Rituximab Plus CHOP Research Articles

Comparison of the effectiveness of RB and R-CHOP regimens in first-line therapy in 277 patients with grade 1–2 follicular lymphoma: a retrospective single-center analysis

Background. Chemoimmunotherapy, including cytotoxic drugs and anti-CD20 monoclonal antibodies have significantly improved outcomes in patients with newly diagnosed follicular lymphoma (FL) compared with chemotherapy. A number of clinical studies have compared the effectiveness of the two most popular treatment regimens, rituximab plus bendamustine (RB) and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), with conflicting results.Aim. To conduct a retrospective analysis of the treatment results of a large cohort of patients with grade 1–2 FL who received RB or R-CHOP regimens in the first line therapy in real-life clinical practice, to analyze the impact of individual prognostic factors, as well as rituximab maintenance therapy on survival, the incidence of secondary malignancies and causes of mortality.Materials and methods. Data were collected on patients with grade 1–2 FL who were treated at the Botkin Hospital from November 2006 to November 2022. The inclusion criteria for the study were newly diagnosed histologically confirmed FL of grade 1–2, age ≥18 years, RB or R-CHOP therapy as first line. No radiation therapy was allowed. Response assessment was performed according to the 2007 International Working Group criteria.Results. The inclusion criteria for the study were met by 277 patients; 164 patients received R-CHOP and 113 patients received RB. Overall response rate was comparable between groups (96 % vs 94 % in the RB and R-CHOP groups, respectively, p = 0.3396). The median followup period was 35 (3–117) months in the RB group and 50 (3–200) months in R-CHOP group. The median progression-free survival (PFS) in the R-CHOP group was 86 months, while the median of PFS in the RB group was not reached, the differences did not reach statistical significance (hazard ratio (HR) 0.65; 95 % confidential interval (CI) 0.42–1.004; p = 0.0665). Three-year PFS was 81 and 72 %, and five-year PFS was 66 and 57 % in the RB and R-CHOP groups, respectively. Progression within 24 months of initiation of therapy was more common in R-CHOP group (20 % vs 11 %, p = 0.0466). The median time to next therapy in R-CHOP group was 90 months and was not reached in RB group (HR 0.75; 95 % CI 0.48–1.18; p = 0.2277). Unifactor analysis of individual prognostic factors showed superior PFS in most subgroups receiving RB regimen. R-CHOP regimen showed a trend towards improved PFS only in patients with maximum standardized uptake value (SUVmax) >14 (HR 2.46; 95 % CI 0.52–11.62; p = 0.2211). The use of rituximab maintenance therapy improved PFS in both treatment groups: in R-CHOP group, the differences reached the level of significance (HR 0.22; 95 % CI 0.05–1.01; p<0.0001) , in RB group they did not reach the level of significance (HR 0.41; 95 % CI 0.02–8.67; p = 0.3605). There were no significant differences in overall survival. The 5-year cumulative incidence of secondary malignancies as well as the incidence of grade 5 infections were comparable between groups.Conclusion. In summary, our study shows that RB regimen generally has comparable long-term efficacy to R-CHOP regimen in first-line therapy in patients with grade 1–2 FL. Unifactor analysis of individual prognostic factors showed better PFS in most subgroups using the RB regimen. The use of rituximab maintenance therapy significantly improved PFS in R-CHOP group compared with RB regimen. Our study with a significant median follow-up did not find differences in the incidence of secondary malignancies or non-lymphoma related mortality.

Comparison of zuberitamab plus CHOP versus rituximab plus CHOP for the treatment of drug-naïve patients diagnosed with CD20-positive diffuse large B-cell lymphoma: a phase 3 trial

BackgroundIn patients with untreated CD20-positive diffuse large B-cell lymphoma (DLBCL), a phase 3 trial was carried out to evaluate the efficacy and safety of zuberitamab plus CHOP (cyclophosphamide, doxorubicin, vincristine,...

A single-centre, real-world study of BTK inhibitors for the initial treatment of MYD88mut /CD79Bmut diffuse large B-cell lymphoma.

