ALBERT

Description: Key Points TP53 3′UTR variations demonstrate prognostic value in DLBCL.

Description: Objective :To evaluate the prognostic significance of RELamplification, expression and c-Rel activation in DLBCL patients and to identify potential mechanisms for impact of c-Rel activation on patient survival. Patients and Design : The study cohort consists 460 de novo DLBCL patients (median follow-up, 46.8 moths) treated with R-CHOP. We assessed the nuclear expression/activation of c-Rel and other NF-κB subunits by immunohistochemistry, REL gene amplification by fluorescence in situ hybridization, and gene expression profiling using Affymetrix GeneChips array. Correlations between expression of nuclear c-Rel, REL mRNA, and expression of TP53, MDM2, MDM4, MYC, BCL2, AKT1, NFKB1, RELA, NFKB2, and RELB, both at the mRNA and protein levels were analyzed using t-tests. The prognostic significance of c-Rel activation, REL mRNA expression, and REL amplification was evaluated in the overall cohort, and different subgroups stratified by COO, status of TP53 mutation (wide type/WT, or mutated/MUT) and expression, Myc, Bcl-2 overexpression, and nuclear expression of other NF-κB subunits. Results :Nuclear c-Rel expression was observed in 29.6% of DLBCL patients and did not correlate with REL mRNA levels (P=0.95) and COO (P=0.77). In contrast, REL mRNA was significantly higher in germinal center B-like (GCB) subtype (P

Description: Context and objective Approximately 5-10% of diffuse large B-cell lymphoma (DLBCL) patients carry MYC gene translocations (MYC-translocation+) with a poor prognosis after standard chemotherapy. MYC-translocation+ DLBCL patients carrying BCL2 translocations (MYC+/BCL2+ double-hit lymphoma) have a worse survival. The efficacy of adjuvant radiotherapy in this setting is unknown. The purpose of this study is to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL. Patients and methods From the International DLBCL R-CHOP consortium program, we selected 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy (diagnosed and treated from 2000 to 2010). We excluded patients with transformed DLBCL, primary mediastinal, cutaneous, testicular or central nervous system large B-cell lymphomas, patients with HIV infection, and patients not treated with R-CHOP. The median follow-up was 54.9 months. Fluorescence in situ hybridization assessing MYC was performed for all the patients (n=581) and results were correlated with available clinical data to identify clinicopathologic features associated with MYC translocation, and to evaluate the prognostic significance of MYC translocations regarding overall survival (OS, from the time of diagnosis to death from any cause) and progression-free survival (PFS, from the time of diagnosis to relapse or death from any cause). In the MYC-translocation+ DLBCL group, 38 patients received chemotherapy alone and 21 patients received chemotherapy with adjuvant radiation therapy. The clinicopathologic features and survival of MYC-translocation+ DLBCL patients treated with (n=21) and without radiotherapy (n=38) after immunochemotherapy were compared to in order to evaluate the radiotherapy efficacy and other confounding factors. Results MYC translocations were detected in 59 DLBCL patients (10.2%). Patients with MYC-translocation+ DLBCL more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.20 - 3.35, P= .0083) and PFS (HR: 1.96, 95% CI: 1.22 - 3.13, P= .0005) independent of the International Prognostic Index score. Poor survival was primarily attributable to patients with MYC+/BCL2+ double-hit DLBCL who were predominantly of germinal center B-cell subtype. Among MYC-translocation+ DLBCL patients, a better survival was achieved in patients who received radiotherapy (for OS, HR: .32, 95% CI: .15 - .71, P= .0049; for PFS, HR: .35, 95% CI: .17 - .73, P= .0043). Conversely, radiotherapy abolished the adverse impact of MYC translocations. In addition, radiotherapy was associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma (P = .017 for OS, and P = .05 for PFS). However, owing to the common use of radiotherapy as consolidation therapy, the favorable prognoses in the group of patients who received radiotherapy could also be attributed to limited-stage disease and more frequent complete remission (CR) after first-line treatment and therefore these factors confound interpretation of the data. To address these issues, we evaluated radiotherapy efficacy in separate patient groups: patients who achieved CR, non-CR (PR/SD/PD) patients, and patient with stage I/II, or stage III/IV disease. The efficacy of radiotherapy appeared more apparent in patients with advanced disease who did not achieve CR after first-line chemotherapy. Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 - .80, P= .015) of MYC-translocation+ DLBCL patients. Conclusions The presence of MYC translocations in DLBCL is an important biomarker that facilitates prognostic prediction and treatment stratification independent of the IPI score. For chemoresistant MYC-translocation+ DLBCL patients, radiotherapy seems to be an effective adjuvant regimen likely due to the higher frequency of extranodal involvement and bulky disease in MYC-translocation+ DLBCL patients. Our results provide a rationale for larger scale studies to assess the potential role of radiotherapy in the management of MYC-translocation+ DLBCL patients, particularly patients with MYC+/BCL2+double-hit DLBCL. Disclosures: Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.

