Rituximab, Cyclophosphamide, Doxorubicin, Vincristine And Prednisone Research Articles

COO and MYC/BCL2 status do not predict outcome among patients with stage I/II DLBCL: a retrospective multicenter study

AbstractIn advanced-stage diffuse large B-cell lymphoma (DLBCL), the presence of an activated B-cell phenotype or a non–germinal center (GCB) phenotype, coexpression of MYC and BCL2 by immunohistochemistry, and the cooccurrence of MYC and BCL2 or BCL6 rearrangements are associated with inferior outcomes. It is unclear whether these variables remain prognostic in stage I/II patients. In this retrospective study, we evaluated the prognostic impact of cell of origin (COO), as well as dual-expressor (DE) status and molecular double-hit (DH) status, in stage I/II DLBCL by positron emission tomography with computed tomography (PET-CT). A total of 211 patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)–like regimens, with or without radiotherapy, was included. The median follow-up in the entire cohort was 4 years (range, 0.4-9.4), with estimated 4-year progression-free survival (PFS) and overall survival (OS) rates of 85% (95% confidence interval [CI], 79-89) and 88% (95% CI, 83-92), respectively. By univariable analysis, DE (PFS: hazard ratio [HR], 1.27; 95% CI, 0.58-2.81, P = .55 and OS: HR, 1.40; 95% CI, 0.60-3.30; P = .44), DH (PFS: HR, 1.21; 95% CI, 0.27-5.31; P = .80 and OS: HR, 0.61; 95% CI, 0.08-4.73; P = .64), and non-GCB status (PFS: HR, 1.59; 95% CI, 0.83-3.03; P = .16 and OS: HR, 1.80; 95% CI, 0.89-3.67; P = .10) were associated with poorer outcomes. In patients with PET-CT–defined stage I/II DLBCL treated with R-CHOP–like therapy, with or without radiation, COO and DE and DH status were not significantly associated with inferior PFS or OS.

What is the most appropriate regimen for untreated Waldenström macroglobulinemia? - An updated analysis of rituximab and half-dose CHOP therapy and cost effectiveness

What is the most appropriate regimen for untreated Waldenström macroglobulinemia? - An updated analysis of rituximab and half-dose CHOP therapy and cost effectiveness

Reduction of Chemotherapy in Aggressive Non-Hodgkin's Lymphoma with Favorable Prognosis

Background: Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP-like chemotherapy are the standard treatment for aggressive B-cell non-Hodgkin's lymphoma. We hypothesized that four cycles of CHOP plus six applications of rituximab (4x R-CHOP+2xR) are non-inferior to six cycles of R-CHOP in a population with favorable prognosis. Methods: We randomized patients 18 to 60 years of age, stage I-II disease, normal serum lactate dehydrogenase concentration, good ECOG performance status 0-1, without bulky disease (maximal tumor diameter <7.5 cm) to receive 6x R-CHOP or 4x R-CHOP+2xR. The primary endpoint was progression-free survival after three years. Findings: After a median follow-up of 66 months, 3-years progression-free survival of patients with 4x R-CHOP+2xR was 96% (95% confidence interval [CI]: 94%; 99%), which was 3% (95% CI (one-sided): 0%; 6%) better than 6x R-CHOP, demonstrating the non-inferiority of 4x R-CHOP+2xR. Survival after 3 years was 99% (95% CI: 98% - 100%) with 4x R-CHOP+2xR versus 98% (95% CI: 96% - 99%) with 6x R-CHOP. Relapse rates were 4% (95% CI: 2% -7%) in the 4x R-CHOP+2xR group versus 5% (95% CI: 3% - 8%) in the 6x R-CHOP group, respectively. Interpretation: In young patients with aggressive B-cell non-Hodgkin's lymphoma and favorable prognosis outcome after 4 cycles of R-CHOP is non-inferior compared to 6 cycles of R-CHOP, with relevant reduction of toxicity. Thus, chemotherapy can be reduced without compromising outcome in this population. Trial Registration: ClinicalTrials.gov number, NCT00278421. Funding Statement: It was coordinated by the German Study Group for high-grade Non-Hodgkin Lymphoma (DSHNHL) and funded by a German non-profit foundation, the “Deutsche Krebshilfe” (German Cancer Aid), reference number 106369. Declaration of Interests: Referring the Work under Consideration for Publication/During the Conduct of the study: Grants: V. Poeschel: Deutsche Krebshilfe (Non-Profit/Charity Organization); H. Holte: Deutsche Krebshilfe, Roche; Personal Fees: U. Keller: Roche; Relevant financial activities outside the submitted work: Personal Fees: V. Poeschel: Hexal; G. Held: BMS, Roche, Amgen, Spectrum, MSD; A. Viardot: Roche, Kite/Gilead, Pfizer, BMS, Amgen; C. Schmidt: Novartis AG, Gilead, Takeda; L. Truemper: Takeda; U. Keller: Janssen Cilag, BMS, Gilead, Takeda, Amgen, Hexal, Celgene, Astra Zeneca, MSD; R. Marks: Roche, Servier, Merck; M. Kneba: Astra Zeneca; F. Merli: Roche, Takeda, Celgene, Janssen, Gilead, Mundipharma; P. de Nully Brown: Roche; F. Hartmann: BMS, Roche, Boehringer Ingelheim, Sanofi, Celgene, Novartis, Ipsen, Janssen, Gilead; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Grants: V. Poeschel: Abbvie, Amgen, Roche; G. Held: BMS, Roche; C. Schmidt: Janssen Cilag, Gilead, Takeda; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Non-financial support: C. Schmidt: Janssen Cilag, Gilead, Takeda; F. Merli: Takeda, Celgene; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis All other authors declared no conflicts of interest. Ethics Approval Statement: The study was conducted in accordance with the Helsinki declaration. The protocol and its amendments were approved by the ethics committee of each participating center.

