Rituximab, Cyclophosphamide, Doxorubicin, Vincristine And Prednisone Regimen Research Articles

A study on the prevention of hemorrhage and perforation in patients with primary gastric diffuse large-B cell lymphoma during treatment with immunochemotherapy.

Stomach hemorrhage and perforation are very severe and common complications in patients with primary gastric diffuse large B-cell lymphoma (PG-DLBCL) during treatment with immunochemotherapy. However, no relevant clinical studies have been performed on the prevention of these serious complications. Patients diagnosed with PG-DLBCL were enrolled in this retrospective study. The prevention group received standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) treatment without prednisone combined with antacids and anti-Helicobacter pylori (Hp) therapy. These patients received R-CHOP-based treatment until the complete recovery of gastric ulcers, as proven by gastroscopy. The control group received a standard R-CHOP regimen. Toxicity and survival were the main endpoints. A total of 52 patients received preventative treatment, while 146 patients did not. Among patients with stage I, II-1, and II-2 disease, the prevention group had a lower rate of hemorrhage and perforation (0/40) than the control group (10/78, p=0.044). At a median follow-up time of 25 months, the 5-year event-free survival (EFS) rates were 97.1% in the prevention group and 66.1% in the control group (p=0.025), and the 5-year overall survival (OS) rates were 100% and 72.0%, respectively (p=0.021). However, the differences in the 5-year EFS and OS of patients with disseminated disease were not statistically significant. Preventative treatment can decrease the risk of hemorrhage and perforation in patients with localized PG-DLBCL during immunochemotherapy, leading to better EFS and OS in these patients. However, preventative treatment failed to reduce the risk of gastric hemorrhage and perforation and did not improve survival (EFS and OS) in advanced-stage patients.

DA.R-EPOCH Vs. R-CHOP for High-Risk Diffuse Large B- Cell Lymphoma: The Mayo Clinic Florida Experience

▪BACKGROUNDDiffuse large B cell lymphoma (DLBCL) is a heterogeneous entity with varied outcomes. A subset of DLBCL with high-risk features carries poor prognosis with an increased relapse rate when treated with chemoimmunotherapy regimen incorporating rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH) regimen is a high intensity regimen commonly used for the upfront treatment of high-risk DLBCL, especially DLBCL with c-Myc ± BCL2/BCL6 translocation. A phase 3 study (CALGB 50303) comparing R-CHOP and DA.R-EPOCH in untreated DLBCL did not show any difference in progression free survival (PFS) or overall survival (OS), however specific outcomes of high-risk DLBCL are unknown. (Wilson et al. ASH 2016) In this study, we analyzed the clinical outcomes in a longitudinal cohort of patients with high-risk DLBCL who received DA.R-EPOCH, and compared it to the similar group of patients who received R-CHOP during the same period at our institute.METHODPatients diagnosed with DLBCL who received chemo-immunotherapy at our center between January 2011 to December 2016 were included in the analysis. High-risk DLBCL was defined by the presence of any of the following features at the time of diagnosis: International prognostic index (IPI) score >/= 4, tumor measuring >/=5 cm, c-Myc ± BCL2/BCL6 translocation by FISH or overexpression by immunohistochemistry, Ki-67 index >/= 80% and activated B-cell (ABC) phenotype by Han's algorithm. Patients without these features were deemed to have standard risk-DLBCL. Clinical characteristics, grade 3/4 toxicities (CTCAE v4) and need for hospitalization and transfusion support were reviewed. Responses were evaluated at middle and end of chemotherapy. Overall (OS) and progression free survival (PFS) were calculated. Cox proportional hazard regression was performed to assess influence of clinical and treatment variables on OS and PFS.RESULTSA longitudinal cohort of 95 patients was included in this analysis. All standard risk DLBCL (N=15) patients were treated with R-CHOP. Eighty patients with high-risk DLBCL were treated with R-CHOP (N= 52, 65%) and DA.R-EPOCH (N= 28, 35%) respectively. Table 1 shows baseline clinical characteristics of all high-risk DLBCL patients. DA.R-EPOCH cohort had more patients with higher Ann Arbor stage, ABC phenotype and BCL2/BCL6 expression. Rate of treatment completion and complete response rate at the end of treatment were similar in both groups. DA.R-EPOCH was associated with increased grade 3/4 neutropenia and need for transfusions during treatment. The median follow up was 13.3 months and 10.9 months for DA.R-EPOCH and R-CHOP group respectively. There was no significant difference in OS and PFS among high-risk DLBCL patients treated with DA.R-EPOCH compared to R-CHOP: 3-year estimates of PFS with DA.R-EPOCH vs. R-CHOP was 77% and 71% respectively, while the 3-year estimates of OS was 80% and 66% respectively. The hazard ratio (HR) for PFS was 0.79 (95% CI- 0.28-2.29, P=0.67) and OS was 0.86 (95% CI- 0.26-2.78, P- 0.80). (Figure 1) Low baseline serum albumin levels, ECOG performance status >/=2, elevated LDH and high IPI were associated with poor OS and PFS.CONCLUSIONIn our retrospective analysis, treatment of patients with high-risk DLBCL with DA.R-EPOCH resulted in similar clinical outcomes, but was associated with increased incidence of grade 3/4 neutropenia and need for transfusions during treatment when compared to those receiving R-CHOP regimen. Patients receiving DA.R-EPOCH regimen had more adverse features in terms of disease stage and phenotype. A prospective randomized comparison is warranted between these two regimens for high-risk DLBCL. Until such prospective studies show benefit in any sub-set of DLBCL, DA.R-EPOCH should be used with judicious clinical discretion. [Display omitted] DisclosuresAilawadhi:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Research Funding; Novartis: Consultancy, Honoraria.