Description: Abstract 949 Introduction: Diffuse large B cell lymphoma (DLBCL) has a highly variable outcome, and individual risk assessment is largely based on clinical features. Gene expression profiling (GEP) stratifies patients into those with germinal center B-cell (GCB) and activated B-cell subtype (ABC) subtype with different prognoses. These groups have been shown to predict prognosis in patients treated with CHOP or R-CHOP. Conversely, the role of other recognized prognostic markers, such as BCL2 gene abnormalities or Bcl2 expression has been questioned in the new therapeutic era. Materials and Methods: In 438 patients treated with R-CHOP for de novo DLBCL, we analyzed the tumors by immunohistochemistry for Bcl2 protein expression and by interphase fluorescence in situ hybridization (FISH) for BCL2 translocation and other abnormalities. All cases were successfully studied by GEP. The cutoff for Bcl2 protein expression, 60%, used as prognostic factor was determined using receiver operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were assessed. Results: The t(14;18)(q32;q21) was detected in 82 cases (18.7%) and BCL2 gains occurred in 63 cases (14.3%). Both t(14;18) and BCL2 gains strongly correlated with higher levels of Bcl2 protein expression (p

Description: Abstract 3601 Richter syndrome (RS) represents the development of diffuse large B-cell lymphoma (DLBCL) in the context of chronic lymphocytic leukemia (CLL). Despite the availability of clinical predictors, the identification of RS patients projected to experience long survival represents an unresolved issue that may benefit from the development of novel RS prognosticators. The study was based on 86 RS classified as DLBCL after pathological review. Clonal relationship between CLL/RS pairs was assessed by immunoglobulin gene analysis. RS was clonally related to the CLL phase in 49/59 (83.1%) cases, and clonally unrelated in 10/59 (16.9%). In 27 cases, clonal relationship remained undetermined because of unavailability of paired CLL samples. Out of the molecular features investigated, the prevalence of TP53 disruption by mutations and/or deletion was significantly higher in clonally related RS (23/36, 63.9%) compared to clonally unrelated cases (1/8, 12.5%) (p=.015). Among immunogenetic features, usage of stereotyped VH CDR3 occurred in 25/49 (51.0%) clonally related RS, while was very rare among clonally unrelated cases (1/10, 10.0%) (p=.032). The difference in stereotyped VH CDR3 frequency occurred irrespective of IGHV gene mutation status. All clonally unrelated RS tested negative for EBV infection and none received alemtuzumab before DLBCL development. Clonally related and clonally unrelated RS were indistinguishable in terms of clinical features at presentation. However, RS survival was significantly shorter in clonally related (median: 14.2 months) versus clonally unrelated cases (median: 62.5 months) (p=.017) (Fig. 1A). This survival difference was observed even though clonally related RS received SCT in 8/48 (16.7%) cases, while clonally unrelated RS received in all cases conventional chemotherapy without SCT consolidation. Other variables that were associated with poor RS survival were TP53 disruption (p60 years (p=.005), ECOG PS 〉1 (p5 cm (p=.001), platelets 1.5 ULN (p=.002), and having received SCT (p=.027). None of the pathologic features of DLBCL diagnostic biopsies correlated with RS prognosis. After adjusting for clinical variables associated with RS survival, diagnosis of clonally unrelated RS translated into a 80% reduction in risk of death when compared to clonally related RS (HR: 0.22; p=.036). By recursive-partitioning analysis, clonal relationship, TP53 disruption and ECOG PS were the major determinants of RS survival, and classified RS patients according to risk of death (Fig. 1B). All clonally unrelated RS displayed a low risk of death (median survival 62.5 months; 95% CI: 33.7–91.3), irrespective of TP53 disruption and ECOG PS (Fig. 1B; Group 1). Among clonally related RS and RS with undetermined clonal relationship, patients presenting with ECOG PS ≤1 and no TP53 disruption had a low risk of death (median survival: 55.4 months) (Fig. 1B; Group 2). Patients presenting with ECOG PS ≤1 in the presence of TP53 disruption had an intermediate risk of death (median survival: 27.0 months) (Fig. 1B; Group 3). Patients presenting with ECOG PS 〉1 had a high risk of death, irrespective of TP53 disruption (median survival: 7.8 months) (Fig. 1B; Group 4). Based on c-statistics, the model including clonal relationship, ECOG PS and TP53 status had a 90% probability of correctly discriminating a priori RS survival (c-statistic=.90±.07). These observations suggest that clonally related and clonally unrelated RS are biologically and clinically distinct disorders, and that clonally unrelated RS should be considered as a secondary DLBCL arising de novo in the context of CLL, rather than a true RS. Therefore, we propose that the diagnosis of RS should be restricted to clonally related cases. Disclosures: No relevant conflicts of interest to declare.