High Red Cell Distribution Width is an Adverse Predictive and Prognostic Factor in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemoimmunotherapy

IntroductionThe red blood cell distribution width (RDW) is an easy-to-obtain laboratory value that has emerged as a potential prognostic factor in solid and hematologic malignancies. Patients and MethodsWe evaluated 121 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with standard chemoimmunotherapy at our institution between 2010 and 2012. We categorized patients with high RDW (> 14.6%) and normal RDW (11.6%-14.6%). We fitted multivariate regression models for complete response (CR) and overall survival (OS). ResultsPatients with high RDW were less likely to achieve CR to chemoimmunotherapy than patients with normal RDW (48% vs. 83%; P < .001). The 5-year OS rate for patients with high RDW was lower than in patients with normal RDW (51% vs. 79%; P = .001). In multivariate regression models, high RDW was independently associated with lower odds of achieving CR (odds ratio, 0.32; 95% confidence interval [CI], 0.12-0.83; P = .02) and with higher risk of death from any cause (hazard ratio [HR], 2.04; 95% CI, 1.03-4.02; P = .04) than normal RDW in patients with DLBCL treated with chemoimmunotherapy. High RDW remained an independent adverse factor for OS after adjustment for the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index scores with HR 2.20 (95% CI, 1.12-4.31; P = .02) and HR 2.67 (95% CI 1.28-5.59; P = .009), respectively. ConclusionHigh RDW appears to be an adverse predictive and prognostic factor in patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).

Temporal trends in treatment and survival of older adult diffuse large B-Cell lymphoma patients in the SEER-Medicare linked database

To describe temporal trends in treatment among older adult (≥66 years) patients diagnosed with diffuse large B-cell lymphoma (DLBCL), we analyzed 18,058 DLBCL patients from the Surveillance, Epidemiology, and End Results linked Medicare (SEER-Medicare) database diagnosed between 2001 and 2013. Among 65% of patients receiving treatment after diagnosis, R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) was the most common frontline therapy, increasing with more recent treatment year: 51% (2001–2003) vs. 69% (2010–2014). Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) was uncommon in these Medicare patients. As the addition of rituximab increased over time, we also observed an improved survival rate over time. It is possible there is an association, but we cannot make this inference as effectiveness was not measured in this study. Overall survival estimates indicated that survival probabilities steadily improved in more recent years; however, 5-year survival was <40%, indicating the need for improved treatment options for older adult DLBCL patients.

PF496 TREATMENT PATTERNS AMONG PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA

Background:Follicular lymphoma (FL) is the second most common form of non‐Hodgkin lymphoma, accounting for about 35% of cases in the United States. Despite a high 5‐year survival rate (53–91%), FL is considered incurable with cycles of relapse and remission occurring frequently. Treatment may involve radiation or chemoimmunotherapy (drug treatment) according to disease stage. However, standard guidelines recommend a number of options for both first‐ (1L) and second‐line (2L) therapy with no dominant choice for clinical decision‐makers.Aims:To examine real‐world 2L treatment patterns among patients with relapsed FL.Methods:Using 2007–2014 Surveillance, Epidemiology, and End Results (SEER)‐Medicare data, we identified patients diagnosed with FL (International Classification of Diseases for Oncology, 3rd edition [ICD‐O‐3] codes 9690–9691, 9695, 9698) who initiated a target 1L treatment for FL during the identification period of January 1, 2008 to December 31, 2012. Date of diagnosis occurred on or before the first claim date for 1L treatment (index date). Patients using any drug treatment for FL before the index date were excluded. Patients were followed for ≥1 year (except due to death) until death, disenrollment, or study end. Target 1L treatments were identified by the presence of a claim for all agents (except prednisone): rituximab monotherapy (R‐mono); rituximab + bendamustine (BR); R‐CVP (rituximab, cyclophosphamide, vincristine, prednisone); R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). As physicians may modify the combination of CHOP agents, patients who were not on R‐CVP but received rituximab and ≥1 agent of cyclophosphamide, doxorubicin, and vincristine were classified as R‐CHOP‐like. Patients who started 2L therapy after ≥4 cycles of index therapy and a remission period of ≥90 days (≥180 days for R‐mono) were considered to have relapsed FL. New drug treatment received before completing all cycles and achieving full remission was considered part of the previous line of therapy. We examined 2L treatment patterns, such as the type and frequency of 2L regimens. Baseline measures included demographics, Ann Arbor staging, and number of chronic conditions.Results:2,515 patients who initiated 1L therapy for FL and who met all selection criteria were identified. Mean age (standard deviation [SD]) was 74.1 (8.2) years, 87.2% were white, and 53.8% were female. All stages were represented: stage III (28.4%), IV (26.8%), I (20.8%), II (17.1%), and unknown (6.8%). Mean (SD) number of chronic conditions was 6.9 (2.1). Two‐thirds of patients (66.4%) completed 1L therapy and entered remission during follow‐up. Among these patients, 26.4% (n = 440) experienced a relapse and began 2L therapy. R‐mono, R‐CHOP‐like, R‐CVP, and BR were most commonly initiated as 2L therapy (97.2%). Many patients moved on to a second (12.3%) or third or more (5%) 2L regimen until completing a full course of therapy or reaching study end. Considerable heterogeneity was observed in 2L regimens (Table). In addition, treatment failure was somewhat common; among the 206 patients who completed 2L therapy and entered remission 27.7% (n = 57) experienced relapse and began third‐line therapy.Summary/Conclusion:Many patients with FL who receive 1L therapy experience relapse and move on to subsequent lines of therapy. Regimens received as part of 2L therapy are heterogeneous and over a quarter of 2L regimens completed result in failure, suggesting an unmet need for alternative treatment options among relapsed FL patients.image

Functionally Defective T Cells After Chemotherapy of B-Cell Malignancies Can Be Activated by the Tetravalent Bispecific CD19/CD3 Antibody AFM11.

Immunotherapy of B-cell malignancies with bispecific antibodies is an emerging treatment option. However, not all patients benefit from these therapies, presumably due to pretreatment regimens. Therefore, we determined the effect of different treatment lines on the activity of T cells and their responsiveness to AFM11. AFM11 is a tetravalent, bispecific CD19/CD3 immunoengager based on Affimed's ROCK platform, currently being investigated in phase I clinical trials for non-Hodgkin lymphoma and acute lymphoblastic leukemia. T cells from B-cell lymphoma patients treated with either rituximab+bendamustine (R-Benda), rituximab+CHOP (R-CHOP), or with high-dose BEAM chemotherapy (HD-BEAM) and autologous HSCT were compared with T cells from healthy donors. Overall, in these patients, T-cell numbers were significantly reduced. To determine whether distinct chemotherapy affects AFM11 efficacy, functional T-cell assays were performed. It is interesting to note that, only in assays that combine target cell lysis, cytokine production and proliferation over 4 days at an effector to target ratio of up to 1:25 significant differences could be detected between the different treatment groups: T cells after R-CHOP showed only modest decrease in their functionality when compared with healthy controls, whereas R-Benda and HD-BEAM had a profound effect on AFM11-induced T-cell cytotoxicity. In conclusion, T cells from lymphoma patients are reduced in number and have functional defects following treatment with certain chemotherapy regimens, also reducing AFM11 efficacy. Importantly, AFM11 was still able to trigger B-cell-directed T-cell immunity in all treatment groups.