Interstitial pneumonia in patients with diffuse large B-cell lymphoma receiving RCHOP and RCDOP regimens

目的比较RCHOP和RCDOP方案治疗弥漫大B细胞淋巴瘤（DLBCL）后间质性肺炎的发生情况。方法回顾性分析2013年1月至2018年8月上海交通大学医学院附属瑞金医院血液科收治的DLBCL患者836例，其中接受RCDOP方案者114例，根据年龄、性别、IPI评分等因素1∶1配对，选出114例接受RCHOP方案的患者作为对照组。收集患者的基础疾病状况、性别、年龄、有无B症状、IPI评分、疾病分期、血LDH、血β2-微球蛋白等相关临床资料，进一步分析间质性肺炎发生的危险因素。结果RCHOP方案和RCDOP方案治疗DLBCL后间质性肺炎的发生率分别为2.60％和28.95％，差异有统计学意义（P<0.01）。RCDOP方案中，随着脂质体阿霉素剂量自25～30 mg/m2增加至35~40 mg/m2，患者的完全缓解率自76.90％增至85.50％（P>0.05），间质性肺炎的发生率也自17.30％增至38.71％（P<0.05）。多因素回归分析显示，应用RCDOP方案、治疗前Ann Arbor分期高是患者预后不良的独立危险因素。结论应用RCDOP方案治疗DLBCL时需加强对间质性肺炎的预防和监测。

Prediction of High-Risk Group of Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Patients Using a CT-Based Radiomics Model with Machine Learning