Description: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin Lymphoma. Although a typical presentation as an indolent lymphoma, without systemic symptoms and with a good performance status, the mantle cell lymphoma is an aggressive one, hardly curable with standard chemo-immunotherapy. Although current approaches to mantle cell lymphoma, including newer agents (such as bortezomib, lenalidomide, temsirolimus and ibrutinib) and autologous stem cell transplantation, have greatly improved the outcomes of affected patients, this disease is still characterized by high relapse rates, with most patients eventually dying of lymphoma progression. Before official approval by EMA, patients with relapsed/refractory mantle cell lymphoma with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program in Italy (NPP, DM 8 May 2003). This observational, non-interventional, retrospective, multicenter study focuses on collecting information about the effectiveness and safety of ibrutinib as single-agent in patients who received at least one dose of ibrutinib under the NPP in the period between 29/Jul/2014 and 25/Jan/2015 in Italy. Data from patients treated with ibrutinib outside a controlled clinical trial within a NPP could give additional information about the clinical use, treatment duration, efficacy and toxicity of ibrutinib given to relapsed or refractory MCL patients in a real life context. Fifty-three heavily pretreated patients were enrolled. They had received a median of previous therapies of 3, comprising lenalidomide, bortezomib, temsirolimus and autologous stem transplant. Ninety-one percent had measurable disease and 83.0% had and ECOG performance status ≤2. At the end of therapy there were 11 complete responses (20.8%), 7 partial responses, 5 stable diseases and 30 progressions with an overall response rate of 33.9%. Twenty-six patients received ≥3 concomitant medications during ibrutinib therapy. At 20 months overall survival (OS) was 26.8% (median reached at 9 months) and disease free survival (DFS) 75% at 15 months: 10/11 patients are in continuous complete response with a median of 10.5 months. Hematological toxicities were manageable, 6 thrombocytopenia occurred, of which only 2 grade 4 (due to disease bone marrow infiltration) and the other 4 related to ibrutinib. Main extra-hematological toxicities were diarrhea (9.4%) and lung infections (7.5%) which all lead to early drug discontinuation. The observed occurrence of diarrhea by severity was 0 for CTCAE Grade 1, 4 for Grade 2, 2 for Grade 3 and 0 for Grade 4. Lung infection had a lower occurrence: 0, 2, 2 and 0 split by CTCAE Grade 1, 2, 3 and 4 respectively. There is a boundary zone in the passage from phase III to phase IV trials, i.e. from experimental to marketing and free use phases: in this zone we can find NPP and compassionate and off-label use. Despite the known potential bias of all the observational retrospective studies, reports on the real life experience make an important contribution to medical knowledge prior to widespread utilization: ibrutinib therapy is effective and tolerable also in a clinical setting mimicking the real world. Our results, in fact, are superimposable to those obtained in clinical trials: for safety, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; for effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL. Disclosures Cascavilla: Janssen-Cilag: Honoraria. Zinzani:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celegene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees.

