Poor-risk Diffuse Large B-cell Lymphoma Research Articles

Prognostic models integrating quantitative parameters from baseline and interim positron emission computed tomography in patients with diffuse large B-cell lymphoma: post-hoc analysis from the SAKK38/07 clinical trial.

Positron emission computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) enrolled in a prospective clinical trial were reviewed to test the impact of quantitative parameters from interim PET/CT scans on overall (OS) and progression-free (PFS) survival. We centrally reviewed baseline and interim PET/CT scans of 138 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone given every 14 days (R-CHOP14) in the SAKK38/07 trial (ClinicalTrial.gov identifier: NCT00544219). Cutoff values for maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic heterogeneity (MH) were defined by receiver operating characteristic analysis. Responses were scored using the Deauville scale (DS). Patients with DS 5 at interim PET/CT (defined by uptake >2 times higher than in normal liver) had worse PFS (P = 0.014) and OS (P < 0.0001). A SUVmax reduction (Δ) greater than 66% was associated with longer PFS (P = 0.0027) and OS (P < 0.0001). Elevated SUVmax , MTV, TLG, and MH at interim PET/CT also identified patients with poorer outcome. At multivariable analysis, ΔSUVmax and baseline MTV appeared independent outcome predictors. A prognostic model integrating ΔSUVmax and baseline MTV discriminated three risk groups with significantly (log-rank test for trend, P < 0.0001) different PFS and OS. Moreover, the integration of MH and clinical prognostic indices could further refine the prediction of OS. PET metrics-derived prognostic models perform better than the international indices alone. Integration of baseline and interim PET metrics identified poor-risk DLBCL patients who might benefit from alternative treatments.

CAR T-cell therapy for B-cell lymphomas: clinical trial results of available products.

Adoptive cellular immunotherapy with chimeric antigen receptor (CAR) T cell has changed the treatment landscape of B-cell non-Hodgkin’s lymphoma (NHL), especially for aggressive B-cell lymphomas. Single-center and multicenter clinical trials with anti-CD19 CAR T-cell therapy have shown great activity and long-term remissions in poor-risk diffuse large B-cell lymphoma (DLBCL) when no other effective treatment options are available. Two CAR T-cell products [axicabtagene ciloleucel (axi-cel) and tisagenlecleucel] have obtained US Food and Drug Administration approval for the treatment of refractory DLBCL after two lines of therapy. A third product, liso-cel, is currently being evaluated in clinical trials and preliminary results appear very promising. CAR T-cell-related toxicity with cytokine-release syndrome and neurotoxicity remain important potential complications of this therapy. Here, we review the s biology, structure, clinical trial results and toxicity of two commercially approved CAR T-cell products and others currently being studied in multicenter clinical trials in B-cell NHLs.

Deep Phenotypic Analysis Reveals a Monocyte Subpopulation Predictive of Relapse/Refractory Diffuse Large B-Cell Lymphoma

