vitro and in vivo. Using in vitro screening, we discovered that the combination of PLS‐123 and the mammalian target of rapamycin (mTOR) inhibitor everolimus exert synergistic activity in attenuating proliferation and motility of MCL cell lines. Simultaneous inhibition of BTK and mTOR resulted in marked induction of apoptosis and cell cycle arrest in the G1 phase, which were accompanied by upregulation of pro‐apoptotic proteins (cleaved Caspase‐3, cleaved PARP and Bax), repression of anti‐apoptotic proteins (Mcl‐1, Bcl‐xl and XIAP), and downregulation of regulators of the G1/S phase transition (CDK2, CDK4, CDK6 and Cyclin D1). Gene expression profile analysis revealed simultaneous treatment with these agents led to inhibition of the JAK2/STAT3, AKT/mTOR signaling pathways and SGK1 expression. Finally, the anti‐tumor and pro‐apoptotic activities of combination strategy have also been demonstrated using xenograft mice models. Taken together, simultaneous suppression of BTK and mTOR may be indicated as a potential therapeutic modality for the treatment of MCL.

Prognostic value of interim (18)F-FDG PET/CT in diffuse large B-cell lymphoma.

OBJECTIVE Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. The prognostic factor currently used is not accurate enough to predict the outcomes of patients with DLBCL. The prognostic significance of interim PET/CT in DLBCL remains controversial. The aim of this study is to determine the predictive value of interim (18)F-FDG PET/CT after first-line treatment in patients with DLBCL. METHODS Thirty-two patients with DLBCL underwent baseline, interim and post-treatment (18)F-FDG PET/CT scans. Imaging results were analyzed for the survival of patients via software SPSS 13.0, retrospectively. RESULTS Thirty-one of the 32 patients were treated with R-CHOP regimen, and interim (18)F-FDG PET/CT of 24 patients was performed after 2 cycles of treatment. After a median follow-up period of 16.7 months, the 2-year progression-free survival (PFS) rates were significantly different between the groups above and below SUV(max) cut-off value of 2.5 (P=0.039). No significant differences were found in the 2-year PFS rates if SUV(max) cut-off values were set as 2.0 and 3.0, respectively (P=0.360; P=0.113). CONCLUSIONS Interim PET/CT could predict the prognosis of DLBCL patients with the SUV(max) cut-off value of 2.5, but more clinical data should be concluded to confirm this conclusion. KEY WORDS Fludeoxyglucose F18; lymphoma; large cell; diffuse; prognosis; standard utility value.

Can the SUVmax-liver-based interpretation improve prognostic accuracy of interim and posttreatment 18F-FDG PET/CT in patients with diffuse large B-cell lymphoma?

Abstract In order to investigate whether the SUVmax-liver-based interpretation could improve prognostic accuracy of interim (PET-4) and posttreatment PET/CT (PET-end), 115 patients with newly diagnosed DLBCL were recruited in the study. ROC analysis revealed the optimal threshold is 1.6-fold of SUVmax-liver for PET-4 and 1.4-fold of SUVmax-liver for PET-end. The SUVmax-liver-based interpretation had a perfect interobserver agreement, higher prognostic accuracy and positive predictive value than 5-point scale and %ΔSUVmax criteria in both PET-4 and PET-end. Dramatic differences in the outcome between patients with positive and negative PET-4/PET-end were demonstrated using Kaplan–Meier survival curves (p < .05). Univariate and multifactor analysis found PET-4 and PET-end were independent prognostic factors for the outcome of DLBCL. In conclusion, the SUVmax-liver-based interpretation were superior to 5-point scale and %ΔSUVmax criteria in analyzing the PET-4 and PET-end for the prognosis of DLBCL patients.

Evaluating early interim fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography with the SUVmax-liver-based interpretation for predicting the outcome in diffuse large B-cell lymphoma

Abstract Interim 18F-FDG PET/CT is an effective predictor in patients with DLBCL, but the standard evaluating criteria were controversial. In this study, investigators tried to investigate whether the liver SUVmax (SUVmax-liver)-based interpretation could improve the accuracy of predicting the outcomes, comparing with the Deauville five-point scale (5-PS) and the reduction rate of the maximum standardized uptake value (ΔSUVmax) criteria. In 119 patients, PET/CT after two chemotherapy cycles (PET2) were evaluated with the SUVmax-liver-based interpretation, 5-PS, and ΔSUVmax criteria. Uni- and multivariate analyses were performed. The optimal threshold for the SUVmax-liver-based interpretation was 1.6 fold of SUVmax-liver. Using the SUVmax-liver-based interpretation, the 3-year PFS and OS were 19.9% and 33.0% for patients with a positive residue while 78.2% and 86.4% for patients with negative results (p < .001). SUVmax-liver-based interpretation demonstrated slightly superior accuracy, and was independent predictor for PFS and OS (p ≤ .001). Thus, early interim 18F-FDG PET/CT effectively predicts the outcome in patients with DLBCL using SUVmax-liver-based interpretation.