PS1074 SANDOZ RITUXIMAB FOR THE TREATMENT OF DIFFUSE LARGE B‐CELL LYMPHOMA: INTERIM SAFETY RESULTS OF THE PROSPECTIVE NON‐INTERVENTIONAL, OBSERVATIONAL, MULTICENTER, OPEN‐LABEL REFLECT STUDY

Background:Sandoz rituximab (SDZ‐RTX) is approved in Europe, Japan, Australia, and New Zealand for use in all indications of reference rituximab. Approval was based on the totality of evidence for biosimilarity, including extensive physicochemical and structural data, as well as preclinical and clinical pharmacokinetic, pharmacodynamic and immunogenicity data, and also clinical trials including a Phase III confirmatory trial in patients with follicular lymphoma. REFLECT is the first post‐approval study for a rituximab biosimilar in diffuse large B‐cell lymphoma (DLBCL). REFLECT is a prospective, non‐interventional, open‐label study of the effectiveness and safety of SDZ‐RTX as curative therapy in patients with treatment‐naïve CD20+ DLBCL.Aims:To report study design and interim baseline patient demographics and safety data to September 6, 2018, when recruitment was approx. 50% complete.Methods:The study includes patients aged ≥18 years with CD20+ DLBCL, eligible for treatment with rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone (R‐CHOP). Exclusion criteria include any prior DLBCL treatment or contraindication to rituximab. R‐CHOP is administered according to product label. The primary endpoint is complete response rate, assessed by the treating physician at the end of treatment. Secondary endpoints include: overall response rate; 12‐month progression‐free survival; quality of life; and adverse events (AEs). Data are collected at baseline, and at every study visit for 12 months (efficacy) and until ≥30 days after the last SDZ‐RTX dose (safety). No imputation for missing data is planned and endpoints are summarized descriptively.Results:The interim full analysis set comprised 80 patients, of which 38 were male (48%) and 42 were female (53%). Median age was 68.5 years and 70% of patients were aged ≥60 years. In total, 6 patients (8%) have discontinued the study. Median baseline BMI was 25 (min 20, max 48), and mean time from diagnosis to start of treatment was 1.5 months (SD 5.1). Most patients had little or no restriction in daily activities, with &gt;80% of patients having an ECOG score of 0 (34%) or 1 (50%). No ECOG score &gt;2 was observed. Similar results were observed on the Karnofsky performance scale: 76% of patients scored ≥80%. The most commonly reported baseline symptoms were enlarged lymph nodes (n = 48, 60%) and disease‐related pain (n = 21, 26%). B symptoms were reported in 15 patients (19%). Extranodal infiltration was observed in 40 patients (50%), bulky disease in 9 patients (11%), and spleen involvement in 2 patients (3%). Early‐stage disease (0–IIB) was reported for 64% of patients, and low‐to‐intermediate risk disease (IPI 0–2) for 61% (Table).imageSafety is summarized in the Table. AEs were reported in 53 patients (66%), serious AEs were reported in 19 patients (24%), and treatment‐related AEs were reported in 13 patients (16%). The most frequent AEs were polyneuropathy (n = 10, 13%), anemia (n = 8, 10%), and fatigue (n = 8, 10%).Summary/Conclusion:REFLECT provides the first prospective real‐world data for a rituximab biosimilar and CHOP as a curative therapy for CD20+ DLBCL. In this interim analysis, baseline patient data and disease characteristics were as expected for treatment‐naïve patients with CD20+ DLBCL, and safety was as expected for rituximab‐based treatment. Recruitment is ongoing and expected to be completed by March 2019. Biosimilar rituximab has the potential to provide savings for healthcare systems and broaden patient access to rituximab‐based chemotherapy, supporting the sustainability of cancer care.

GX-G3, a long-acting G-CSF, compared with pegfilgrastim in reducing duration of severe neutropenia after chemotherapy for non-Hodgkin’s lymphoma.