Introduction Approximately 15% of diffuse large B-cell lymphomas (DLBCL) do not respond to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or equivalent regimen. These primary refractory cases (prDLBCL) have a particularly poor survival. There are currently no reliable biomarkers to a priori identify prDLBCL patients and include them in clinical trials, while avoiding needless toxicity from predictably ineffective therapy. In this study, we evaluated the potential for radiomic analysis with machine learning for predicting prDLBCL. Method This study included adult patients with prDLBCL from a single institution from 2009 to 2018, who had first-line treatment with an R-CHOP like regimen, had never received systemic treatment for indolent lymphoma, and who had a CT scan at the time of diagnosis. Refractory (R) patients were defined by progression of disease (PD) after completion of at least one cycle, or failure to achieve a complete response (CR) after at least 4 cycles, as per Lugano criteria (Cheson, JCO 2014). Non-refractory (NR) patients were matched 1:1 on sex and R-IPI for the comparison group. Enlarged lymph nodes (≥1.5 cm in greatest diameter) were eligible for evaluation. The 6 largest nodes were selected at each node site (abdomen, chest, axilla and neck) and for each node category (refractory node (RN), partial response (PR) and CR, as per Lugano criteria). 3D Slicer software was used for the delineation of the region of interest (ROI) either for subsequent 2D analysis (largest axial section) or 3D analysis (total node volume). Each node was manually contoured by two independent readers and also was reviewed by an experienced senior oncologic radiologist. A total of 788 and 1218 features were extracted from 2D and 3D regions of interest, respectively, using Pyradiomics open source software. Two independent machine learning approaches, Random Forests (RF) and Support Vector Machine (SVM), were tested for constructing the prediction models. 70% of cases were randomly assigned to the training set and 30% to the independent testing set. In the node model (NM) each independent node's response to treatment was predicted. In the patient model (PM), groups of nodes per site (abdomen, chest, axilla and neck) were used to predict the overall patient response. Results A total of 26 refractory patients were identified with a total 149 nodes (RN=55, PR=20, CR=74) and matched to 26 NR patients for comparison, with a total of 105 CR nodes. Seventeen nodes with significant artifact were excluded from the analysis (7 from NR patients and 10 from R patients). RF had consistently superior performance compared to SVM and was used for constructing the final prediction models. Furthermore, 2D radiomic analysis had superior performance compared to 3D radiomic analysis. In the independent testing (prediction) set, the mean accuracy between the 2 readers for this model for distinguishing a R from NR patient was 80% (mean sensitivity and specificity, 73% and 88%, respectively). This model was able to predict a R patient (positive predictive value (PPV)) in 100% and 71% of the case, respectively for readers 1 and 2. The area under the ROC curve (AUC) was 0.96 and 0.81 for reader 1 and 2, respectively (Figure 1A). For performance of the radiomic model for distinguishing individual refractory from responsive nodes, the independent testing set had a mean accuracy of 75% (mean sensitivity, specificity, PPV, and NPV of 80%, 69%, 78%, and 71% respectively). The AUC per reader were 0.82 and 0.85 (Figure 1B). Conclusion We demonstrate that the use of CT radiomic analysis with machine learning for identifying a priori primary refractory DLBCL patients is feasible. These models provide a relatively high prediction accuracy, which currently cannot be done in the clinical setting based on standard, largely qualitative, imaging characteristics. The main limitations of our study include small patient numbers in this pilot study and exclusion of extranodal sites. The next step for this project would be to evaluate this approach in a larger cohort that includes a second independent institution. CT-based radiomics is promising and should be further explored to achieve this unmet need for predicting prDLBCL prior to therapy initiation. Disclosures Forghani: GE Healthcare: Consultancy, Honoraria, Research Funding; 4Intel Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Founder. Reinhold:FRQS: Other: FRQS Grant. Assouline:Pfizer: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria.

CD20 Is an Unstable Target in Primary-Refractory High-Grade Lymphomas

Introduction: A third of patients with diffuse large B cell lymphoma (DLBCL) are not cured with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). Approximately 20% of DLBCLs will lose CD20-protein expression (CD20-neg) at the time of relapse. The incidence of CD20-neg relapses in other aggressive B cell lymphomas is unknown. CD20 is not only targeted by rituximab but other antibody-based therapies that are being investigated in salvage regimens. We hypothesized that prolonged exposure to anti-CD20 containing regimens may lead a CD20-neg relapse. Our goal was to determine the clinical and genetic factors associated with loss of CD20 expression in high-grade lymphomas treated with curative intent. Method: We consented 374 patients with B cell high-grade lymphomas that were treated with RCHOP or more intensive regimens at the time of diagnosis or had a histological transformation from a prior indolent lymphoma (TLy). We recorded the baseline clinical characteristics, histological diagnosis, date of first relapse and the number of treatment regimens prior to their second biopsy. CD20 expression and cell of origin (COO) were determined by immunohistochemistry and, in the latter, using Hans criteria. We performed targeted sequencing of 63 lymphoma-related genes, including MS4A1, the gene that encodes CD20. Sequencing was performed using circulating tumor DNA in the plasma or DNA from the tumor biopsy, both obtained at the time of relapse. Results: Relapse occurred in 170/374 (45%) of patients: 102/253 DLBCL, 55/96 TLy, 6/16 primary mediastinal B cell lymphoma (PMBCL) and 7/9 high grade B cell lymphomas (HGBL) with or without translocations in MYC and BCL2 or BCL6. The median age at diagnosis was 62 years old, 54% were male and 85% had an elevated international prognostic index of ≥ 2. Of these, 104 had a biopsy taken at first (47%) or subsequent relapse (53%) to confirm the diagnosis or performed in the context of a clinical trial. CD20 could be assessed in 100 cases, of which 26 had CD20-neg lymphoma cells: 15/56 (27%) of DLBCL, 7/38 (18%) of TLy, 2/3 (66%) PMBCL and 2/3 (66%) HGBL. Relapsed PMBCL and HGBL combined, appeared to have an increased risk of CD20 negativity at relapse compared to DLBCL and TLy (p=0.043). A GCB phenotype in DLBCL was present in 35% of cases and was not associated with CD20 status. The mean number of therapies given before the second biopsy was similar in both groups (CD20+ = 2.2 and CD20-neg = 2.7, p=0.2). In fact, 11/26 (44%) of CD20-neg cases had biopsies taken after RCHOP alone. Additional chemo-immunotherapy (range 2 to 8) did not increase the risk of having a CD20-neg relapse (p=0.5), suggesting that unlike follicular lymphoma, the emergence of CD20-neg cells occurs early after rituximab exposure in high-grade lymphomas. Supporting this hypothesis, patients with a CD20-neg relapse had a shorter progressive free survival (PFS) after RCHOP (1,7 vs 3,2 years, p=0.025). Patients with primary treatment failure, defined here as a PFS of &amp;lt; 1 year, had a significantly increased risk of having a CD20-neg relapse (hazard ratio 7.9, p= 0.005). Sequencing was performed in 75/100 patients. MS4A1 mutations were present in 16% of CD20-neg cases, while none were present in the CD20+ cases (p=0.003). There was no significant difference in the mutation rate of TP53 (47%) or histone-modifying genes based on CD20 expression status. Conclusion: Decreased CD20 expression occurs early in high-grade lymphomas under the selective pressure of RCHOP, 16% of which are a consequence of MS4A1 mutations, suggesting that other mechanisms also modulate CD20 expression. In patients with a PFS of &amp;lt; 1 year, a repeat biopsy would be recommended if primary anti-CD20-targeted therapy is considered. Disclosures Assouline: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Johnson:Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.