Background: Diffuse large B cell lymphoma (DLBCL) is the most frequent lymphoma subtype with up to two thirds of patients achieving cure following standard immuno-chemotherapy. However, approximately 10-15% will be primary refractory and a further 20-30% relapse. There is an urgent need for improved biomarkers to identify these poor risk patients at diagnosis who are destined to fail standard therapy so that novel approaches can be considered. The diagnostic peripheral blood monocyte count is known to be predictive of outcome in DLBCL, with higher counts identifying patients with worse outcome but mechanistic understanding is currently lacking. The aim of this study was to investigate the peripheral blood monocyte population driving this phenomenon and we present here a deep phenotypic analysis of the monocyte compartment at diagnosis in patients with extremes of outcome following immuno-chemotherapy.Methods: We identified 112 immuno-chemotherapy treated DLBCL patients with viably cryopreserved peripheral blood mononuclear cells (PBMCs) in our tissue bank. The diagnostic absolute monocyte (AMC) and lymphocyte counts (ALC) were examined as prognostic variables. For phenotypic analysis a subset of 20 patients, 10 with relapse/refractory disease within 12 months of therapy (Poor risk) and 10 with continued complete remission >24 months post therapy (Good risk), were selected. PBMCs from these patients were stained with a panel of 29 metal-tagged antibodies designed to identify immune populations and characterize the monocyte compartment and analyzed using cytometry by time-of-flight (CyTOF2TM). Samples were acquired in batches run with the same healthy donor control PBMCs to ensure consistency of staining. Normalized data were subjected to traditional Boolean gating in Cytobank (www.mrc.cytobank.org) to identify CD45+ live single cells and further analyzed using FlowSOM and CITRUS.Results: In the full 112 patient cohort, a higher diagnostic AMC (≥0.6 x 109/L) predicted worse outcome (5-year OS, 59% vs 74%, p=0.047*). The lymphocyte to monocyte ratio (LMR) was more discriminatory, with a low LMR (<2.6) predicting worse outcome (5-year OS, 49% vs 81%, p=0.0009*). CyTOF analysis of the CD45+ events from all 20 DLBCL patients were clustered in an unsupervised manner with FlowSOM and visualized according to the tSNE algorithm. This identified all expected immune populations with further subdivision into multiple clusters / sub-populations based on protein marker expression. Repeating the FlowSOM analysis by outcome revealed clusters with clear differences between the 2 groups, including striking changes to the monocyte compartment (Figure 1). CITRUS, an algorithm for automated biomarker discovery, was used to further assess the differences in the monocyte compartments between poor risk and good risk DLBCL patients. This identified a monocyte subset, representing approximately 10% of non-lymphoid CD45+ PBMCs, with increased abundance in poor risk patients with relapsed/refractory disease (p=0.0028*, Figure 2). This subset expressed markers including HLA-DR, CD11b, CD13, CD14, CD33, SIRPα (CD172a), CCR2 (CD192, monocyte chemo-attractant protein receptor), CD206 and PD-L1 (CD274).Conclusions: We confirmed the previous finding that the diagnostic AMC is predictive of outcome in our cohort of DLBCL patients and have identified differences in the peripheral blood monocyte compartment between patients with good and poor risk disease. Unsupervised analysis using FlowSOM identified monocyte clusters with greater abundance in poor risk patients. A second high-dimensional single cell data analysis algorithm, CITRUS validated this finding by revealing a stratifying monocyte sub-population that was enriched in poor risk patients. This phenotype of peripheral blood monocytes may account for the adverse nature of a higher AMC at diagnosis. We are now functionally characterizing these monocytes and evaluating their relationship to differences between the lymphoid populations of good and poor risk patients. [Display omitted] DisclosuresSeymour:Celgene: Research Funding. Gribben:Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria; Abbvie: Honoraria; Kite: Honoraria; Acerta Pharma: Honoraria, Research Funding; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; NIH: Research Funding; Unum: Equity Ownership; Roche: Honoraria; Novartis: Honoraria; Cancer Research UK: Research Funding; Medical Research Council: Research Funding; TG Therapeutics: Honoraria.

PILLAR-2: A randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus (EVE) in patients (pts) with poor-risk diffuse large B-cell lymphoma (DLBCL).

7506Background: The goal of PILLAR-2 (NCT00790036) was to reduce DLBCL relapse by providing 1 year of adjuvant EVE to poor-risk (International Prognostic Index [IPI] ≥3) pts who had achieved a CR with R-chemo. Methods: PILLAR-2 was a multicenter double-blind, placebo (PBO)-controlled, phase 3 study. Pts with histologically confirmed stage III/IV poor-risk (IPI ≥3) DLBLC who had a PET/CT-confirmed CR to first-line R-chemo were randomized 1:1 to EVE 10 mg/day or PBO for 1 year or until disease relapse, unacceptable toxicity, or death. The primary endpoint was disease-free survival (DFS) by local assessment using revised IWRC; secondary endpoints were overall survival (OS), lymphoma-specific survival (LSS), and safety. Results: Median study follow-up was 50.4 months (range, 24.0–76.9 months). Of the 742 pts randomized, 177 (48%) pts in the EVE and 249 (67%) in the PBO arms completed the study treatment as per protocol. Overall, 47% pts were ≥65 years, 50% were male and 42% had an IPI of 4+5. Adjuvant EVE did...

Early Treatment Intensification with R-ICE Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) Using Zevalin-BEAM for Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) As Identified By Interim PET/CT Scan Performed after Four Cycles of R-CHOP-14: A Multicenter Phase II Study of the Australasian Leukaemia Lymphoma Study Group (ALLG)

Early Treatment Intensification with R-ICE Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) Using Zevalin-BEAM for Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL) As Identified By Interim PET/CT Scan Performed after Four Cycles of R-CHOP-14: A Multicenter Phase II Study of the Australasian Leukaemia Lymphoma Study Group (ALLG)

Rituximab and CODOX-M / IVAC Without Stem Cell Transplantation For Poor Risk Diffuse Large B Cell Lymphoma (IPI3-5) and Burkitts Lymphoma Is Feasible and Gives a High Response Rate: Preliminary Results Of a Phase 2 UK National Cancer Research Institute Trial

