scholarly journals A Registry-Based Geodemographic Assessment of Non-Hodgkin Lymphoma Subtypes in North Carolina

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2503-2503
Author(s):  
Jennifer Morgan ◽  
Jennifer S Smith ◽  
Chandrika Rao ◽  
Dominic T. Moore ◽  
Christopher Dittus
Keyword(s):  
North Carolina ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Effusion Lymphoma ◽  
B Cell Lymphoma ◽  
The North ◽  
Large B Cell Lymphoma ◽  
Incidence And Mortality ◽  
Large B Cell

Abstract Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the United States. NHL comprises a heterogeneous group of over 40 histological subtypes, each of which has distinct genetic, morphologic and clinical features. While NHL epidemiology as a single entity has been well-characterized using population-based cancer registry data, the epidemiology of NHL subtypes is not well understood and even less data are available for rarer subtypes. We aimed to determine geodemographic correlates for NHL subtypes in North Carolina to provide rarely reported epidemiologic characterization of each distinct malignancy. Methods: Demographic data were obtained on all NHL subtypes reported in persons >18 years of age from 2009-2019 from the North Carolina Central Cancer Registry (NCCCR). NHL subtypes were determined based on World Health Organization International Classification of Diseases for Oncology,Third Edition (ICD-O-3) Morphology codes provided by NCCCR. Crude incidence and mortality rates were estimated per 100,000 persons for the 10-year period using 2019 population data from the U.S Census Bureau. Urban and rural residence designations were based on zip code using rural-urban commuting codes developed by the Rural Health Research Center. County tier designations were used as markers of economic prosperity, with 3 being most prosperous, and provided by the North Carolina Department of Commerce. Data are being mapped using ESRI ArcMap 10.8.1. Results: A total of 25,627 incident cases of NHL and 9,930 associated deaths were reported between 2009 and 2019 in North Carolina. Therefore, the standard NHL incidence and mortality rates are 24.1 and 9.3 per 100,000 persons. For incident NHL cases, median age at diagnosis was 68 years (range 19-103), 55% were male and 45% female. Most (83%) identified as white, 14% as black, and 3% as other. Median age at death was 70 years (range 19-106). Twenty-eight NHL subtypes were identified with the four most common NHL subtypes being Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), and Marginal Zone Lymphoma with 6.54, 6.42, 3.55, and 2.0 cases (per 100,000 persons), respectively. Least common subtypes included Intravascular Large B Cell Lymphoma, Primary Effusion Lymphoma, Primary Cutaneous Gamma Delta T-cell Lymphoma (PCGD-TCL) and Subcutaneous Panniculitis-Like T-cell Lymphoma, all with 0.01 cases per 100,000 persons (or 15, 14, 9 and 6 cases respectively). The distribution of NHL subtypes varied according to demographics with several notable findings. DLBCL had the highest crude mortality rate of 2.98 deaths/100,000 persons, followed by CLL (2.12 deaths/100,000 persons), FL (0.98 deaths/100,000 persons) and Lymphoma NOS (0.51 deaths/100,00 persons). Mediastinal Large B-cell Lymphoma (MLBCL) was diagnosed in the youngest individuals with median age of 36 (range 20-74), whereas PCGD-TCL occurred in the oldest with median age of 74 (range 31-99). Primary Effusion Lymphoma had the highest male predominance (93%) and MLBCL had the highest female predominance (73%). Mantle Cell Lymphoma had the highest predominance of persons who identify as white (90%), Anaplastic Large Cell Lymphoma (ALK+/-) with those who identify as black (66%), and Primary Effusion Lymphoma with those who identify as other (14%). Predominance of rurality and county tier designations varied by NHL subtype. Conclusions: A registry-based assessment of NHL subtypes illustrates the heterogeneous nature of this group of malignancies and highlights significant variation in the geodemographic features of each subtype. Evaluating geodemographic correlates deepens our understanding of NHL subtypes and can inform populations at risk for each unique NHL subtype. Figure 1 Figure 1. Disclosures Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding.