POLARIX: A phase 3 study of polatuzumab vedotin (pola) plus R-CHP versus R-CHOP in patients (pts) with untreated DLBCL.

TPS7571 Background: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) remains the standard of care in pts with previously untreated diffuse large B-cell lymphoma (DLBCL) but outcomes remain poor in pts with high-risk disease. Pola is an antibody–drug conjugate targeting CD79b; it delivers the antimitotic agent monomethyl auristatin E. Addition of pola to bendamustine and R in pts with transplant-ineligible DLBCL resulted in improved OS (Sehn et al, 2018). In front-line treatment of DLBCL, pola is being evaluated as a replacement for vincristine within the R-CHOP regimen. In a phase Ib/II study in pts with higher risk DLBCL, pola + R-CHP demonstrated promising efficacy and a safety profile similar to that observed in the R-CHOP arm of the GOYA study (Tilly et al, 2017; Vitolo et al, 2017). The phase 3 POLARIX study investigates pola + R-CHP in untreated DLBCL. Methods: POLARIX is an ongoing, international, randomized, double-blind, active-placebo-controlled, phase 3 study in pts with previously untreated DLBCL. Pts aged 18–80 years with CD20-positive DLBCL (including DLBCL not otherwise specified, GCB, and ABC subtypes), ECOG performance status 0–2, and IPI score 2–5, are stratified by IPI score (2 vs 3–5), bulky disease and geographical region and randomized (1:1). Pts receive 6 cycles of either: pola 1.8 mg/kg on Day 1 plus R-CHP (standard dosing schedule) plus vincristine placebo; or pola placebo plus R-CHOP (standard dosing schedule). R monotherapy is administered in cycles 7 and 8 (both arms). PET-CT and CT scans are obtained at screening, after 4 cycles (planned interim assessment), and 6–8 weeks after end of study treatment. Follow-up will continue for 5 years after treatment. Primary endpoint: investigator-assessed progression-free survival (PFS; Lugano classification). Secondary endpoints: independent review committee-assessed PET-CT complete response rate at end of treatment, event-free survival, 2-year PFS rate, and OS. Enrolment began Nov 2017. This trial is currently recruiting, and plans to enrol 875 patients in 24 countries. Clinical trial information: NCT03274492.

Clinical Outcomes and Cost Analysis of Dose-Adjusted R-EPOCH Vs R-CHOP in Treatment of Diffuse Large B- Cell Lymphoma with High Risk Features