IntroductionR-CHOP is the standard of care for patients with diffuse large B cell lymphoma (DLBCL) however poor risk patients (IPI 3-5) still have an inadequate outcome. Neither first remission high dose chemotherapy and peripheral blood stem cell transplantation (HDC+PBSCT) nor selection of cases for intensification by interim PET scanning have demonstrated a proven benefit. In the case of Burkitts lymphoma (BL) there is a paucity of data on the addition of Rituximab to the CODOX-M and IVAC regimen. Patients and Methods113 patients with DLBCL and 37 with BL were recruited from 53 UK sites between May 2008 and April 2013. Median age was 49 years (18-65). For DLBCL patients IPI scores were 3 – 72 ( 64%), 4 -40 (35%) and 5 – 1 (1%). All patients received the modified CODOX-M and IVAC regimen including all CNS directed therapy( Mead et al Ann Oncol. 2002 Aug;13(8):1264-74) and 8 doses of rituximab. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included toxicity and CR rate. ResultsThe main toxicities reported were neutropenia ( 89% grade 3 or 4), thrombocytopenia (84.2% grade 3 or 4), infection 61.6% grade 3 or 4 and mucositis (30.1% grade 3 or 4). 4 patients were excluded from toxicity assessment as they did not start therapy after registration. There were 8 treatment related deaths observed (infection with neutropenia (5), GI haemorrhage (1), acute cerebral haemorrhage (1) and bowel perforation (1) ). 78 patients with DLBCL and 31 with BL have completed all therapy ( 78.5 % of patients with available data) with an overall response rate of 92 % for DLBCl and 94% for BL. In patients who completed all therapy CR was achieved in 34 (44%), CR (u) in 8 (10%) and PR in 30 (38%) for DLBCL patients and CR was achieved in 21 (68%), CR (u) in 6 (19%) and PR in 2 (6%) in BL patients. 3 patients ( 2 DLBCL and 1 BL) who progressed during therapy have been included in the response analysis. End of treatment PET scanning was not obligatory. 80 patients with DLBCL and 30 patients with BL remain alive and without progression at a median follow up of 18.6 and 19.3 months respectively. ConclusionThe R-CODOX-M -R-IVAC regimen can be delivered to patients with poor risk DLBCL in a multicentre setting. High rates of haematological toxicity and consequent infection are inevitable with treatment of this intensity but appear acceptable when compared with other treatments such as HDC+PBSCT. Response rates are encouraging in view of the very poor risk IPI profile of the patients included in this study. Burkitts lymphoma patients also achieved an excellent response rate with no apparent additional toxicity attributable to the addition of rituximab to the regimen. We currently plan the first analysis for the primary endpoint of PFS in 2015.The Trial was supported by Leukaemia and Lymphoma Research (LLR). Disclosures:McMillan:Roche: Consultancy, Honoraria; Amgen: Research Funding. Off Label Use: Rituximab usage in Burkitts Lymphoma. Ardeshna:Roche: Honoraria, Research Funding. Jack:Roche/Genentech: Research Funding. Patmore:Roche: Consultancy, Honoraria. Pettengell:Roche: Honoraria; Amgen: Honoraria. Linch:Roche: Honoraria, Research Funding.

Comparison Of R-CHOP14 and R-CHOEP14 As First Line Treatment In Young Patients With High-Risk (aaIPI 2-3) Diffuse Large B-Cell Lymphoma (DLBCL): A Joint Analysis Of Two Prospective Phase III Randomized Trials Conducted By The Fondazione Italiana Linfomi (FIL) and The German High-Grade Lymphoma Study Group (DSHNHL)