e19065 Background: G-CSF is used in patients at significant risk for developing severe neutropenia (neutrophil count &lt; 0.5 × 109/L or grade 4 neutropenia) following myelosuppresive chemotherapy. GX-G3, human G-CSF fused to hyFc is a proposed alternative to Neulasta. Methods: An open-label, randomized, phase II study was designed to compare the effects of subcutaneous (SC) injection of GX-G3 (a long-acting G-CSF) at doses of 150, 250 and 350 μg/kg with Neulasta 6 mg administered SC in patients receiving R-CHOP for advanced NHL (n = 65). The primary objective was to assess the duration of severe neutropenia after 1st cycle of chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). The following parameters were also assessed: duration of severe neutropenia after 2nd cycle of chemotherapy, optimal time for GX-G3 intervention (two GX-G3 250 μg/kg cohorts; administered 24 and 72 hours after R-CHOP), incidence of severe neutropenia and febrile neutropenia post R-CHOP, pharmacokinetics, and safety. Patients were randomly assigned to receive GX-G3 or reference drug, Neulasta, one dose after 1st and 2nd cycle of R-CHOP for a total of 2 doses. Results: The mean duration of severe neutropenia after 1st cycle was shortest in GX-G3 350 μg/kg group [GX-G3 150, 250 (24h, 72h), 350 μg/kg and Neulasta®; 3.2, 2.3, 2.0, 1.3 and 2.4 days, respectively]. The results of all GX-G3 groups and Neulasta were not significantly different for duration of severe neutropenia after 2nd cycle of R-CHOP, incidence of severe neutropenia and febrile neutropenia, or toxicity profile. The elimination half-life of GX-G3 and Neulasta ranged from 29.8 to 66 hours and 19.2 to 76.8 hours, respectively. Conclusions: GX-G3, in all tested dosage regimen, was safe and well tolerated in this patient population. A single injection of GX-G3 per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by Neulasta. GX-G3 administration after 24 hours, compared to 72 hours post R-CHOP treatment resulted in relatively shorter duration of severe neutropenia. Clinical trial information: 2015-002693-20.

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.

High Expression of CXCR4, Instead of PD-L1, Is Correlated with Poor Clinical Response to R-CHOP Therapy in Diffuse Large B-cell Lymphoma Patients

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin Lymphoma worldwide. Rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine and prednisone (R-CHOP) are the current standard therapy. About 10% cases of DLBCL were refractory to these immunochemotherapy and may have poor prognosis. Latest studies showed that C-X-C chemokine receptor type 4 (CXCR4) and Programmed Death Ligand 1 (PD-L1) were involved in DLBCL biology and correlated with patients’ poor survival. This study aimed to investigate the expression of CXCR4 and PD-L1 with clinical characteristics and its response to R-CHOP in DLBCL and their potential benefit as future predictive biomarkers.&#x0D; Methods: Thirty four cases of newly diagnosed DLBCL were selected from Hasan Sadikin General Hospital, Bandung, Indonesia, during 2015-2018. Treatment outcome was retrieved from patients’ medical records. The expression of CXCR4 and PD-L1 in patients’ tumor tissues were detected using immunohistochemistry.&#x0D; Results: Five of 34 cases (14.70%) showed poor clinical response to R-CHOP. High CXCR4 expression was detected in 11 of 34 cases (32.35%), it was significantly correlated with clinical stage (p = 0.0003) and poor clinical response (p = 0.029). High PD-L1 expression was detected in 10 of 34 cases (29.41%) and was significantly correlated with patients’ gender (p = 0.022) but was not correlated with poor clinical response (p = 0.138).&#x0D; Conclusions: CXCR4 in DLBCL increased probability of poor clinical response to R-CHOP, but not PD-L1 expression. This finding provides the ground for further research which relates to CXCR4 as a future predictive biomarker for this challenging malignancy.

Real world data on follicular lymphoma patients treated by rituximab-containing immunochemotherapy and rituximab maintenance.

Background/AimsReal-world data about the treatment outcomes of patients receiving rituximab-containing immunochemotherapy followed by rituximab maintenance are required to understand better the treatment for follicular lymphoma (FL).MethodsA cross-sectional study analyzed FL patients who were treated with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and rituximab maintenance.ResultsOf 139 patients, 85 patients received R-CVP and 54 received R-CHOP. The characteristics did not differ significantly between the groups. Only grade 3 of FL was more common in R-CHOP. The complete response rate did not differ significantly between R-CHOP (50/54, 92.6%) and R-CVP (77/85, 90.6%). The number of disease relapses during rituximab maintenance did not differ significantly between the groups (p = 0.798). Therefore, the comparison of progression-free survival (PFS) showed no significant difference: the 3-year PFS rates for R-CVP and R-CHOP were 77% and 85%, respectively (p = 0.567). Although five of 56 hepatitis B virus (HBV) core antibody (anti-HBc)-positive patients experienced HBV reactivation, all cases of HBV reactivation were identified during regular monitoring for HBV DNA in blood, and were successfully managed with antiviral treatment.ConclusionsThe survival outcomes of FL patients on rituximab maintenance after responding to R-CVP or R-CHOP were similar. Rituximab-containing immunochemotherapy followed by rituximab maintenance can be safely used for anti-HBc-positive patients if HBV DNA titer in blood can be regularly monitored.

Immune Profiling and Quantitative Analysis Decipher the Clinical Role of Immune-Checkpoint Expression in the Tumor Immune Microenvironment of DLBCL.

PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for 13 types of cancers and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for the PD-1 immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants. In both training and validation cohorts, results demonstrated a central role of the tumor immune microenvironment, and when its functionality was impaired by deficiency in tumor-infiltrating T cells and/or natural killer cells, high PD-1 expression (but not CTLA-4) on CD8+ T cells, or PD-L1 expression on T cells and macrophages, patients had significantly poorer survival after rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. In contrast, tumor-cell PD-L2 expression was associated with superior survival, as well as PD-L1+CD20+ cells proximal (indicates interaction) to PD-1 + CD8+ T cells in patients with low PD-1 + percentage of CD8+ T cells. Gene-expression profiling results suggested the reversibility of T-cell exhaustion in PD-1+/PD-L1+ patients with unfavorable prognosis and implication of LILRA/B, IDO1, CHI3L1, and SOD2 upregulation in the microenvironment dysfunction with PD-L1 expression. This study comprehensively characterized the DLBCL immune landscape, deciphered the differential roles of various checkpoint components in rituximab-CHOP resistance in DLBCL patients, and suggests targets for PD-1/PD-L1 blockade and combination immunotherapies.

Stratification by MYC expression has prognostic impact in MYC translocated B-cell lymphoma-Identifies a subgroup of patients with poor outcome.

In patients with large B-cell lymphoma (LBCL) according to WHO, the prognostic significance of MYC translocation is still not sufficiently clarified. We therefore aimed to investigate whether prognostication could be improved in patients with MYC translocation positive LBCL by additional stratification according to MYC and BCL2 protein expression levels or MYC translocation partner gene as well as concurrent BCL2 and/or BCL6 translocation (DH). From an unselected consecutive cohort of >600 patients with LBCL investigated with fluorescent in situ hybridization (FISH), 64 patients were diagnosed with MYC translocation positive LBCL and included in the study. They were further investigated for supplemental translocations with FISH and MYC and BCL2 protein expression with immunohistochemistry (IHC). MYC expression >75% was associated with both reduced progression-free survival (PFS) and overall survival (OS) (PFS: HR 6.8 (95% CI 1.5-31), P=0.004. OS: HR 4.3 (95% CI 0.9-21), P=0.05). Immunoglobulin (IG) MYC translocation partner gene was related to high MYC protein expression (P=0.047) but was not prognostic for PFS (P=0.8) or OS (P=0.6). DH did not confer a worse outcome compared to MYC single hit (SH). These findings were confirmed in a comparable, independent validation cohort of 28 patients with MYC translocation positive LBCL. All patients included in the survival analyses were treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or R-CHOEP (R-CHOP+etoposide). These findings suggest that in patients with LBCL stratification by MYC protein expression level significantly improves the prognostic impact associated with MYC translocation.

Addition of high-dose methotrexate to standard treatment for patients with high-risk diffuse large B-cell lymphoma contributes to improved freedom from progression and survival but does not prevent central nervous system relapse

Combination of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is regarded as standard care for diffuse large B-cell lymphoma (DLBCL) and upfront intensification of therapy is still controversial. The current study aimed to dertermine whether the addition of high-dose methotrexate (HDMTX) affects long-term outcomes and could also prevent central nervous system (CNS) relapse. Medical records of 480 patients with DLBCL treated between 1994 and 2013 at Rambam and Hadassah medical centers in Israel were reviewed; 130 (27%) had received HDMTX. Patients receiving HDMTX generally had higher International Prognostic Index (IPI) and CNS-IPI scores. HDMTX addition significantly improved progression free and overall survival (p = .001) and this advantage was maintained in multivariate analysis (HR for OS 0.3; 95% CI 0.19–0.47; p < .0001). Thirty-one (6.5%) patients had CNS relapse and in these cases high CNS-IPI, but not HDMTX treatment, was independently associated with CNS relapse (HR 1.2; 95% CI 1.2–11.5; p = .02). In conclusion, the addition of HDMTX to CHOP/RCHOP independently and significantly improved prognosis of patients with high-risk DLBCL, irrespective of their risk for CNS relapse.

The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper.

This Good Practice Paper was compiled according to the British Society for Haematology (BSH) process at http://www.b-s-h.org.uk/guidelines. The BSH produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org and is also detailed in Table 1.