Description: Context and objective Approximately 5-10% of diffuse large B-cell lymphoma (DLBCL) patients carry MYC gene translocations (MYC-translocation+) with a poor prognosis after standard chemotherapy. MYC-translocation+ DLBCL patients carrying BCL2 translocations (MYC+/BCL2+ double-hit lymphoma) have a worse survival. The efficacy of adjuvant radiotherapy in this setting is unknown. The purpose of this study is to evaluate the efficacy of radiotherapy as a part of the therapeutic regimen for patients with MYC-translocation+ DLBCL. Patients and methods From the International DLBCL R-CHOP consortium program, we selected 581 patients with de novo DLBCL treated with standard R-CHOP immunochemotherapy (diagnosed and treated from 2000 to 2010). We excluded patients with transformed DLBCL, primary mediastinal, cutaneous, testicular or central nervous system large B-cell lymphomas, patients with HIV infection, and patients not treated with R-CHOP. The median follow-up was 54.9 months. Fluorescence in situ hybridization assessing MYC was performed for all the patients (n=581) and results were correlated with available clinical data to identify clinicopathologic features associated with MYC translocation, and to evaluate the prognostic significance of MYC translocations regarding overall survival (OS, from the time of diagnosis to death from any cause) and progression-free survival (PFS, from the time of diagnosis to relapse or death from any cause). In the MYC-translocation+ DLBCL group, 38 patients received chemotherapy alone and 21 patients received chemotherapy with adjuvant radiation therapy. The clinicopathologic features and survival of MYC-translocation+ DLBCL patients treated with (n=21) and without radiotherapy (n=38) after immunochemotherapy were compared to in order to evaluate the radiotherapy efficacy and other confounding factors. Results MYC translocations were detected in 59 DLBCL patients (10.2%). Patients with MYC-translocation+ DLBCL more often had bulky tumors, involvement of multiple extranodal sites, and poorer OS (hazard ratio [HR]: 2.0, 95% confidence interval [CI]: 1.20 - 3.35, P= .0083) and PFS (HR: 1.96, 95% CI: 1.22 - 3.13, P= .0005) independent of the International Prognostic Index score. Poor survival was primarily attributable to patients with MYC+/BCL2+ double-hit DLBCL who were predominantly of germinal center B-cell subtype. Among MYC-translocation+ DLBCL patients, a better survival was achieved in patients who received radiotherapy (for OS, HR: .32, 95% CI: .15 - .71, P= .0049; for PFS, HR: .35, 95% CI: .17 - .73, P= .0043). Conversely, radiotherapy abolished the adverse impact of MYC translocations. In addition, radiotherapy was associated with better survival in the subset of patients with MYC+/BCL2+ double-hit lymphoma (P = .017 for OS, and P = .05 for PFS). However, owing to the common use of radiotherapy as consolidation therapy, the favorable prognoses in the group of patients who received radiotherapy could also be attributed to limited-stage disease and more frequent complete remission (CR) after first-line treatment and therefore these factors confound interpretation of the data. To address these issues, we evaluated radiotherapy efficacy in separate patient groups: patients who achieved CR, non-CR (PR/SD/PD) patients, and patient with stage I/II, or stage III/IV disease. The efficacy of radiotherapy appeared more apparent in patients with advanced disease who did not achieve CR after first-line chemotherapy. Multivariate analysis after adjustment for stage and IPI score validated that radiotherapy significantly improved OS (HR: .28, 95% CI: .10 - .81, P= .018) and PFS (HR: .32, 95% CI: .13 - .80, P= .015) of MYC-translocation+ DLBCL patients. Conclusions The presence of MYC translocations in DLBCL is an important biomarker that facilitates prognostic prediction and treatment stratification independent of the IPI score. For chemoresistant MYC-translocation+ DLBCL patients, radiotherapy seems to be an effective adjuvant regimen likely due to the higher frequency of extranodal involvement and bulky disease in MYC-translocation+ DLBCL patients. Our results provide a rationale for larger scale studies to assess the potential role of radiotherapy in the management of MYC-translocation+ DLBCL patients, particularly patients with MYC+/BCL2+double-hit DLBCL. Disclosures: Winter: Millenium: Research Funding; Novartis : Research Funding; Pfizer (Wyeth): Research Funding; Seattle Genetics: Research Funding; Spectrum: Research Funding; Janssen (Pharmacyclics): Research Funding; Spectrum (Allos): Consultancy; Sanofi Aventis: Consultancy; Tgen: Consultancy; AMBIT Biosciences (Spouse): Research Funding; Celgene (Spouse): DSMB, DSMB Other, Research Funding; Ariad Pharmaceuticals (Spouse): Research Funding; Novartis (Spouse): Consultancy, Research Funding; Amgen (Spouse): Consultancy, Research Funding; Astellas (Spouse): Research Funding; Caremark/CVS: Consultancy; Pfizer (Spouse): Consultancy; Sanofi Aventis (Spouse): DSMB, DSMB Other; Bristol Myers Squibb (Spouse): DSMB, DSMB Other; UptoDate, Inc.(Spouse): Patents & Royalties.

Description: Introduction Fludarabine, cyclophosphamide and rituximab (FCR) and bendmaustine rituximab (BR) combinations have both been evaluated as salvage regimens in Waldenstrom's Macroglobulinemia. FCR exerts good quality of responses but there are some concerns regarding its use mainly for tardive myelosuppression and long term toxicity. BR showed to be effective with an excellent short term toxic profile but in literature there are no data on long term follow-up and toxicity. The aim of this study was to evaluate long term outcome and long term toxicity of patients treated with FCR and BR. Patients and Methods We analyzed 87 relapsed and refractory Waldenstrom's Macroglobuklinemia patients enrolled in two retrospective Italian multicenter studies in which FCR or BR were administered as salvage regimens. Patients treated with both bendamustine and fludarabine were excluded from the study. For each treatment group we compared: clinical and disease characteristics, Progression free survival (PFS) defined as progression or death for any cause from the beginning of salvage treatment; Event free survival (EFS) defined as progression or development of major infection, solid tumor, secondary MDS/AML, DLBCL, or death due to any cause. Results Of the 87 patients, 37 had received FCR and 50 BR. The two groups of patients did not differ in sex, median age, median number of prior treatments, previous therapy with alkylating agents, disease status, median IgM level, presence of adenopathies and/or splenomegaly at CT performed before salvage treatment. The significant differences between the two groups were: higher number of patients 〉70 years in the BR group (P=0.01) and lower number of patients previously treated with monoclonal antibody in the FCR population (P