IntroductionThe prognosis of young DLBCL patients at high risk treated with standard R-CHOP is still rather poor. With the aim to improve outcome of these patients the Italian (Vitolo U et al, Blood, ASH annual Meeting 2012) and German (Schmitz N et al, Lancet Oncology 2012:13,1250) cooperative study groups conducted two randomized phase III studies aimed to compare conventional chemotherapy with intensified chemotherapy with stem cell support both in combination with Rituximab (R). The standard reference arms were R-CHOP14 in the Italian and R-CHOEP14 in the German study. No randomized studies comparing R-CHOP14 and R-CHOEP14 exist. Therefore, FIL and DSHNHL did a joint analysis of the two randomized trials, with the aim to compare the two conventional arms R-CHOP14 and R-CHOEP14. Patients and MethodsThe primary endpoint of this joint analysis was to compare the progression free survival (PFS) of DLBCL patients treated with R-CHOP14 or R-CHOEP14 within the two prospective trials. Inclusion criteria were superimposable for the two studies as follows: age 18-60 years; untreated CD20+ DLBCL or follicular lymphoma grade IIIb; age-adjusted IPI (aa-IPI) score 2 or 3. FIL patients were treated with R-CHOP14 for 8 courses; DSHNHL patients were treated with R-CHOEP-14 for 8 courses. Involved-field radiotherapy (IF-RT) for patients with extranodal sites or with bulky disease was based on the investigator choice in the FIL trial and was mandatory in the DSHNHL study. Central nervous system prophylaxis was done in patients at risk for CNS recurrence. Response criteria used were the same in both studies (Cheson 1999). ResultsFrom June 2005 to September 2010 100 patients were enrolled in the FIL study and treated with R-CHOP14. From March 2003 to April 2009, 130 patients were enrolled in the DSHNHL study and treated with R-CHOEP14. All 230 patients were included in the present analysis. Clinical characteristics were: median age 49 (IQR 38; 55); stage III/IV 96%; LDH > normal 93%; ECOG PS >1 38%; aa-IPI score 2/3 74/26%; extranodal sites >1 41%, bulky disease 50% and bone marrow (BM) involvement 16%. All characteristics were well balanced between patients treated with R-CHOP14 or R-CHOEP14 with the exception of significantly more patients with elevated LDH and bulky disease in the R-CHOEP14 group (98% vs 87%; 59% vs 37%) and more patients with PS >1 in the R-CHOP14 group (45% vs 32%). IF-RT consolidation was less frequently used in the R-CHOP14 group (16% vs 74%). Median follow-up times were: 47 (R-CHOP14) and 42 (R-CHOEP14) months. Patients treated with R-CHOP14 had a 3-year PFS of 63% (95% CI:52-71%) compared to 74% of those treated with RCHOEP14 (95% CI:65-81%); p = .177 (Figure 1). In a Cox model for PFS including treatment arm, age, gender, aaIPI, extranodal sites, bulky disease and BM involvement the adjusted HR was 0.68 (95% CI: 0.42-1.2) in favor of RCHOEP14, but this difference was not significant (p = .128). The analysis of the role of consolidation IF-RT is ongoing. ConclusionsThis analysis comparing R-CHOP14 and R-CHOEP14 as standard arms in two prospective trials suggests that RCHOEP14+RT has high activity in young poor-risk DLBCL. To confirm these encouraging findings, a formal joint FIL/ DSHNHL randomized study comparing R-CHOEP+RT vs R-CHOP+RT +/- novel drugs is planned by the two cooperative groups. [Display omitted] Disclosures:Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Prognostic Value of Interim PET/CT in Patients with Poor Risk Diffuse Large B-Cell Lymphoma (DLBCL). Experience of the Spanish Geltamo Group

AbstractAbstract 5076 Background:Interim FDG-PET appears to be useful to guide risk stratification of patients with DLBCL, but remains controversial because the absence of consensus criteria for assessment. The reduction of maximum Standardized Uptake Value (SUVmax) between baseline and interim PET improves the accuracy and reproductibility of this method (Casasnovas, Blood 2011). Patients and Methods:A prospective non randomized phase II trial (EudraCT:2006-005254-68) was undertaken in young patients (pts) newly diagnosed of poor risk DLBCL. Therapy was changed after 3 cycles of R- MegaCHOP based on PET (using local assesment and visual scale); pts with positive PET received early salvage therapy. Primary end points were Progression free survival (PFS) and Overalll survival (OS). Retrospectively, central review was done by three experts using visual assessment (Deauville criteria) and semiquantitative asessment. Baseline and interim SUVmax, and ΔSUVmax were evaluated (cutt off ΔSUVmax: 66%). Significance of PET parameters in OS was analyzed. Results:71 pts were enrolled and central review was possible in 50 pts, from which 80% have complete follow up (mean 37, 6 months, 3. 4–56. 4). OS was significantly influenced by interim PET result, using visual (p=0. 046) but mainly by semiquantitative analysis (p=0. 0008). ΔSUVmax had impact on the overall survival (p=0. 007) whereas basal SUVmax did not. Conclusions:Our preliminary results show that outcome of DLBCL pts with a positive interim PET is worse despite change of therapy. Semiquantitative PET evaluation seems to be necessary, being ΔSUVmax a good prognostic parameter. Disclosures:No relevant conflicts of interest to declare.

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

PILLAR-2: A randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus in poor-risk diffuse large B-cell lymphoma (DLBCL).