▪BackgroundDiffuse large B cell lymphoma (DLBCL) with high-risk features carries a poor prognosis despite treatment with immunochemotherapy regimen incorporating rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Hence, dose adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA.R-EPOCH), a higher intensity regimen, is suggested as an upfront treatment of high-risk DLBCL. In our study, we analyzed the outcomes in a prospectively followed cohort of patients with de novo high-risk DLBCL who received DA.R-EPOCH, and compared them to the patients who received R-CHOP. Furthermore, we conducted a cost analysis to determine which of the two treatments produces a larger financial burden.MethodPatients diagnosed with DLBCL who received chemo-immunotherapy at our center between January 2011 to December 2016 were included in the analysis. High-risk DLBCL was defined by the presence of any of the following features at diagnosis: NCCN- IPI score ≥4, tumor measuring ≥5 cm, MYC ± BCL2 or BCL6 rearrangement by FISH or MYC overexpression (>40% by immunohistochemistry [IHC]), Ki-67 index ≥80% and non-GCB immunophenotype by Hans algorithm. Responses were evaluated at middle and end of chemotherapy. Overall (OS) and progression free survival (PFS) were calculated. For the cost analysis, standardized costs were obtained from Mayo Clinic Florida cost data warehouse based upon patient encounters and treatments. Report cost-to-charge ratios were multiplied by the charges for all hospital billed services, and all resulting costs were adjusted to 2016 dollars with the Gross Domestic Product (GDP) Implicit Price Deflator. Patients who did not receive their complete planned treatment at our facility were excluded from the cost analysis.ResultsOf 80 patients with high-risk DLBCL, 52 (65%) patients were treated with R-CHOP and 28 (35%) with DA.R-EPOCH. The median follow-up was 11.2 months (range: 0.7- 151.3 months). The planned treatment completion rate and complete remission rate at the end of treatment were similar in both groups. There was no significant difference in OS and PFS among the patients treated with DA.R-EPOCH compared to R-CHOP. The hazard ratio (HR) for PFS was 0.79 (95% CI- 0.28-2.29, P=0.67) and OS was 0.86 (95% CI- 0.26-2.78, P=0.80) (Figure 1). In Cox-regression analysis, low baseline albumin, ECOG performance status ≥2, above-normal LDH, high NCCN- IPI and low cumulative chemotherapy doses were associated with poor OS and PFS. Overall incidence of grade ≥ 3 neutropenia, neuropathy, and unplanned hospitalizations were similar between the two treatment groups. Patients treated with DA.R-EPOCH required more red cell transfusions during the treatment (P=0.004). The total mean cost associated with DA.R-EPOCH and R-CHOP regimens was $106,940 ± $39,351 and $58,509 ± 24,588, respectively (P<0.001). The cost associated with hospital services, laboratory testing and evaluation and management were higher in DA.R-EPCOH group compared to R-CHOP group (P<0.001) (Table 2).ConclusionOur study showed that there was no significant difference in PFS and OS of patients with DLBCL with high-risk features when treated with R-CHOP compared to DA.R-EPOCH. DA.R-EPOCH was associated with higher red cell transfusion requirement and treatment related expenses. A prospective randomized comparison is warranted between these two regimens specifically for patients with high-risk DLBCL. DisclosuresNo relevant conflicts of interest to declare.

FOXO1 promotes resistance of non-Hodgkin lymphomas to anti-CD20-based therapy

ABSTRACTDiminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen. We found CD20 transcription is negatively regulated by FOXO1 in NHL cell lines and in human lymphoma specimens carrying activating mutations of FOXO1. Furthermore, both the expression of exogenous mutants of FOXO1 and the inhibition of AKT led to FOXO1 activation in lymphoma cells, increased binding to MS4A1 promoter and diminished CD20 expression levels. In contrast, a disruption of FOXO1 with CRISPR/Cas9 genome-editing (sgFOXO1) resulted in CD20 upregulation, improved the cytotoxicity induced by rituximab and the survival of mice with sgFOXO1 tumors. Accordingly, pharmacological inhibition of FOXO1 activity in primary samples upregulated surface CD20 levels. Importantly, FOXO1 was required for the downregulation of CD20 levels by the clinically tested inhibitors of BTK, SYK, PI3K and AKT. Taken together, these results indicate for the first time that the AKT-unresponsive mutants of FOXO1 are important determinant of cell response to rituximab-induced cytotoxicity, and suggest that the genetic status of FOXO1 together with its transcriptional activity need further attention while designing anti-CD20 antibodies based regimens for the therapy of pre-selected lymphomas.