TIME FROM DIAGNOSIS TO 2ND TREATMENT IS A PROMISING SURROGATE FOR OVERALL SURVIVAL IN PATIENTS WITH ADVANCED STAGE FOLLICULAR LYMPHOMA

FLIPI risk category progressed in 60.5% (N = 69), which was associated with inferior outcome compared with pts with stable FLIPI (39.5%, N = 45), p = 0.006 (Figure 1C). In contrast, annual FLIPI risk categories over 5 yrs in 156 observed pts who never required therapy were stable in 72 (46%), progressed in 27 (17%), were not assessed in 57 (37%). Pts with progressed versus stable FLIPI had higher risk of transformation (25.2% vs 11.3%, p < 0.001) and were treated more often initially with R‐monotherapy (38.8% vs. 19.1%, p < 0.001). Conclusions: Despite improvement in OS over the last two decades, PFS after 4th line of therapy remains less than 1 year. The data benchmarks PFS by lines of therapy, which will facilitate drug development in pts with multiply relapsed FL. The inferior outcome for pts who progress and alter their FLIPI may represent pts with adverse biology at diagnosis. We hope to identify biomarkers in this high‐risk group that would permit identification for early treatment intervention.

A PHASE I STUDY OF CHIMERIC ANTIGEN RECEPTORMODIFIED T CELLS DIRECTED AGAINST CD19 IN PATIENTS WITH RELAPSED OR REFRACTORYCD19(+) B CELL LYMPHOMAS: INTERIM ANALYSIS

271 A PHASE I STUDY OF CHIMERIC ANTIGEN RECEPTORMODIFIED T CELLS DIRECTED AGAINST CD19 IN PATIENTS WITH RELAPSED OR REFRACTORYCD19(+) B CELL LYMPHOMAS: INTERIM ANALYSIS Z. Ying* | X. Xiang | Y. Song | N. Ding | Y. Lin | W. Zheng | X. Wang | N. Lin | M. Tu | Y. Xie | C. Zhang | W. Liu | L. Deng | Y. Liu | Y. Yue | X. Yu | H. Liu | P. Duan | F. Chen | X. Wu | X.F. Huang | L. Jones | X. Kang | S. Chen | J. Zhu Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China; Department of medicine, Marino Biotechnology Co., Ltd., Beijing, China; Department of Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA

DEFINING PROGRESSION FREE SURVIVAL AFTER MULTIPLE LINES OF THERAPY AND IMPACT OF DYNAMIC CHANGES IN FLIPI FOR MULTIPLY RELAPSED FOLLICULAR LYMPHOMA IN THE RITUXIMAB ERA

(OS). CR30 was calculated according to original method (Qian Shi et al. JCO, 2017). To align the endpoints, POD24 and CR30 are labeled as fail (F) for progression within 24 months, no CR30 and achieve (A) for no POD24 and achieve CR30, respectively. Results: Median follow‐up was 84 months (range 1–119). One hundred and forty‐one patients (28%) failed POD24, and 235 (47%) failed the CR30 endpoint. Five‐year OS was 79% and 95% for patients failing and achieving POD24 (p < 0.001) and was 82% and 98% for patients failing to achieve and achieving CR30 (p < 0.001). Prognostic role of POD24 and CR30 was observed for all three study arms (p < 0.001). Both indexes retained their prognostic role for OS after adjustment by FLIPI (p < 0.001) and FLIPI2 (p < 0.001). In POD24 analysis, the OR adjusted by FLIPI2 between R‐CHOP vs. R‐CVP was 0.70 (95%CI 0.43–1.13, p = 0.148) and 0.58 (95%CI 0.36–0.94, p = 0.027) between R‐FM vs. R‐CVP. In CR30, the OR adjusted by FLIPI2 between R‐CHOP vs. R‐CVP was 0.63 (95%CI 0.40‐0.98, p = 0.043) and 0.57 (95%CI 0.36–0.89, p = 0.013) between R‐FM vs. R‐CVP. Five‐year OS was 95% for patients achieving both POD24 and CR30 (267; 53%), 86% for those failing CR30 (94; 19%) and 74% for patients failing both POD24 and CR30 (141; 28%) (Figure 1. OS stratified by groups obtained combining POD24 with CR30). Conclusions: In patients with advanced stage FL who received standard immunochemotherapy in the FOLL05 trial, both POD24 and CR30 were significant prognostic factors for OS although. CR30 was better than POD24 to identify low risk patients, while POD24 was more accurate for the identification of high‐risk subjects. POD24 and CR30 showed a comparable behavior and a satisfying correlation with PFS and can be used for the early assessment of patient outcome.