TPS8118 Background: Effective DLBCL adjuvant therapy after first-line chemotherapy is needed as high-risk DLBCL is associated with a poor 4-year overall survival (OS) rate (Sehn et al, Blood 2007;109:1857-61). In a phase II study of the oral mammalian target of rapamycin inhibitor everolimus in relapsed, aggressive non-Hodgkin lymphoma, DLBCL patients (n=47) had a 30% overall response rate (Witzig et al, Leukemia 2011;25:341-7). Methods: PILLAR-2 is an ongoing international, randomized, double-blind, phase 3 study designed to compare everolimus efficacy and safety with that of placebo in poor-risk DLBCL patients who achieved complete response (CR) with first-line rituximab-based chemotherapy (R-chemo) (ClinicalTrials.gov: NCT00790036; sponsor: Novartis Pharmaceuticals). Eligibility criteria include age ≥18 years; confirmed stage II bulky, III, or IV DLBCL and International Prognostic Index 3-5 at diagnosis; confirmed CR per revised International Workshop Response Criteria for malignant lymphoma (Cheson et al, J Clin Oncol 2007;25:579-86) after first-line R-chemo regimen completed 6-14 weeks before study drug start; Eastern Cooperative Oncology Group performance status ≤2; no ongoing or post–R-chemo radiation; and no myelosuppressive chemotherapy or biologic therapy within 3 weeks. Patients are randomized 1:1 to everolimus 10 mg once daily or matching placebo and treated for 12 months or until disease relapse, unacceptable toxicity, or death. Radiologic tumor assessment is performed at baseline, every 12 weeks during years 1 and 2, every 24 weeks during years 3 and 4, and annually thereafter until start of new anticancer therapy or 5 years after last patient randomization. The primary endpoint is disease-free survival (DFS). Secondary endpoints are OS, lymphoma-specific survival, and safety. Expected enrollment is 687 patients. Final analysis will be performed when 279 DFS events occur; survival follow-up will continue until 338 deaths occur and the last randomized patient has been followed for ≥5 years. Currently, 422 patients are enrolled. The data monitoring committee last reviewed the trial in July 2011 and recommended that it continue as planned.

Prox1 Suppressed Tumor Cell Growth by the Down Regulation of PKCβII Through the DNA Methylation

Abstract 5227 BACKGROUND:The homeobox gene Prox1 is a transcription factor related to the Drosophila prospero gene and known to be the master gene which controls the development of lymphatic vasculature. Recent studies have suggested that Prox1 is a strong candidate tumor suppressor gene in several kinds of malignancies. We previously demonstrated that the expression of Prox1 gene was frequently silenced by aberrant DNA methylation in about 60% of diffuse large B cell lymphoma (DLBCL). In this study, we showed that Prox1 regulated Protein Kinase C beta II (PKCβII) expression, which was overexpressed in poor risk DLBCL, and analyzed the inhibitory mechanism of tumor suppression by Prox1. METHODS and RESULTS:We established the Prox1 stable transformants of Hela cells which originally lacked Prox1 expression, and examined them in vitro cell proliferation and in vivo tumor formation using nude mice. Our experiments showed that Prox1 had inhibitory effect on both cell proliferation and tumor formation. cDNA microarray analysis indicated that the expression of PKCβII was highly suppressed by Prox1 overexpression. In Prox1-expressing Hela cells, mRNA expression of PKCβII was undetectable and protein was significantly down-regulated compared with Mock cells. The selective PKCβII inhibitor, enzastaurin was less effective on cell proliferation of Prox1-expressing cells compared with Mock cells. These results showed that PKCβII was required for tumor cell proliferation. We focused on the regulatory mechanism of PKCβII expression by Prox1. The 5’-promoter analysis of PKC-β gene revealed that the proximal region between 110bp of the promoter containing 2 Sp1 binding sites was responsible for the endogenous promoter activity, and Prox1 did not affect that. Mithramycin A, a relatively specific Sp1 inhibitor, and Sp family knockdown by siRNA on Hela cells decreased PKCβII expression, suggesting that Sp family was important for PKCβII transcription. Interestingly, 5-aza-deoxycytidine (5-Az) treatment restored PKCβII mRNA expression in Prox1-expressing Hela cells, suggesting that 5’-promoter region of PKCβII was methylated in these cells. Actually, bisulfite sequencing showed that the predicted CpG island of PKC-β gene, especially around these Sp1 binding sites, was highly methylated in Prox1-expressing Hela cells compared with Mock cells and 5-Az relieved DNA methylation. CONCLUSION:Our study suggested that the decreased PKCβII expression suppressed tumor cell proliferation and Prox1 down-regulated PKCβII expression by enhancing DNA methylation of PKC-β 5’-promoter around Sp1 binding sites. This is the first to report the inverse relationship between Prox1 and PKCβII expression in cancer cells and the novel regulatory mechanism of PKC-β gene expression by Prox1 transcription factor. Disclosures:No relevant conflicts of interest to declare.

Biweekly rituximab, cyclophosphamide, vincristine, non‐pegylated liposome‐encapsulated doxorubicin and prednisone (R‐COMP‐14) in elderly patients with poor‐risk diffuse large B‐cell lymphoma and moderate to high ‘life threat’ impact cardiopathy

This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high ‘life threat’ impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73 years, range: 62–82; 37% >75 years) at a median interval of 15·6 (range, 13–29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n = 3), therapy discontinuations (no-response n = 2; toxicity n = 6), relapse (n = 6) and death in CR (n = 3). Incidence of cardiac grade 3–5 adverse events was 7/41 (17%; 95% confidence interval: 8–31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P = 0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P = 0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.