Diffuse large B-cell lymphoma: standard treatment and research questions

In 2018 the practical guidelines for hematological malignancies, edited by Japanese Society of Hematology, underwent major revision for the first time in five years. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard treatment for diffuse large B-cell lymphoma (DLBCL) in line with the prior 2013 guidelines. R-CHOP has been considered as the standard treatment for DLBCL since early 2000s, when a 20% improvement in survival was observed when adding rituximab to CHOP. Following this, several clinical trials were conducted, but most attempts to exceed R-CHOP have failed. Moreover, this evidence has raised further research questions. In this report, the current evidence and the problems associated with DLBCL treatments have been reviewed.

Dermoscopic follow-up of therapeutic response in mantle cell lymphoma with secondary involvement of the scalp.

The scalp is a potential location for both benign and malignant tumors. Lymphoproliferative diseases can involve the skin as a primary or secondary manifestation. Dermoscopy is a noninvasive diagnostic tool for rapid diagnosis, screening, and follow-up of the majority of skin tumors. Mantle cell lymphoma (MCL), a rare type of aggressive systemic lymphoma, usually occurs as a generalized lymphadenopathy, commonly with infiltration of the bone marrow, spleen, gastrointestinal tract, and Waldeyer's ring. In rare cases, it can also involve other structures, such as the lungs, central nervous system, liver, or skin. We report the case of a 74-year-old male patient suffering from MCL since 2015. Complete remission was obtained after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment. During maintenance therapy with rituximab, a solitary tumor occurred on the scalp. Dermoscopy of the lesion suggested relapse because of the presence of multiple chaotically distributed short linear vessels with multiple red dots within the hair follicles. Histological examination confirmed the diagnosis of MCL. After second-line therapy with rituximab and bendamustine (R-B), the tumor of the scalp completely disappeared and dermoscopy showed no abnormalities.

R-CHOP with or without Lenalidomide/Bortezomib As a First Line Treatment for Patients with Non-Germinal Center Diffuse Large B Cell Lymphoma (DLBCL) Subtype: Son Espases University Hospital Experience

INTRODUCTIONThe standard first line treatment for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) independently of cell origin subtype. Retrospective studies have shown that non-germinal center (NGC) subtype is associated with a worse progression free survival (PFS) and overall survival (OS) compared to germinal center subtype. In phase II studies the combination of lenalidomide (lena) or bortezomib (bor) with R-CHOP in this lymphoma subtype has shown better results in comparison to R-CHOP alone. For this reason, the aim of our study is to analyze the efficacy and toxicity of R-CHOP plus lena/bor in comparison with R-CHOP alone in patients with NGC DLBCL.PATIENTS AND METHODSIn order to avoid selection bias, all patients with NGC DLBCL (confirmed by immunohistochemistry with Hans algorithm) who received R-CHOP or R-CHOP-lena/bor (25mg lenalidomide daily from day 1 to 10 / bortezomib 1.3mg/m2 days 1 and 4) were retrospectively selected from the Pharmacy Registry. Patients in our center received R-CHOP from March 2002 to June 2013, R-CHOP-bor from June 2013 to July 2015 and R-CHOP-lena from November 2014 until now. Cheson and Lugano criteria were used to confirm response rates. Toxicity was checked with CTCAE v4-5 criteria.RESULTSFifty-five patients with NGC DLBCL were identified from 2002 to 2018, 18 of whom were treated with R-CHOP-lena/bor and 33 with R-CHOP. Baseline characteristics are specified in Table 1. Overall response rate was similar in both treatment regimens, 94% versus 87%, respectively. 12.5% progression/stable disease cases were identified with R-CHOP alone compared to 5.3% with R-CHOP-lena/bor. With a median follow-up of 45 months (6-126) for R-CHOP and 22 months (6-59) for R-CHOP-lena/bor, the median PFS was 65 months for R-CHOP and was not reached for R-CHOP-lena/bor. 47% versus 9% of progressions were observed in R-CHOP and R-CHOP-lena/bor, respectively (p=0.006). Regarding OS, the death rate in the R-CHOP group was 45% in comparison with 23% in R-CHOP-lena/bor group (p=0.015). Higher hematological toxicity was observed in the R-CHOP-lena/bor group comparing with R-CHOP: neutropenia (95% versus 68%), grade 3-4 neutropenia (81% versus 37%) and anemia (81% vs 56%) (p<0.05) (Table 2) being manageable in all cases.CONCLUSIONSThe addition of lenalidomide or bortezomib to R-CHOP seems to be a good option in NGC DLBCL, with a lower progression rate, refractoriness and less mortality in comparison with R-CHOP alone. R-CHOP-lena/bor is associated to higher rates of hematological toxicity but manageable in all cases. These retrospective data should be confirmed in ongoing phase III clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Impact of Incomplete Cycles and Dose Attenuation of Rituximab-Bendamustine on Survival Outcomes in Low-Grade Non-Hodgkin Lymphomas