MCD (MYD88L265P /CD79Bmut ) diffuse large B-cell lymphoma has a poor prognosis. There is no published clinical research conclusion regarding zanubrutinib or orelabrutinib for the initial treatment of MCD DLBCL. This study aimed to analyse the efficacy and safety of Bruton's tyrosine kinase inhibitor (BTKi) (zanubrutinib or orelabrutinib) therapy for newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut . Twenty-three newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut from June 2020 to June 2022 received BTKi combined with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab + lenalidomide (R2 ). A control group of 17 patients with MYD88mut and/or CD79Bmut DLBCL who received the standard R-CHOP therapy was also assessed. We retrospectively analysed clinical characteristics, safety, overall response rate (ORR), complete response (CR) rate and progression-free survival (PFS) of the two groups. The main clinical features were a high International Prognostic Index (IPI) score (≥3, 22/40, 55%) and a high rate of extranodal involvement (27/40,67.5%). Among the 23 DLBCL patients, 18 received BTKi + R-CHOP, and five elderly DLBCL patients were treated with BTKi + R2 . Compared with those in the control group (ORR 70.6%, CRR 52.9%, 1-year PFS rate 41.2%), improved ORR, CRR and PFS results were observed in the BTKi + R-CHOP group (100%, 94.4% and 88.9%, p = 0.019, 0.007, and 0.0001). In subgroup analyses based on genetic subtypes, cell origin, dual expression or IPI score, patients in the BTKi + R-CHOP group had better PFS than patients in the control group. In the BTKi + R-CHOP group, no significant difference was found in ORR, CRR and PFS based on subtype analysis, while BTKi-type subgroups exhibited statistically significant differences in 1-year PFS (p = 0.028). There were no significant differences in grade 3-4 haematological toxicity (p = 1) and grade 3-4 non-haematological toxicity (p = 0.49) between the BTKi + R-CHOP and R-CHOP treatment groups. In the BTKi + R2 group, the ORR was 100%, the CRR was 80%, and the 1-year PFS rate was 80%. The incidences of grade 3-4 haematologic toxicity and non-haematological toxicity were both 40%. No bleeding or cardiovascular events of grade 3 or higher occurred in any patients. The efficacy of BTKi combined with R-CHOP was similar to previous reports, which was significantly better than R-CHOP alone. It is necessary to fully consider that 14 patients in the BTKi + R-CHOP group received a BTKi as maintenance therapy when evaluating efficacy. Meanwhile, the addition of a BTKi may improve the prognosis of non-GCB, DEL or high-IPI-score DLBCL patients with MYD88mut and/or CD79Bmut . In our study, five elderly DLBCL patients with MYD88mut and/or CD79Bmut were achieved better ORR, CRR, PFS than the historical data of R-miniCHOP treatment and Ibrutinib + R2 treatment. However, the efficacy and benefit of BTKis for this type of DLBCL need to be further analysed using a larger sample size. This study suggests that newly diagnosed DLBCL patients with MYD88mut and/or CD79Bmut may benefit from BTKis according to real-world clinical data.

Identification of novel prognostic autoantibodies in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone via a high-throughput antigen microarray.

R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is a standard first-line treatment for diffuse large B-cell lymphoma (DLBCL). However, 20%-40% of patients survive less than 5years. Novel prognostic biomarkers remain in demand. Baseline plasma autoantibodies (AAbs) were assessed in 336 DLBCLs. In the discovery phase (n=20), a high-density antigen microarray (∼21,000 proteins) was used to expound AAb profiles. In the verification phase (n=181), with a DLBCL-focused microarray, comparative results based on event-free survival at 24months (EFS24) and lasso Cox regression models of progression-free survival (PFS) and overall survival (OS) were integrated to identify potential biomarkers. They were further validated by enzyme-linked immunosorbent assay in validation phase 1 (n=135) and a dynamic cohort (n=12). In validation phase 2, a two-AAb-based risk score was established. They were further validated in an immunohistochemistry cohort (n=55) and four independent Gene Expression Omnibus datasets (n=1598). Four AAbs (CREB1, N4BP1, UBAP2, and DEAF1) were identified that showed associations with EFS24 status (p<.05) and superior PFS and OS (p<.05). A novel risk score model based on CREB1 and N4BP1 AAbs was developed to predict PFS with areas under the curve of 0.72, 0.71, 0.76, and 0.82 at 1, 3, 5, and 7years, respectively, in DLBCL treated with R-CHOP independent of the International Prognostic Index (IPI) and provided significant additional recurrence risk discrimination (p<.05) for the IPI. CREB1 and N4BP1 proteins and messenger RNAs were also associated with better PFS and OS (p<.05). This study identified a novel prognostic panel of CREB1, N4BP1, DEAF1, and UBAP2 AAbs that is independent of the IPI in DLBCL.

Lower Prognostic Performance of the International Metabolic Prognostic Index Compared to the Conventional IPI and NCCN-IPI in a Real-World Cohort of Diffuse Large B-Cell Lymphoma