Non-pegylated liposomal doxorubicin (Myocet®) in patients with poor-risk aggressive B-cell non-Hodgkin lymphoma

The incidence of non-Hodgkin lymphomas increases with age. Non-pegylated liposomal formulations of doxorubicin (Myocet®) reduce systemic and cardiac toxicity especially in the elderly, who often have cardiac diseases. We treated 80 patients (mean age 70.9 years) with poor-risk diffuse large B-cell lymphoma with the R-COMP 21 regimen (Myocet® 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, rituximab 375 mg/m2, prednisone 100 mg/day). In all, 82.5% and 13.7% patients showed complete and partial responses, respectively. Sixty-two of the 80 patients are alive and disease-free (77.5%), while 3/80 are alive with active disease and 15 patients (18.7%) have died (median follow-up: 31 months). The estimated probability of overall survival at 12/24 months from admission was 93.5/87.3%, respectively. There were no therapy-related cardiac events and the ejection fraction improved (from 51.6 ± 6.9% to 54.2 ± 3.9%). Grade 3–4 neutropenia occurred in 22% of patients. We concluded that Myocet® shows both efficacy and tolerability, mainly at the cardiac level.

Quality of life in 269 patients with poor-risk diffuse large B-cell lymphoma treated with rituximab versus observation after autologous stem cell transplant

We aimed to assess quality of life (QoL) following front-line autologous stem cell transplant (ASCT) and the QoL relationship with rituximab maintenance, in patients with diffuse large B-cell lymphoma. Patients were then randomized to either one weekly rituximab injection for 4 weeks, or observation alone. Patients (n = 269) were given the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaires. Scales for all symptoms exhibited similar temporal patterns, with a marked increase, followed by a plateau after 1 year. The proportion of patients with a clinically significant improvement varied from 6% (constipation) to 56% (fatigue). Age, gender, and previous treatment-induced toxicities were not predictive of variations in QoL. Rituximab significantly reduced pain and symptom severity. Our results for QoL showed that patients experienced rapid recovery after ASCT in all the domains tested. Differences in QoL improvement with time were not connected with rituximab maintenance.

Novel agents for diffuse large B-cell lymphoma

Introduction: Although diffuse large B-cell lymphoma (DLBCL) is commonly considered as a cancer with a high cure rate with conventional therapies recent studies demonstrate that different biological variants of DBLCL exist, and that patients with one DLBCL variant and DLBCL patients who relapse early following rituximab-based therapy have markedly poorer outcomes with conventional management strategies. Over the last decade, there has been an increasing exploration of novel therapies derived from improved understanding of DLBCL biology and tumor–host interactions.Areas covered: This review examines the biological basis for novel therapeutic approaches in DLBCL and the early clinical data on compounds derived from this research. A description of the expanding options of novel agents and combination therapies for patients with poor risk DLBCL is provided.Expert opinion: Several promising novel agents and novel therapeutic combinations are under development for patients with poor risk DLBCL. Carefully designed clinical trials that build on our improved understanding of DLBCL biology and utilize tissue samples to examine the activity of novel combination therapies should expand treatment options for DLBCL patients in the future.

Post-ASCT Consolidative Immunotherapy with RITUXIMAB, rINF-a2b and rIL2 In Poor-Risk DLBCL: Results of a Phase II Study