IntroductionRituximab and Bendamustine (BR) has been shown to be effective in the treatment of indolent non-Hodgkin's lymphomas (NHLs) with an acceptable safety profile and comparable to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP). However, patients may develop significant cytopenias after Bendamustine exposure leading managing physicians to truncate the suggested treatment course or attenuate treatment dosages. We hypothesize that this reduced treatment intensity may negatively affect treatment outcomes.MethodsWe retrospectively analysed patients who were diagnosed with indolent non-Hodgkin lymphomas (NHL) at the Singapore General Hospital from year 2000 and received BR or R-CHOP frontline. Data was locked at 31 October 2017. Histologic diagnosis was made according to published international guidelines. The safety and efficacy of BR and RCHOP as first line treatment of indolent lymphomas was analyzed. We also evaluated if truncation of immunochemotherapy cycles or dosage attenuation impacts on progression-free survival (PFS). We define patients on BR as i) BR full - having received 6 cycles of BR at 90mg/m2/day for 2 days per cycle ii) BR attenuated - received at least 6 cycles of BR at 70mg/m2/day for 2 days per cycle iii) BR truncated - received less than 6 cycles of BR. The chi-squared and Fisher's exact two-sided tests were used for comparisons between categorical variables and the t-test was used for continuous variables. Survival probabilities were calculated using the Kaplan-Meier estimator, with log-rank analysis used to compare between different groups. All analyses were performed using Stata (Statacorp, College Station, TX, USA).ResultsEighty-seven patients were evaluable of whom 47 received BR and 40 received R-CHOP upfront. Amongst patients who received BR and R-CHOP respectively, histological diagnoses were: follicular lymphoma (19.2% vs 72.5%), marginal zone lymphoma (25.5% vs 7.5%), chronic lymphocytic leukaemia / small B-cell lymphocytic lymphoma (29.8% vs 5.0%), lymphoplasmacytic lymphoma (21.3% vs 7.5%), mantle cell lymphoma (2.1% vs 5.0%) and other B-cell lymphoma not classifiable (2.1% vs 2.5%). Baseline characteristics are presented in Table 1 and treatment related toxicities are presented in Table 2. There was no significant difference in treatment emergent grades 3/4 haematological adverse events between BR and R-CHOP. More patients developed infusional reactions (17.0% vs 2.5%, p =0.04) when treated with BR compared to R-CHOP. Conversely, more patients treated with R-CHOP developed peripheral neuropathy (15.0% vs 0%, p=0.008).More patients who were treated with BR as compared to R-CHOP had treatment truncated (i.e. received less than 6 cycles) or dosages attenuated (46.8% vs 5.0%, p<0.005). The median number of cycles completed for patients who had BR treatment course truncated was 4 (interquartile range 2-4). For patients treated with BR, the reasons for treatment truncation were drug-related toxicity (17.0%), patient's decision (10.6%) and physician's decision (2.1%). 2 patients had early termination with R-CHOP treatment, 1 (2.5%) due to disease progression and another patient (2.5%) due to drug-related toxicity.With a median follow-up of 51.0 months, median PFS for patients treated with BR was 69.5 months versus 76.9 months for patients treated with R-CHOP (p=0.26). BR truncated patients had inferior PFS compared to BR full and BR attenuated patients (Median PFS = 36.5mths vs NR, p=0.01). There was no statistically significant difference in PFS between BR full and BR attenuated patients (Median PFS = 69.5 mths vs NR, p=0.25).ConclusionTreatment efficacies and haematological toxicities were comparable in our patients with indolent NHLs treated with BR or R-CHOP. Despite this, more patients treated with BR had treatment truncated prematurely. The majority of such terminations were for drug-related toxicities. We found inferior PFS in patients who received less than 6 cycles of BR. Patients who completed 6 cycles of BR but had attenuated dosages did not have inferior PFS compared to patients who received 6 cycles of BR at full dose. Our findings suggest that treatment truncation with reduced treatment intensity negatively affects survival outcomes. Patients with cytopenias should be supported or have drug dosages attenuated with the aim to complete the entire treatment course for best outcomes. [Display omitted] DisclosuresChen:Takeda: Honoraria, Other: Travel grant; Janssen: Honoraria; Celgene: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding. Goh:Novartis AG: Honoraria, Other: Non-financial support, Research Funding; Takeda: Other: Non-financial support, Research Funding.