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

Central Nervous System Relapse in Patients with Diffuse Large B-Cell Lymphoma: Analysis of Incidence and Prognostic Factors

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1666-1666
Author(s):  
Masahiro Uni ◽  
Yuki Kagoya ◽  
Yasuhito Nannya ◽  
Fumihiko Nakamura ◽  
Mineo Kurokawa
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Initial Diagnosis ◽  
High Dose ◽  
Cns Involvement ◽  
Large B Cell Lymphoma ◽  
Cns Relapse ◽  
Large B Cell

Abstract The addition of rituximab to CHOP (R-CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisolone) has significantly improved the outcome of diffuse large B-cell lymphoma (DLBCL). However, its secondary involvement in the central nervous system (CNS) is still a fatal event, and optimal therapeutic strategies have remained to be established. Combined immunochemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy and high-dose cytarabine is currently in use for patients with CNS relapse, though treatment outcome has not been evaluated enough. In the present study, we aimed to analyze the incidence and prognosis of CNS relapse of aggressive B-cell lymphoma in comparison with those of systemic relapse in the era of rituximab-containing regimens. We also estimated the risk factors and prognostic factors for CNS relapse. We retrospectively analyzed 278 consecutive adult patients (≥16 years old) who were diagnosed as DLBCL or primary mediastinal large B-cell lymphoma (PMLBL) at The University of Tokyo Hospital, Tokyo, Japan, from August 2003 through August 2013. We excluded patients who had CNS or intraocular involvement at diagnosis since those patients had received high-dose methotrexate-based therapy instead of R-CHOP. Four to six courses of intrathecal administration of methotrexate were performed in patients with adrenal gland, testis or breast involvement as prophylaxis for CNS relapse. The median follow-up period was 42 months, and the median age was 66 years (range, 23-91). Overall, 67 patients (24.1%) had relapse at any site, of which 24 patients (35.8%) had CNS involvement. The median interval between initial diagnosis and the occurrence of secondary CNS involvement was 212 days, and 15 of the 24 patients (62.5%) had CNS relapse within 1 year from the initial diagnosis. Multivariate analysis revealed that multiple or diffuse extranodal involvement at initial diagnosis (hazard ratio [HR] 3.74, 95% confidence interval [CI] 1.28-10.91; P<0.01) was associated with the development of CNS relapse against non-CNS relapse. Chromosomal abnormality was investigated in 112 patients, of which 38 had abnormal karyotypes as identified by G-banding analysis for lymph nodes. Patients with CNS relapse more frequently harbored chromosomal abnormalities compared with those without relapse in univariate analysis (P=0.01). We also analyzed the survival of patients with primary CNS lymphoma (PCNSL) as a control. Only two (7%) of 27 patients with PCNSL died during the follow-up period. Five-year OS from initial diagnosis was 92.3% (95% CI: 82.5-100.0%), and was significantly better than that for patients with CNS relapse (33.9%, 95% CI: 17.3-66.3%, P<0.01). Among 24 patients with CNS relapse, eight (33%) had systemic lesions other than CNS when diagnosed as CNS relapse, and four (17%) patients newly developed systemic lesions while treated for CNS relapse. Patients without concurrent systemic lesions attained a rather good prognosis by chemo-radiotherapy, while those harboring concurrent systemic lesions had dismal outcome (one-year OS after the diagnosis of relapse: 74.0% versus 12.4%, P<0.01, Figure 1, systemic relapse was treated as a time-dependent covariate). These results indicate that controlling systemic lesions as well as CNS ones is essential for treating patients with secondary CNS involvement of DLBCL. CNS lesions would be well controlled with R-MPV implementation as salvage therapy, nevertheless we should be careful for concurrent systemic lesions which might require different therapeutic strategies. Disclosures Nannya: Chugai Pharmaceutical　CO., LTD: Speakers Bureau; Pfizer: Research Funding. Kurokawa:Chugai Pharmaceutical　CO., LTD: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding.