AbstractAbstract 3558 Introduction:A minority of patients with diffuse large B cell lymphoma (DLBCL) can really be cured and the early or late relapse rate remains a subject of major concern. The occurrence of disease relapse, even in patients with documented complete remission (CR), is thought to be induced both by resistant minimal residual tumor cells and the lack of immunocompetent mechanisms to eradicate them. Thus, it has been postulated that post-autologous stem cell transplantation (ASCT) consolidative immunotherapy might eradicate minimal residual disease and, therefore, reduce relapse rate and even improve overall survival (OS). This view has led to a considerable interest in immunotherapy as a promising therapeutic line to restore and enhance the impaired anti-tumor immune surveillance in the setting of post-ASCT low tumor burden. Purpose:We conducted a phase II study to compare OS, relapse-free survival (RFS), death rate and overall relapse rate between patients with poor-risk DLBCL receiving consolidative immunotherapy combining recombinant interleukine-2 (rIL-2), recombinant interferon-α-2b (rINF-α-2b) and Rituximab after ASCT, with the aim of controlling minimal residual disease, and other patients with poor-risk DLBCL treated with ASCT alone. Patients and Methods:On 180 patients, 27 with DLBCL from Brest, autografted in complete remission (CR) ≥ 1 or partial remission (PR), were considered eligible for the study. They received, on adequate post-ASCT hematologic reconstitution, 4 weekly IV injections of Rituximab administered on an outpatient fashion. This was followed by a home-based program of subcutaneous injections of rIL2 (6 million UI × 3/week in 1st cycle; 9 million × 3/week in 2d) and rINF-α-2b (1.5 million UI × 3/week in 1st cycle; 3 million × 3/week in 2d) administered over two 7-week cycles. These two cycles were separated by a two-week free interval. One hundred and fifty three patients from Brest, Lille and Tours did not receive any additional treatment after ASCT and served as controls. Results:The two groups were comparable, except for age, which was older in the study group (p=0.018) and for pre-ASCT response pattern, which was better in the control group. There was no influence of recruitment center, sex, disease Ann Arbor stage, IPI score, RITUXIMAB administration before ASCT, graft source or ASCT conditioning regimen on the final results. Median OS and RFS were not reached in any group and are still under study. The median follow-up was 54.9 months in the study group and 48.8 months in the control group. In univariate analysis, the prevalence of death rate was 7.4% and 26.2% in the study group and the control group, respectively (OR = 0.23, 95%CI [0.05-0.99], p=0.03), and the overall relapse rate was 11.1% (3 patients) and 22.9% (35 patients), respectively (OR=0.42, 95%CI [0.12-1.48], p=0.17). In multivariate analysis, the risk of death was significantly decreased (OR 0.196; 95%CI [0.046-0.827] p=0.027) and there was a trend toward a decreased relapse rate (OR 0.348; 95%CI [0.104-1.168], p=0.088) in the study group compared to the control group. In addition, older age was independently associated with an increased risk of death (OR=1.053, 95%CI [1.02-1.09], p=0.002).Adverse events were generally mild, consisting essentially of fever and chills with the rIL-2 and rINF-α-2b subcutaneous injections responding well to PARACETAMOL, fatigue, grade 2 abnormal liver function tests in one third of patients, grade 3 neutropenia in 45% of patients and hypothyroidism in one patient. Conclusion:We found that post-ASCT immunotherapy with rIL2, rINF-α-2b and RITUXIMAB has a statistically significant favorable impact on death rate and a positive, although not statistically significant, effect relapse rate. In view of its toxicity profile, it appears to be quite feasible and safe and might be considered as a promising line of treatment designed for post-ASCT minimal residual disease and worth being evaluated within the frame of a prospective randomized trial. Disclosures:No relevant conflicts of interest to declare.

Quality of life in 269 poor-risk diffuse large B-cell lymphoma patients treated with rituximab versus observation after front-line auto transplantation: The GELA LNH98-3 randomized trial.

8082 Background: Little is known about the longitudinal course of health-related quality of life (QoL) in DLBCL patients during their post-treatment follow-up. We report on the QoL of patients trea...

Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma

BackgroundThis study compared the induction regimens doxorubicin, cyclophosphamide and etoposide (ACE) with doxorubicin, cyclophosphamide, vincristine, bleomycin and prednisone (ACVBP) before high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) for patients with poor-risk diffuse large B-cell lymphoma (DLBCL). A second randomisation compared rituximab with observation post-ASCT. Materials and methodsFour hundred and seventy-six patients <60 years old with newly diagnosed CD20+ DLBCL were randomised to induction with ACE or ACVBP. Three hundred and thirty responders received HDT followed by ASCT. After ASCT, 269 patients were re-randomised to receive either maintenance rituximab or observation alone. Randomisation was stratified by the quality of response to ASCT. The primary end point of this study was event-free survival (EFS). ResultsAt a median of 4 years’ follow-up from the second randomisation, there was a trend (P=0.1) towards increased EFS for patients who received rituximab compared with observation. ConclusionThe type of induction therapy (ACVBP or ACE) did not significantly affect overall survival at a median 51 months’ follow-up.

Biweekly Rituximab, Cyclophosphamide, Vincristine, Non-Pegylated Liposome-Encapsulated Doxorubicin (Myocet®) and Prednisone (R-COMP-14) as Induction Treatment in Poor R-IPI Risk Elderly Patients with Diffuse Large B-Cell Lymphoma (DLBCL) and Pre-Existing Heart Disease.