PEG-asparaginase in BFM-90 regimen improves outcomes in adults with newly diagnosed lymphoblastic lymphoma

Objective Although L-asparaginase (L-ASP) is a standard treatment for lymphoblastic lymphoma (LBL), hypersensitivity reactions by some patients limit its application. Polyethylene glycol-conjugated asparaginase (PEG-ASP) has a lower immunogenicity and is a standard treatment in all pediatric acute lymphoblastic leukemia (ALL). In this study, we investigated the efficacy and toxicity of PEG-ASP instead of L-ASP as used in the BFM-90 regimen (PEG-ASP-BFM-90) for adult LBL. Methods Between June 2012 and July 2015, we treated 30 adult patients with newly diagnosed LBL, using PEG-ASP-BFM-90 in a prospective, multicenter and single-arm clinical study at 5 participating institutions in China. Results All the 30 patients, including 19 males and 11 females with a median age of 30 (range: 18–62) years, completed 128 times of the PEG-ASP, with the median of 4 (range: 2–6) times. Patients did not receive radiotherapy at this time. The overall response rate was 86.7% (26/30), with 50.0% (15/30) complete response and 36.7% (11/30) partial response. The 3-year overall survival was 46.0% [95% confidence interval (95% CI), 28.2%–64.8%], and the 3-year progression-free survival was 43.0% (95% CI, 25.7%–62.0%). Major adverse events were myelosuppression, reduced fibrinogen, liver dysfunction and digestive tract toxicities. No allergic reaction and no treatment-related mortality or severe complications were recorded. Conclusions Our clinical data and observed outcomes indicate that 1 dose of PEG-ASP can replace multiple doses of native L-ASP in BFM-90, with predominantly grade 3–4 neutropenia for adult LBL, and no therapy-related deaths. The effect is similar to previous reports of PEG-ASP-containing regimens for adult ALL. Major advantages include less serious allergic reactions, 2–3 weeks of action duration, and convenience for patients and physicians.

Prognostic value of pre- and post-transplantation F-18-fluorodeoxyglucose positron emission tomography results in non-Hodgkin lymphoma patients receiving autologous stem cell transplantation

Objective High-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) is the standard of care in the upfront or relapsed/refractory setting in some patients with non-Hodgkin lymphoma (NHL). However, a proportion of patients do not respond to ASCT. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) has been widely used for staging, response evaluation, and prognosis prediction. Here, we investigated the prognostic role of PET/CT in NHL patients before and after ASCT. Methods A retrospective study was conducted at Peking University Cancer Hospital. All NHL patients who underwent ASCT between March 2010 and July 2016 were identified. Patients who had PET/CT scan before and after ASCT were included. Deauville criteria (5-point scale) were used to interpret PET scans. Univariate and multivariate survival analyses were performed using Cox regression. The predictive value of PET scanning was estimated by comparing the area under the receiver operating characteristic (ROC) curve. Results In total, 79 patients were enrolled in this study. In univariate analysis, pre- and post-ASCT PET result was identified as prognostic factors for 3-year progression-free survival (PFS) and overall survival (OS). Patients with negative pre-ASCT PET result demonstrated significantly better PFS (84.2% vs. 54.2%) and OS (89.2% vs. 63.6%) than patients with positive pre-ASCT PET result. PFS (91.6% vs. 25.3%) and OS (96.5% vs. 36.8%) were also significantly different between patients with negative and positive post-ASCT PET result. Multivariate analysis also showed a significant association between survival and post-ASCT PET result. ROC analysis revealed that the predictive value of post-ASCT PET result was superior to that of pre-ASCT PET result alone. Combined pre- and post-ASCT PET result is better for predicting outcomes in patients with NHL receiving transplantation. Deauville criteria score >3 was identified as the best cutoff value for post-ASCT PET. Conclusions Post-ASCT PET result was more important than pre-ASCT PET result in predicting outcomes for NHL patients who underwent ASCT. The prognostic significance can be improved when combining pre-ASCT PET result with post-ASCT PET result. Deauville criteria can be used for interpreting PET scans in this scenario.