Introduction: The international metabolic prognostic index (IMPI) is a recently proposed model that shows improved outcome prediction for patients with diffuse large B-cell lymphoma (DLBCL) compared to the International Prognostic Index (IPI) (Mikhaeel et al.). IMPI combines total metabolic tumor volume (TMTV) as continuous variables with clinical factors, allowing individualized prognosis estimation. However, the applicability of IMPI to routine clinical practice remains uncertain since the model construction was based on data from clinical trials. Furthermore, the comparison of the model performance between IMPI and the National Comprehensive Cancer Network IPI (NCCN-IPI) is not reported so far. Methods: We performed retrospective analysis of consecutive patients with newly diagnosed DLBCL who were initially treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) at Kameda Medical Center between 2006 and 2020. Patients who had no fluorodeoxyglucose-avid lesions were excluded. TMTV was defined as the volume of lymphoma-associated lesions with a standardized uptake value of ≥4 as the absolute threshold (Metavol, Hokkaido University, Japan). According to the original study (Mikhaeel et al.), IMPI was calculated using the following formula: 0.003077330 × (MTV lower than the median of 307.9ml) - 0.002761985 × (MTV higher than the median of 307.9ml) + 0.008092449 × Age -0.114645415 × Stage 2 + 0.281141117 × Stage 3 + 0.322247142 × Stage 4. The receiver operating curve (ROC) for predicting 5-year survival was compared among IMPI-, IPI-, and NCCN-IPI-based classifications. The predictive performance of these three systems was evaluated using the Akaike information criterion (AIC) and Harrell's concordance index (c-index). Results: A total of 314 patients were included in the study. The median age was 72 years old (interquartile range [IQR] 64-79), which was younger than the original data (median 62, IQR 51-70). Regarding the distributions of IPI risk groups, this cohort had a lower number of low-risk patients (27.0% vs. 32.4%) and a higher number of high-risk patients (23.9% vs. 19.5%). The median TMTV was 168 (IQR 47-530), which was approximately two times lower than that in the original study (median 307, IQR 77-838). After calculating and ranking the individual IMPI scores, nearly half of the patients (n=147, 46.8%) were reclassified into different risk groups from the original IPI categories (Figure 1); 76 (51.7%) were upstaged, and 71 (48.3%) were downstaged. Of note, the reclassification resulted in a significantly better OS prediction only for the IPI high-risk group (5-year OS rate, IMPI high-risk vs. IMPI not high-risk, 41.9% vs. 59%, P =0.042), while it did not for the IPI low-, low-intermediate-, and high-intermediate-risk groups. The area under the curve (AUC) from the ROC curve predicting 5-year survival was not significantly different between IMPI- (AUC 0.65) and either IPI- (AUC 0.67, P =0.42) or NCCN-IPI-categories (AUC 0.68, P=0.25). Finally, the predictive performance and model fitness were compared among these three indices. IMPI had the highest AIC (1117.68) and the lowest c-index (0.643) for OS prediction, whereas NCCNIPI yielded the best performance (AIC 1097.66 and c-index 0.677) (Table 1). Conclusions: We demonstrated that the IMPI model did not outperform the conventional IPI and NCCN-IPI systems in a real-world cohort of DLBCL patients. The difference in age and tumor burden, which are the major components of IMPI, may lead to poorer prognostic performance. Further large-scale studies are warranted to validate the prognostic value of IMPI outside of clinical trials.

Positron emission tomography-adapted therapy in low-risk diffuse large B-cell lymphoma: results of a randomized, phase III, non-inferiority trial.

The current standard of care for non-bulky diffuse large B-cell lymphoma (DLBCL) patients with an International Prognostic Index (IPI) of 0 is four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) but whether the same efficacy can be achieved with reduced chemotherapy regimen of four cycles for non-bulky DLBCL patients with an IPI of 1 remains unclear. This study compared four cycles versus six cycles of chemotherapy in non-bulky low-risk DLBCL patients with negative interim positron emission tomography with computed tomography (PET-CT, Deauville 1-3), irrespective of age and other IPI risk factors (IPI 0-1). This was an open-label, randomized, phase III, non-inferiority trial. Patients aged 14-75 years with newly diagnosed low-risk DLBCL, according to IPI, achieving PET-CT confirmed complete response (CR) after four cycles of R-CHOP were randomized (1:1) between four cycles of rituximab (4R-CHOP+4R arm) or two cycles of R-CHOP plus two cycles of rituximab (6R-CHOP+2R arm). The primary endpoint was 2-year progression-free survival (PFS), conducted in the intention-to-treat population. Safety was assessed in patients with at least one cycle of assigned treatment. The non-inferiority margin was -8%. A total of 287 patients were included in the intention-to-treat analysis, the median follow-up was 47.3 months, and the 2-year PFS rate was 95% (95% confidence interval [CI], 92% to 99%) and 94% (95% CI, 91% to 98%) for the 4R-CHOP+4R and 6R-CHOP+2R arm. The absolute difference in 2-year PFS between the two arms was 1% (95% CI, -5% to 7%), supporting the non-inferiority of 4R-CHOP+4R. Grade 3-4 neutropenia was lower in the last four cycles of rituximab alone in the 4R-CHOP+4R arm (16.7% versus 76.9%), with decreased risk of febrile neutropenia (0.0% versus 8.4%) and infection (2.1% versus 14.0%). For newly diagnosed low-risk DLBCL patients, interim PET-CT after four cycles of R-CHOP was effective in identifying patients with Deauville 1-3 who would have a good response and Deauville 4-5 patients who might have high-risk biological features or develop resistance. Reducing the standard six cycles to four cycles of chemotherapy had comparable clinical efficacy and fewer adverse events in low-risk, non-bulky DLBCL with interim PET-CT confirmed CR.

Simultaneous quantification of pirarubicin, doxorubicin, cyclophosphamide, and vincristine in human plasma of patients with non-Hodgkin's lymphoma by LC–MS/MS method