Abstract 1664Poster Board I-690 BackgroundDelivering of dose-dense R-CHOP represents a critical factor for improving response rate and survival outcomes in poor risk DLBCL patients (pts) but it may turn a very challenging goal to achieve in elderly pts with severe cardiac comorbidities. In this subset of pts, tachyarrhythmias, conduction disturbances, ventricular dysfunction, and a pericarditis-myocarditis syndrome, may occur during or immediately after the administration of doxorubicin hydrochloride, independently from total cumulative dose. This may lead to early treatment discontinuation and even death, strongly hampering the chance of receiving adequate chemotherapy. We have conducted a pilot study first exploring the feasibility of a dose-dense biweekly R-CHOP-like regimen including non-pegylated liposome-encapsulated doxorubicin in elderly pts at a high risk for both disease presentation and cardiac conditions. Liposomal anthracyclines, beyond the potential of a more selective uptake by lymphoma cells, may broaden the feasibility of a dose-effective treatment through a reduction of early and late cardiotoxicity. Patients and MethodsUntreated pts with poor R-IPI risk DLBCL and moderate to high ‘life threat' impact cardiopathy (NIA/NCI index) were scheduled to receive six courses of a R-COMP-14 regimen in which an equal dose (50 mg/sqm) of non-pegylated liposome-encapsulated doxorubicin (Myocet®) was substituted for doxorubicin hydrochloride within the R-CHOP platform. Treatment was given every two weeks with G-CSF support. Responses and endpoints were evaluated according to the International Harmonization Project with treatment failure defined as discontinuation of R-COMP-14 for any reason (e.g., disease progression, toxicity, initiation of new treatment without documented progression, or death). ResultsThirty-seven pts, median age 72 years (r, 62-82) with pre-existing heart disease [history of myocardial infarction (n=10), atrial fibrillation (n=8), valve disease (n=6), conduction disturbances (n=9), hypertensive cardiomyopathy (n=4)] and R-IPI score ≥ 3, were accrued in this prospective study. Thirty-three pts were in advanced stage [stage IV (n=25) + stage III (n=8): 89%], 18 (49%) had B symptoms, 29 (78%) displayed abnormal LDH and 11 (30%) presented involvement of > 2 extra nodal sites. According to Charlson, median Comorbidity Index and Score were 5.5 (r, 2-8) and 8.5 (r, 5-11), respectively. Pre-treatment left ventricular ejection fraction (LVEF) ranged between 42% and 67% (median, 57%). One-hundred eighty-four total courses were delivered (median 6, range,1-8). The median time to recycling was 15.9 days (r, 13-29) and 67% of pts received the 6 scheduled courses. Hematologic toxicity was tolerable, with CTCAE v3.0 G3/G4 thrombocytopenia and G3/G4 infections being recorded in 6 (16%) 5 (12%) pts, respectively. Seventeen failures were documented; they were due to progression (n=2), early death (n=3), treatment discontinuation (n=6) and disease recurrence (n=6). Early deaths occurred at day +12, +13 of the 1st course and day + 18 of the 2nd course, accounting for a treatment mortality rate of 8%. Treatment was discontinued because of a > 15% reduction in LVEF occurring at the 3rd and 4th courses (n=3) and the occurrence of symptomatic arrhythmia (n=3). The overall response rate was 71 % (95% CI: 53-84) with 24 complete responses and 2 partial responses. Time to Treatment Failure and Time to Progression at 28 mo.s were 51% and 63%, respectively. Disease Free Survival was 69% at a median follow-up of 14 mo.s. DiscussionThe present study documented the attractive therapeutic potential of the R-COMP-14 regimen in the setting of poor-risk elderly DLBCL pts with moderate and high impact cardiac comorbidity, in terms of both response rate and time to progression. Survival endpoints were more than satisfactory in a such unfavourable cohort of subjects for which treatment recommendations are still controversial, also due to lack of international guidelines on cardioprotective agents and strategies. Although cardiac events have occured in a fraction of pts, very early and independently from cumulative doses, they did not substancially affect the feasibility of the regimen, provided that a close clinical monitoring was ensured. R-COMP-14 represents an active dose-dense therapeutic platform for pts with cardiac comorbidity. DisclosuresNo relevant conflicts of interest to declare.

Rituximab compared to observation after high-dose consolidative first-line chemotherapy (HDC) with autologous stem cell transplantation in poor-risk diffuse large B-cell lymphoma: Updated results of the LNH98-B3 GELA study

8012 Background: Rituximab has been evaluated as a single agent and also in combination with chemotherapy in aggressive and indolent lymphomas with evidence of efficacy. More recently, rituximab maintenance therapy has been successfully used to keep responding patients in remission. We have shown that consolidative HDC improves outcome of poor risk responder-patients (pts) with aggressive lymphoma. Methods: The aim of the present study was to evaluate the potential benefit, as randomly compared to observation, rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1-d3) as compared to the standard ACVBP induction regimen (R1). Four cycles were delivered every 15 days. In responding pts, HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 × 4d, etoposide 250 mg/m2 × 4d and carmustine 300 mg/m2) was started between d80 and d90. Results: From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. 237 pts were assigned to ACE and 239 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively). Death rate during induction phase was 4% in both arms. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two severe VZV infections. With a median follow-up of 4 years after R2, a trend toward a better 4y-EFS was observed in the rituximab group (80% vs 71%, p=0.098). In addition, a two-sided log-rank test stratified by aa-IPI, induction treatment and response after HDC was performed and confirmed the results of the unstratified analysis. Conclusions: We conclude that early and brief rituximab maintenance is feasible after HDC and may prolong remission status. [Table: see text]