Addition of Intermediate-Dose Methotrexate Is Beneficial in Terms of Both Progression-Free Survival and Overall Survival for Patients with Diffuse Large B Cell Lymphoma Receiving Either R-CHOP or CHOP

Introduction: Patients with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal disease are at an increased risk of systemic and central nervous system (CNS) relapse. Presently, the management of DLBCL patients at the Rambam Health Care Campus (Haifa, Israel) and Hadassah Medical Center (Jerusalem, Israel) includes 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) along with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenousMTX (ID-MTX). The current study compared progression-free survival (PFS), overall survival (OS) and CNS relapse rate in a cohort of DLBCL patients with risk factors for CNS relapse who did or did not undergo prophylactic therapy with ID-MTX.Methods: Four hundred and eighty DLBCL patients treated at two tertiary care centers (Rambam and Hadassah) between the years 1991 and 2013 were retrospectively evaluated. The cohort included 224 females and 256 males at a median age of 58 years (range18-76). OS, PFS and CNS involvement at relapse were analyzed. The study incorporated all patients with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (2%), breast (1%), testicular (3%) or orbita (1%) involvement, bone marrow involvement (21%), stage IV disease (64%), LDH higher than normal (70%), ≥1 extra-nodal site (28%), IPI ≥3 (36%). Eight percent of patients had stage I-IE disease, 17% - stage II-IIE, 11% - stage III, 64% - stage IV, 29% had B symptoms. Patients with CNS involvement at diagnosis were excluded from the analysis.Results: Four hundred and seventy three patients (99%) were treated with either CHOP or CHOP-like regimen, and 384 (80%) patients received rituximab (R). In the R-CHOP cohort, 23% of patients with IPI 0/1, 28% with IPI 2 and 42% with IPI ≥3 were given prophylaxis. One hundred and thirty patients received ID-MTX (27%), 35 patients (7%) received IT-MTX only, while no prophylaxis was administered to 315 patients (66%). The cumulative incidence of CNS relapse at 5 years was 6%, with no difference in the incidence between the patients who received prophylaxis with ID-MTX, IT-MTX or were given no prophylaxis at all. Patients with IPI ≥3 treated with ID-MTX had a decreased overall relapse rate and significantly superior OS and PFS (Table 1; Figure 1).Conclusion: In the current study, the addition of two cycles of ID-MTX to the standard R-CHOP regimen resulted in improved 5-year PFS and OS of DLBCL patients with IPI ≥3. These data need to be further confirmed in a randomized controlled study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Complete response to azacitidine priming and nab-paclitaxel in non-Hodgkin lymphoma resistant to biochemotherapy.

The standard of care for first-line therapy in diffuse large B-cell lymphoma (DLBCL) is the rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen. For patients who fail to respond, have an incomplete response or relapse, numerous effective options exists besides salvage cisplatin-based regimen and autologous stem cell therapy. Even with this approach, the outcome remains very poor for this group of patients. The present case illustrates a 55-year-old woman diagnosed with DLBCL, who experienced an early incomplete response, later progression during treatment with the R-CHOP regimen. The patient received salvage therapy with rituximab, cisplatin and gemcitabine, again with an incomplete response. The patient declined consideration for stem cell therapy. Her disease progressed and she enrolled in the present phase I trial using azacitadine priming and nanoalbumin-bound (nab)-paclitaxel. After three cycles, follow-up positron emission tomography/computed tomography revealed a complete response for the first time since her initial diagnosis and the patient has remained disease-free for >6 years. Azacitadine and nab-paclitaxel combination appeared to be an effective regimen for the treatment of this patient with refractory DLBCL.

Classical Case of Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) usually occurs in elderly patients and in most cases affects lower legs. A 76-year old man presented with red-brown coloured patches and plaques with irregular borders and multiple firm nodes on the anterior surface of the right lower leg. The excision biopsy of a node and histological examination has confirmed the diagnosis of PCDLBCL-LT. Clinical, laboratory and radiological examination showed no evidence of systemic involvement. The treatment was started with R-CHOP (rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. The patient died within 10 months due to cardiac complications since the initial diagnosis.

Treatment of Diffuse Large B-Cell Lymphoma and Preexisting Congestive Heart Failure: A Retrospective Analysis from Moffitt Cancer Center TCC Database