Pirarubicin (THP), doxorubicin (DOX), cyclophosphamide (CTX), and vincristine (VCR) are widely used in the treatment of patients with non-Hodgkin's Lymphoma. Herein, a precise and sensitive method was developed for the determination of THP, DOX, CTX and VCR in human plasma by high-performance liquid-chromatography–tandem mass spectrometry (LC-MS/MS). Liquid-liquid extraction was applied to extract THP, DOX, CTX, VCR, and the internal standard (IS, Pioglitazone) in plasma. Agilent Eclipse XDB-C18 (3.0 mm × 100 mm) was utilized and chromatographic separation was obtained in eight minutes. Mobile phases were composed of methanol and buffer (10 mM ammonium formate containing 0.1% formic acid). The method was linear within the concentration range of 1–500 ng/mL for THP, 2–1000 ng/mL for DOX, 2.5–1250 ng/mL for CTX, and 3–1500 ng/mL for VCR. The intra- and inter-day precisions of QC samples were found to be below 9.31 and 13.66%, and accuracy ranged from −0.2 to 9.07%, respectively. THP, DOX, CTX, VCR and the internal standard were stable in several conditions. Finally, this method was successfully utilized to simultaneously determine THP, DOX, CTX and VCR in human plasma of 15 patients with non-Hodgkin's Lymphoma after intravenous administration. Finally, the method was successfully employed in the clinical determination of THP, DOX, CTX, and VCR in patients with non-Hodgkin lymphoma after administration of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens.

The negative influence of baseline cell-free DNA on long-term survival in DLBCL depends on frontline treatment intensity.

In this study, we address the question of the effect of first-line treatment intensity in de novo DLBCL on the impact of baseline cfDNA on long-term survival. The GOELAMS 075 randomized clinical trial compared R-CHOP with high-dose R-chemotherapy plus autologous stem cell transplantation (R-HDT) for patients aged ≤60. An interim PET assessment was used to refer patients for salvage therapy. With a median follow-up of more than 5.8 years, we analyzed the effects of the treatment arm, salvage therapy, and cfDNA level at diagnosis on overall survival (OS). In a representative group of 123 patients, a high cfDNA concentration (>55ng/ml) at diagnosis was associated with poor clinical prognostic factors and constituted a prognostic marker, independently of the age-adjusted International Prognostic Index. A cfDNA level above a threshold value of 55 ng/ml at diagnosis was associated with significantly worse OS. In an intention-to-treat analysis, high-cfDNA R-CHOP patients (but not high-cfDNA R-HDT patients) had worse OS (hazard ratio [95% confidence interval]: 3.99 [1.98-10.74], P=0.006). In patients with high cfDNA levels, salvage therapy and transplantation were associated with a significantly higher OS rate. Among 50 patients with complete response 6 months after the end of treatment, for 11 out of 24 R-CHOP patients, the cfDNA did not fall back to normal values. In this randomized clinical trial, intensive regimens mitigated the negative influence of high cfDNA levels in de novo DLBCL, relative to R-CHOP.

Pretreatment soluble Siglec-5 protein predicts early progression and R-CHOP efficacy in diffuse large B-cell lymphoma.

Aims: To explore the clinical association between soluble Siglec-5/CD163 and clinical feature and prognosis in peripheral blood samples of patients with diffuse large B-cell lymphoma. Method: Significantly elevated cytokines in peripheral blood were characterized by cytokines array and validated by ELISA. Results: Compared with CD163, Siglec-5 exhibited superiority in discriminating patients into low- and high-risk subgroups based on overall survival and progression-free survival. In addition, Siglec-5 was an indicator of rituximab plus cyclophosphamide, doxorubicin, vincristineand prednisone (R-CHOP) treatment efficacy. Conclusion: Siglec-5 may be applied as a reliable independent immune indicator for overall survival and progression-free survival. It may also predict R-CHOP efficacy in diffuse large B-cell lymphoma.

Prognostic Significance of Ribosome-related Genes Signature in Diffuse Large B Cell Lymphoma.

Background: The diffuse large B-cell lymphoma (DLBCL) is a heterogeneous lymphoma with a dismal outcome, due to approximately 40% patients will be relapsed or refractory to the standard therapy of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Therefore, we need urgently to explore the approach to classify the risk of DLBCL patients accurately and accurately targeting therapy. The ribosome is a vital cellular organelle that is mainly responsible for translation mRNA into protein, moreover, more and more reports revealed that ribosome was associated with cellular proliferation and tumorigenesis. Therefore, our study aimed to construct a prognostic model of DLBCL patients using ribosome-related genes (RibGs). Method: We screened differentially expressed RibGs between healthy donors' B cells and DLBCL patients' malignant B cells in GSE56315 dataset. Next, we performed analyses of univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analyses to establish the prognostic model consisting of 15 RibGs in GSE10846 training set. Then, we validated the model by a range of analyses including Cox regression, Kaplan-Meier survival, ROC curve, and nomogram in training and validation cohorts. Results: The RibGs model showed a reliably predictive capability. We found the upregulated pathways in high-risk group most associated with innate immune reaction such as interferon response, complement and inflammatory responses. In addition, a nomogram including age, gender, IPI score and risk score was constructed to help explain the prognostic model. We also discovered the high-risk patients were more sensitive to some certain drugs. Finally, knocking out the NLE1 could inhibit the proliferation of DLBCL cell lines. Conclusion: As far as we know, it is the first time to predict the prognosis of DLBCL using the RibGs and give a new sight for DLBCL treatment. Importantly, the RibGs model could be acted as a supplementary to the IPI in classifying the risk of DLBCL patients.

Outcome of diffuse large B-cell lymphoma patients treated with different chemotherapeutic regimens (R-DA-EPOCH vs R-CHOP)

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of hematological malignancy of large B lymphocytes with a diffuse growth pattern. It is the most common type of adult non-Hodgkin lymphoma (NHL), making up to 30-40% of NHL. Although DLBCL is potentially curable, it remains a challenging lymphoma to manage because of the biological and clinical heterogeneity of the disease.Aim of the study was to compare the outcome of different chemotherapeutic regimens in newly diagnosed DLBCL patients.&#x0D; Methods: This quasi-experimental study was conducted at Department ofHematology,Dhaka Medical College Hospital(DMCH) from January 2018 to June 2019 including nineteen newly diagnosed DLBCL with stage I to IV A/B cases. Protocol was approved by ethical review committee (ERC) of DMCH. Patients aged e”18 years and &lt; 65 years were enrolled for this study and were divided into two groups as arm A treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (10 cases) and arm B treated with rituximab plus dose adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (R-DA-EPOCH)(9 cases).&#x0D; Results: Mean age of all patients was 41 years (range 16 to 60 years). Majority (69%) of the patients were below 50 years of age and M: F ratio was 2:1.Seventy percent of patients had Ann Arbor stage III or IV disease in R-CHOP arm and 67% in R-DA-EPOCH arm although international prognostic index (IPI) score was variable (0-4). Raised serum lactate dehydrogenase (LDH) was observed in 70% and 89% of R-CHOP and R-DA-EPOCH arms respectively. Almost 50% of patients were germinal-center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) in each arm.In arm A, out of ten patients, five (50%) achieved complete remission (CR), one (10%) achieved partial response(PR), three (30%) had progressive disease (PD) and overall response (OR) rate was 60%. In arm B, out of nine patients, five (56%) achieved CR, two (22%) had progressive disease (PD) and two (22%) patients died. In subgroup analysis of outcome of GCB group, there was equal CR rate in both arms(60%, p=0.57), whereas in non-GCB arm, CR was found 40% vs. 50% in R-CHOP vs. R-DA-EPOCH arm respectively (p=0.89).&#x0D; Conclusion: From the result of this study it can be concluded that, there was no statistically significant difference in respect of outcome of chemotherapy among patients treated with R-DA-EPOCH and R-CHOP.&#x0D; BIRDEM Med J 2022; 12(3): 188-194

Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in patients with previously untreated non-germinal centre B-cell-like diffuse large B-cell lymphoma: A Chinese subgroup analysis of the phase III PHOENIX trial.

In this post hoc subgroup analysis of 200 patients enrolled in China from the phase III PHOENIX trial (N=838, NCT01855750), addition of ibrutinib to rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) did not improve event-free survival (EFS) versus placebo+R-CHOP in the intent-to-treat (ITT; n=200, hazard ratio [HR]=0.83, 95% confidence interval [CI]: 0·509-1.349; p=0.4495) or activated B-cell-like (ABC; n=141 [based on available gene-expression profiling data], HR=0.86, 95% CI: 0.467-1.570; p=0.6160) subpopulations. However, ibrutinib+R-CHOP improved EFS (HR=0·50, 95% CI: 0.251-1.003) and progression-free survival (PFS; HR=0.48, 95% CI: 0.228-1.009) versus placebo+R-CHOP in patients aged<60 but not ≥60years. Grade ≥3 serious treatment-emergent adverse events occurred more with ibrutinib+R-CHOP (45·6% vs. 31·3%). The percentage of patients receiving ≥6 cycles of R-CHOP was similar across treatment arms in those<60years. A numerical trend was seen towards improved EFS and PFS with ibrutinib+R-CHOP versus placebo+R-CHOP in patients with MYC-high/BCL2-high co-expression. In this slightly younger Chinese subgroup, ibrutinib+R-CHOP did not improve EFS in the ITT and ABC subpopulations but improved outcomes with manageable safety in patients<60years, consistent with overall PHOENIX study outcomes.

Revising the Treatment Pathways in Lymphoma: New Standards of Care-How Do We Choose?

Diffuse large B-cell lymphoma and follicular lymphoma are the most commonly encountered non-Hodgkin lymphomas in clinical practice. Both are biologically heterogeneous, with management strategies that are becoming increasingly complex. Diffuse large B-cell lymphoma typically exhibits aggressive behavior but can be cured in the majority of cases with immunochemotherapy. While R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for decades, the recent combination of polatuzumab-vedotin-R-CHP (rituximab plus cyclophosphamide, doxorubicin, and prednisone) has demonstrated improved progression-free survival for patients with intermediate- and intermediate-high-risk disease. Numerous novel therapies, including targeted agents and immunotherapy-based approaches, have recently been approved for relapsed/refractory disease and have led to improved outcomes. Follicular lymphoma is an indolent lymphoma that remains incurable with standard approaches. Overall survival in most patients is excellent, although a proportion of patients will have early relapsing disease and poorer outcomes. The availability of novel agents in the relapsed/refractory setting has shifted the treatment algorithm, which requires thoughtful consideration of sequencing. This article will review recent developments in the treatment of diffuse large B-cell lymphoma and relapsed/refractory follicular lymphoma.

Risk Stratification for Diffuse Large B-Cell Lymphoma by Integrating Interim Evaluation and International Prognostic Index: A Multicenter Retrospective Study.