Introduction: The treatment of choice for newly diagnosed patients with advanced diffuse large B-cell lymphoma (DLBCL) is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) [Feugier P, Van Hoof A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2005; 23: 4117-4126]. Anthracycline-based treatment is also superior to other drugs in controlling disease and prolonging survival in elderly patients [Hershman DL, McBride RB, Eisenberger A et al. Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma. J Clin Oncol 2008; 26: 3159-3165], however these individuals frequently have concomitant cardiac comorbidities such as congestive heart failure (CHF) that preclude the use of these agents.Methods: A search of the Moffitt Total Cancer Care™ database between January 1st 2008 and December 31st 2014 identified a cohort of 854 adult patients with a diagnosis of DLBCL. We performed a retrospective chart review of these patients and identified 40 individuals with documented CHF prior to the initiation of chemotherapy, due to either systolic (ejection fraction less than 50%) or diastolic dysfunction. The primary aim was to determine the chemotherapy regimens given to patients with DLBCL and CHF at Moffitt Cancer Center, and their related cardiovascular and oncologic outcomes. The study was approved by the University of South Florida Institutional Review Board.Results: 3 out of the 40 patients did not receive any chemotherapy and were excluded from the analysis. The median age was 71 years (range 21-93) with a median follow-up time of 19 months. Baseline characteristics are represented on table 1. Table 1NPercentage (%)Sex1129.7FM2670.3Race38.1African AmericanAsian12.7White3389.2ECOG PS924.3011643.22821.6NA410.8Baseline Ejection fraction2156.8<50%>=50%1643.2Systolic Heart Failure1540.5NoYes1848.7UNK410.8Diastolic Heart Failure616.2NoYes1643.2UNK1540.5Ann Harbor Stage616.2III513.5III924.3IV1745.925 patients (67%) received R-CHOP or R-CHOP like (R-EPOCH) chemotherapy. The remaining patients received non R-CHOP regimens, being R-ICE (n=3), R-Hyper-CVAD (n=1), R-MTX (n=2), R-Bendamustine (n=2), R-CVP (n=2), R-CEOP (n=3). We observed an association between the type of treatment (R-CHOP vs non R-CHOP) and the type of heart failure, with diastolic CHF patients being more likely to receive a R-CHOP chemotherapy. (Table 2) Table 2R-CHOPnon R-CHOPp-valueOR95% CINPercentage (%)NPercentage (%)Diastolic HFYes1588.2120.00.00530(2.14, 421.12)No211.8480.0Systolic HFYes731.811100<0.0010No1568.200There was a trend toward better response to chemotherapy among patients with diastolic heart failure compared to systolic heart failure. We observed a larger number of cardiac events, defined as hospitalization for CHF, for cerebrovascular insult, for chest pain, for ischemic or non-ischemic cardiac events or cardiac-related deaths, in the group treated with R-CHOP, but this was not statistically significant, given low patients numbers. Although patients treated with a R-CHOP regimen demonstrated higher complete remission rates compared to non R-CHOP regimens (73.7% vs. 55.5% respectively), this result was not statistically significant (p=0.37), and there was no significant difference in overall survival or 2-year relapse free survival.Conclusion: To our knowledge, this is the largest series evaluating DLBCL treatment regimens in elderly patients with baseline cardiac dysfunction. This study demonstrated that elderly patients with DLBCL and baseline systolic CHF were more likely to receive non R-CHOP based regimens compared to patients with diastolic dysfunction. Non R-CHOP treatments seem to be better tolerated with fewer adverse cardiac events. The major limitations of this study are the small sample size from one center and the retrospective design. Future studies examining larger patient populations in a prospective fashion will provide more information about how to best treat DLBCL patients with heart failure. DisclosuresNo relevant conflicts of interest to declare.

R-EPOCH Is Superior to R-CHOP As a First-Line Regimen in De Novo DLBCL Patients with High Ki-67 Expression

Diffuse large B-cell lymphoma (DLBCL) patients with high Ki-67 expression receive limited benefits from R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy. This study aims to compare the R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) and R-CHOP regimens as first-line therapy in DLBCL patients with high Ki-67 expression. Data from 44 untreated DLBCL patients with high Ki-67 expression receiving R-EPOCH therapy were matched with those from 132 untreated DLBCL patients with high Ki-67 expression receiving R-CHOP therapy based on the International Prognostic Index (IPI: age, Ann Arbor stage, performance status, LDH level, number of extranodal sites), gender, and Ki-67 expression. In the R-EPOCH group, 42/44 patients were eligible for response evaluation. A total of 35 patients (83.3%) achieved complete remission (CR); 6 patients (14.3%) achieved partial remission (PR); and one patient (2.4%) exhibited progressive disease (PD) after 2 cycles of therapy. Patients in the R-EPOCH group presented better survival outcomes than those in the R-CHOP group (3-year overall survival [OS]: 89.9% vs. 70.2%, p=0.041; 3-year progression-free survival [PFS]: 86.6% vs. 59.7%, p=0.024). The survival superiority of the R-EPOCH over the R-CHOP regimen persisted when considering only patients of low-to-intermediate IPI risk, but it was not observed in those of high IPI risk. Our data suggest that R-EPOCH is superior to R-CHOP as a first-line regimen in DLBCL patients with high Ki-67 expression, especially in those of low-to-intermediate IPI risk. DisclosuresNo relevant conflicts of interest to declare.