The baseline International Prognostic Index (IPI) is not sufficient for the initial risk stratification of patients with diffuse large B-cell lymphoma (DLBCL) treated with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The aims of this study were to evaluate the prognostic relevance of early risk stratification in DLBCL and develop a new stratification system that combines an interim evaluation and IPI. This multicenter retrospective study enrolled 314 newly diagnosed DLBCL patients with baseline and interim evaluations. All patients were treated with R-CHOP or R-CHOP-like regimens as the first-line therapy. Survival differences were evaluated for different risk stratification systems including the IPI, interim evaluation, and the combined system. When stratified by IPI, the high-intermediate and high-risk groups presented overlapping survival curves with no significant differences, and the high-risk group still had >50% of 3-year overall survival (OS). The interim evaluation can also stratify patients into three groups, as 3-year OS and progression-free survival (PFS) rates in patients with stable disease (SD) and progressive disease (PD) were not significantly different. The SD and PD patients had significantly lower 3-year OS and PFS rates than complete remission and partial response patients, but the percentage of these patients was only ~10%. The IPI and interim evaluation combined risk stratification system separated the patients into low-, intermediate-, high-, and very high-risk groups. The 3-year OS rates were 96.4%, 86.7%, 46.4%, and 40%, while the 3-year PFS rates were 87.1%, 71.5%, 42.5%, and 7.2%. The OS comparison between the high-risk group and very high-risk group was marginally significant, and OS and PFS comparisons between any other two groups were significantly different. This combined risk stratification system could be a useful tool for the prognostic prediction of DLBCL patients.

Efficacy and Safety of Recombinant Human-Mouse Chimeric Anti-CD20 Monoclonal Antibody (SCT400) Combined with CHOP in Patients with Treatment-Naïve Diffuse Large B-Cell Lymphoma: A Multicenter, Randomized, Single-Blind, Parallel Active-Controlled, Phase III Study

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. [Display omitted] DisclosuresHu: Astellas Pharma, Inc.: Research Funding. Xie: Sinocelltech Ltd.: Current Employment, Current equity holder in publicly-traded company.

Exploring the Impact of Diffuse Large B-Cell Lymphoma (International Prognostic Index [IPI] 2-5) on Clinical and Patient-Relevant Outcomes in the Context of a Clinical Trial

Background: Most patients (pts) with diffuse large B-cell lymphoma (DLBCL) receiving first-line (1L) rituximab plus CHOP (R-CHOP) have similar mortality to the general population (gen popn) if they are progression-free at 24 months (PFS24; Maurer et al. Ann Oncol 2018). Characterization of quality of life (QoL) and clinical outcomes may enable more patient-relevant treatment decisions. Using GOYA trial data (NCT01287741) comparing obinutuzumab (G) + CHOP (G-CHOP) with R-CHOP, we present an exploratory analysis of 1L DLBCL pts with IPI 2-5 and assess overall survival (OS) and QoL relative to the gen popn. GOYA was not included in the previous PFS24 analysis by Maurer et al.Methods: We used data from both GOYA treatment arms to identify pts with IPI 2-5 DLBCL (n=1132 pts, intent-to-treat popn). Post-progression survival (PPS) in DLBCL is independent of prior treatment (Coiffier et al. Blood 2010) and as PFS was similar between treatment arms in GOYA, we assumed similar mortality after PFS24. Clinical outcomes were PFS24 (progression-free ≥24 months [m] from treatment start); early relapse (disease progression [PD]<24m from treatment start); late relapse (PD after PFS24). Outcomes for study pts vs gen popn were evaluated using standardized mortality ratios (SMR; deaths in study pts relative to expected deaths in gen popn matched by age, sex, country, and calendar time-at-risk). Expected deaths were derived using the Human Mortality Database, which provides detailed mortality and population data by country and can be used to estimate the background mortality during the observation period.Post-relapse survival in pts with early vs late relapse was assessed using Kaplan-Meier (KM) estimates and Cox regression. QoL was assessed using EQ-5D-3L and UK-based tariffs (Dolan. Med Care 1997); association between QoL and clinical outcomes used a linear mixed-effects model. The proportion of pts with PFS24 reporting QoL problems at baseline and after 24m was compared with age- and country-matched values in the gen popn (Janssen et al. Springer 2014). Data cut-off was Jan 2018 (GOYA final data cut); overall median follow-up was 48m.Results: In the overall IPI 2-5 population, mean age at treatment initiation was 61 yrs. 711 pts reached PFS24, of whom 64 experienced a late relapse (Table 1). Early relapse was experienced by 261 pts, of whom 164 were <6 months from end of treatment (EOT). OS following PFS24 was 98.6% at 2 years (including patients who later relapsed). 2-year PPS was 35.7% for pts with early relapse vs 74.8% for patients with late relapse (Figure 1.)Mortality following PFS24 was 72% of the matched gen popn (SMR 0.72; not significant: 95% CI 0.44-1.11). Mortality following relapse in pts who experienced early relapse was over 33 times higher than expected in the matched gen popn (SMR 33.57, 95% CI 27.69-40.33). However, risk of death following late relapse was reduced by 78% compared with risk following early relapse (HR 0.22 95 CI% 0.12-0.40), and mortality following late relapse was significantly higher than in the matched gen popn (SMR 6.7, 95% CI 3.05-12.67). Mean QoL utility score at baseline was 0.69 for all pts. After pts reached PFS24, estimated mean utility score was 0.86 (95% CI 0.84-0.87) and worsened by -0.07 (95% CI -0.14 to -0.01) at time of subsequent relapse. For early-relapsing pts, the worsening in utility was -0.15 (95% CI -0.20 to -0.10) compared with those still progression-free (Table 2).Among all PFS24 pts at baseline, problems were reported with mobility (28.1%), self-care (12.6%), usual activities (41.8%), pain/discomfort (62.7%), and anxiety/depression (48.8%); these rates were 2.2-4.7 times higher than the gen popn based on age- and country-standardized values. Compared with the gen popn, after pts reached PFS24, pain/discomfort was 10% lower, whereas anxiety/depression was 34% higher and other QoL items were approximately 20% higher.Conclusions: Most of the clinical course of 1L DLBCL occurred ≤2 years after start of treatment. In DLBCL pts with IPI 2-5 achieving PFS24, mortality was similar to the gen popn, and with the exception of mental health metrics, QoL scores were also similar to the gen popn. Late relapse (≥2 yrs) was associated with better post-relapse survival than early relapse (<2 yrs); however, this was inferior to the gen popn. Health state utilities improved whilst patients were relapse-free but the decline in QoL after early relapse was worse than after late relapse. [Display omitted] DisclosuresLaunonen: F. Hoffmann-La Roche Ltd: Current Employment. Ho: F. Hoffmann-La Roche Ltd: Current Employment. Knapp: F. Hoffmann-La Roche Ltd: Current Employment. Canales Ruiz: Clinical Project Manager in Clinica Universidad de Navarra: Current Employment. Simonella: F. Hoffmann-La Roche Ltd: Current Employment. Thuresson: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company.

Clinicopathologic and Prognostic Significance of Bruton's Tyrosine Kinase Expression in Diffuse Large B-Cell Lymphoma.

Bruton's tyrosine kinase (BTK)-mediated B-cell-receptor signaling drives lymphomagenesis of diffuse large B-cell lymphoma (DLBCL). We investigated the clinicopathological significance of BTK positivity in DLBCL according to known molecules related to resistance to BTK inhibitors [BCL2 apoptosis regulator (BCL2)/MYC proto-oncogene, bHLH transcription factor (MYC)]. We evaluated BTK expression immunohistochemically in 106 DLBCLs considering their BCL2/MYC status. Considering the whole cohort, BTK was expressed in 65.1%, including 70.4% (50/71) of non-germinal center B-cell-like (non-GCB) subtype; BCL2 expression was detected in 60.4%, MYC expression in 15.1%, MYC translocation in 4.2% (4/96) and MYC gain/amplification in 7.6% (8/105). Overall and in the non-GCB cohort, BTK positively correlated with high international prognostic index (both p=0.005) and stage (p=0.006 and p=0.002), and with BCL2 intensity (p=0.005 and p=0.026, respectively); MYC gain/amplification total cohort (p=0.038). Moreover, high risk, defined as co-expression of BTK and either or both BCL2/MYC, independently predicted shorter progression-free survival in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) (all R-CHOP-treated patients: hazard ratio=2.565, p=0.044; R-CHOP-treated non-GCB subgroup: HR=3.833, p=0.019). BTK expression may be utilized to stratify risk in patients with DLBCL.

Clinicopathological and prognostic features of hepatitis B virus-associated diffuse large B-cell lymphoma: a single-center retrospective study in China

BackgroundWhile the epidemiologic association between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) is established, little is known about the pathological characteristics and outcome of DLBCL arising in patients with HBV infection.MethodsWe retrospectively studied a cohort of 420 patients with DLBCL for the incidence of HBV infection, and the clinicopathologic features and prognostic factors in HBsAg-positive DLBCL patients in China, a hepatitis B endemic area.ResultsIn our study, 127 (30.2%) patients were HBsAg-positive. HBsAg-positive DLBCL displayed a younger median onset age (50 vs. 54 years, P = 0.002), more frequent involvement of the spleen (19.7% vs. 6.1%, P < 0.001), less frequent involvement of the small and large intestine (2.3% vs. 11.2%, P = 0.003), more advanced disease (stage III/IV: 56.7% vs. 45.1%, P = 0.028), and lower expression rate of MYC (49.1% vs. 66.7%, P = 0.026). The median follow-up time was 61.9 months. Univariate analysis showed that there was no significant difference in overall survival (OS) between HBsAg-negative and -positive DLBCL (P = 0.577). In the HBsAg-positive DLBCL subgroup, age older than 60 years, advanced disease, elevated lactate dehydrogenase (LDH), spleen involvement, B symptoms (fever, night sweats, weight loss), and double expressers of MYC and BCL2 had a significantly worse outcome, and patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) had a better prognosis. Multivariate analysis further confirmed that spleen involvement and rituximab use were independent prognostic factors in HBsAg-positive DLBCL patients.ConclusionsOur study indicates that HBsAg-positive DLBCL has unique clinicopathological features and independent prognostic factors. Moreover, under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV-negative patients, and the use of rituximab significantly improved OS in HBsAg-positive DLBCL patients.