Intermediate Dose Methotrexate Improves Overall Survival and Progression-Free Survival of Patients with Diffuse Large B Cell Lymphoma Treated with the R-CHOP or CHOP Regimen

Introduction: Patients (pts) with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal localization are at a higher risk for relapse with central nervous system (CNS) involvement. The current policy at the Rambam Health Care Campus (Haifa, Israel) is to give DLBCL pts 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) together with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenous MTX (ID-MTX). The present study aimed to compare the outcome of DLBCL pts with risk factors for CNS relapse who did or did not receive prophylaxis with ID-MTX.Methods: We retrospectively evaluated a cohort of DLBCL pts treated at Rambam between the years 1991 and 2012. Overall survival (OS), progression-free survival (PFS) and CNS involvement at relapse were estimated in 203 of 355 pts [96 females, 107 males; median age 59 (range18-90) years]. The study included all pts with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (5%), breast (2%), testicular (3%), orbital (1%) involvement, bone marrow involvement (25%), stage IV disease (63%), LDH > normal (68%), ≥1 extra-nodal site (26%), IPI ≥3 (41%). Ten percent of pts had stage I-IE disease, 15% - stage II-IIE, 12% - stage III, 63% - stage IV, 38% had B symptoms. Pts with CNS involvement at diagnosis were excluded from the study.Results: One hundred and fifty patients (74%) were treated with R-CHOP. In this group, 40% of pts with IPI=0/1, 29% with IPI=2 and 47% with IPI ≥3 received ID-MTX prophylaxis. Sixty four pts received ID-MTX (32%), 14 pts (7%) received IT MTX only, 125 pts had no prophylaxis (62%). At a median follow-up of 92 months, 5% of pts had CNS relapse with no difference in incidence between the study groups. Pts with IPI≥3 treated with ID-MTX had a reduced overall relapse rate and significantly better PFS and OS (table 1).Conclusion: The addition of 2 cycles of ID-MTX to the R-CHOP regimen improved both PFS and OS of DLBCL pts with IPI≥3. A randomized controlled study is warranted to provide stronger evidence.Table 1All patientsPts No.PFS %P*HR95% CIPOS %#HR95% CIID-MTX65601881IT MTX15560.091.920.9-4.10.008433.271.4-7.8No prophylaxis123420.041.581.0-2.490.002512.491.4-4.4R-CHOP DataIPI≥3 no prophylaxis35201261IPI≥3 +ID-MTX31580.0040.380.29-0.850.001670.290.14-0.6No.: number; *HR: hazard ratio for progression; #HR for mortality; CI: confidential interval DisclosuresNo relevant conflicts of interest to declare.

Bortezomib-Based Therapy for Newly Diagnosed Mantle-Cell Lymphoma

BackgroundThe proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.MethodsIn this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival.ResultsAfter a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group.ConclusionsVR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.)

Influence of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone on serologic parameters and clinical course in lymphoma patients with autoimmune diseases

As patients with B-cell lymphomas suffering from an underlying autoimmune condition undergoing therapy with the CD20 antibody rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) offer the unique possibility of monitoring effects of therapy on various rheumatologic parameters, we have evaluated serologic autoimmune markers and the clinical outcome of patients with autoimmune diseases (ADs) who received lymphoma treatment with R-CHOP during the course of their disease. We have retrospectively analysed 13 patients with non-Hodgkin's lymphoma who concurrently suffered from ADs and were treated with the R-CHOP regimen. Subjective parameters along with rheumatoid factor (RF) and antinuclear antibodies (ANA) were serially measured. The median levels of RF were 901 IU/ml [inter-quartile-range (IQR) 189-2520] before and 75 IU/ml (IQR 45-644) after therapy (P = 0.028). The median levels of ANA were 800 (IQR 140-2560) before and 100 (40-1280) after therapy (P = 0.027). Ten (77%) patients showed clinical improvement of their autoimmune symptoms, two (15%) reported no difference and one (7%) patient with rheumatoid arthritis-related worsening symptoms during therapy with R-CHOP. The autoimmune-related symptoms recurred after a median time of 7 weeks (IQR 6-8) in seven patients. In terms of lymphoma response, 11 patients achieved a complete remission and two a partial remission. This analysis indicates that R-CHOP given for lymphoma treatment is also effective for therapy of concurrent rheumatoid diseases. Both rheumatoid parameters as well as clinical symptoms showed a significant decrease during treatment with this immunochemotherapy. The effects on the rheumatic diseases, however, seem to be of limited duration.