Pyruvate dehydrogenase kinase 4-mediated metabolic reprogramming is involved in rituximab resistance in diffuse large B-cell lymphoma by affecting the expression of MS4A1/CD20.

Diffuse large B cell lymphoma (DLBCL) heterogeneity promotes recurrence and anti‐CD20‐based therapeutic resistance. Previous studies have shown that downregulation of MS4A1/CD20 expression after chemoimmunotherapy with rituximab leads to rituximab resistance. However, the mechanisms of CD20 loss remain unknown. We identified that pyruvate dehydrogenase kinase 4 (PDK4) is markedly elevated in DLBCL cells derived from both patients and cell lines with R‐CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resistance. We found that overexpression of PDK4 in DLBCL cells resulted in cell proliferation and resistance to rituximab in vitro and in vivo. Furthermore, loss of PDK4 expression or treatment with the PDK4 inhibitor dichloroacetate was able to significantly increase rituximab‐induced cell apoptosis in DLBCL cells. Further studies suggested PDK4 mediates a metabolic shift, in that the main energy source was changed from oxidative phosphorylation to glycolysis, and the metabolic changes could play an important role in rituximab resistance. Importantly, by knocking down or overexpressing PDK4 in DLBCL cells, we showed that PDK4 has a negative regulation effect on MS4A1/CD20 expression. Collectively, this is the first study showing that targeting PDK4 has the potential to overcome rituximab resistance in DLBCL.

Obinutuzumab Versus Rituximab in Combination with ACVBP-14 or CHOP-14 Following a PET-Driven Strategy in Aa-IPI 1-3 DLBCL Patients (< 60 years): Third Planned Interim and Final Analyses of the Gained Trial

Abstract Background: Rituximab plus CHOP (R-CHOP) remains the standard of care treatment in patients with previously untreated diffuse large B cell lymphoma (DLBCL) despite a risk of about 25-30% of treatment failure during the first 2 years (Cunningham et al Lancet, 2013,). Obinutuzumab (GA101) is a glycoengineered, type II anti-CD20 monoclonal antibody designed to optimize direct cell death induction and antibody-dependent cellular cytotoxicity. GAINED (NCT01659099) is a phase III randomized prospective trial that aimed to randomly compare obinutuzumab to rituximab combined with 4 cycles of intensified chemotherapy as induction treatment (ACVBP14 or CHOP14, according to local center practice) using a PET driven consolidation strategy. Methods: Eligible patients were aged 18-60 y with an aa-IPI 1-3 previously untreated CD20+ DLBCL. Patients were randomized between obinutuzumab (1000mg iv on D1 and D8 cycle 1 and 2, and D1 cycle 3-4) or rituximab (375mg/m2 iv D1) in combination with 4 cycles of ACVBP14 or CHOP14. Randomization was stratified according to aaIPI (1 vs 2-3) and chemotherapy regimen. PET was performed at baseline, after 2 (PET2) and 4 (PET4) cycles of induction immunochemotherapy and centrally reviewed using ΔSUVmax method (Casasnovas et al, 2011 Blood) (See Fig 1). PET2-/PET4- patients were assigned to immunochemotherapy consolidation with either rituximab or obinutuzumab according to the randomization arm; PET2+/PET4- patients received autologous stem cell transplant and PET4+ patients were treated according to investigator' choice. The primary endpoint was 2y-EFS defined by PET positivity after 2 or 4 induction cycles, progression or relapse, modification of planned treatment not due to progression (including radiotherapy) or death of any cause. Safety, response rates, progression free survival (PFS) and overall survival were secondary objectives. Herein, we present the result of the third planned interim analysis. Results: From Sept 2012 to Jul 2015, 670 patients were enrolled. Median age was 48y and 55.7% of patients were male. 41.8% of patients presented with IPI >2 at diagnosis. In all, 336 were randomized in the obinutuzumab plus chemotherapy arm (G-ACVBP, n= 165; G-CHOP, n=171) and 334 in the rituximab plus chemotherapy arm (R-ACVBP, n= 162; R-CHOP, n= 172). Patients' characteristics (age, PS, Ann Arbor stage, LDH level, IPI score) were similar between the two arms except a higher proportion of male patients in the obinutuzumab arm (60.4% vs 50.9%; p Conclusions: Obinutuzumab plus chemotherapy is not superior to rituximab plus chemotherapy delivered every 14 days in young DLBCL patients. Cell of origin data are currently investigated using nanostring technology and will be presented at the time of the meeting. Download : Download high-res image (97KB) Download : Download full-size image Figure 1 . Disclosures Casasnovas: Janssen: Consultancy, Honoraria; MSD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Salles: Janssen: Consultancy, Honoraria; morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Morschhauser: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Tilly: Immunogen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ribrag: BMS: Consultancy; Novartis: Consultancy. Lamy: Roche: Consultancy, Honoraria. Thieblemont: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Haioun: Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria; JANSSEN: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria; PFIZER: Consultancy, Honoraria. Fornecker: Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Feugier: Roche: Consultancy, Honoraria, Research Funding. Delarue: Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Bonnet: Takeda: Other: advisory board. Cartron: Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Celgene: Consultancy, Employment; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Molina: Merck Serono: Honoraria; Novartis: Honoraria; Takeda: Other: travel support to the ASH meeting. Le Gouill: Roche: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.