Outcome of Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP: Subgroup Analysis from the UK NCRI R-CHOP 14 Vs 21 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1516-1516
Author(s):  
Andrea Kühnl ◽  
David Cunningham ◽  
Nicholas Counsell ◽  
Eliza A Hawkes ◽  
Wendi Qian ◽  
...  
Keyword(s):  
Elderly Patients ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Bulky Disease ◽  
Large B Cell Lymphoma ◽  
The Uk ◽  
Large B Cell ◽  
Grade Iii

Abstract Background: Elderly patients with diffuse large B-cell lymphoma (DLBCL) have an inferior prognosis compared to younger patients. Dose intense administration of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP14) is superior to 3-weekly CHOP in elderly DLBCL patients (Pfreundschuh, Blood 2004), but this benefit has not been demonstrated with addition of rituximab (Delarue, Lancet Oncol 2013). We have previously shown that R-CHOP14 did not improve outcome compared to standard R-CHOP21 in newly diagnosed DLBCL patients aged 19-88 years across all subgroups (Cunningham, Lancet 2013). Here, we provide a detailed subgroup analysis of elderly patients (over 60 years) from the UK NCRI R-CHOP14 vs 21 randomised phase 3 trial. Methods: Between 2005 and 2008, 1080 patients were randomly assigned to receive 8 cycles R-CHOP21 or 6 cycles R-CHOP14 (+ G-CSF) with two additional rituximab applications. Of these, 604 patients were over 60 years and included in the current analysis (301 in the R-CHOP21 arm, 303 in the R-CHOP14 arm), with a median follow-up of 45 months. Results: Baseline characteristics were well balanced between treatment arms. 36% of patients were over 70 years, 15% had a WHO performance status (PS) of 2, 65% stage III/IV disease, 44% bulky disease and 42% B symptoms. There was a trend towards a higher rate of BCL6 rearrangements (26% vs. 16%; P=0.10) and concurrent MYC - and BCL2 rearrangements (double hit lymphoma as determined by FISH, 8% vs. 2%; P=0.06) in the R-CHOP14 arm compared to the R-CHOP21 arm. 85% (257/303) of patients received 8 cycles of R-CHOP14, whereas only 76% (230/301) completed all 8 cycles R-CHOP21. However, percentage of patients receiving at least 6 cycles of therapy was similar (88% and 89%, respectively). Dose delays of myelosuppressive drugs occurred more frequently in patients receiving R-CHOP21 vs. R-CHOP14 (51% vs. 39%; P=0.03) due to a higher incidence of haematological toxicities likely related to the reduced use of G-CSF. G-CSF was mandatory for patients on R-CHOP14 and was given to 57% of patients on R-CHOP21 as secondary prophylaxis. The frequency of dose reductions was similar in the R-CHOP21 and R-CHOP14 arms (15% vs. 16%; P=0.73). Toxicities of grade III+ were seen in 72% and 60% of patients in the R-CHOP14 and R-CHOP21 arms, respectively. There was evidence of a higher incidence of grade III+ neutropenia (62% vs. 36%) and a lower rate of thrombocytopenia (7% vs. 12%) in the R-CHOP21 arm compared to R-CHOP14. The incidence of fever and infections was similar in both arms. There was no evidence of a difference in response rates between the R-CHOP14 and R-CHOP21 arms [complete response (CR)/unconfirmed CR (CRu) rates: 62% vs. 67%, respectively; overall response rate both 91%]. CR/CRu rates after 4 cycles of therapy were 33% and 39% respectively (P=0.15). There was no difference regarding progression-free survival (PFS) and overall survival (OS) between arms, neither in the total cohort of elderly patients, nor in the subgroup of patients over 70 years [OS (all elderly): hazard ratio (HR) 0.91 (95% CI: 0.67-1.24); P=0.55; PFS (all elderly): HR 0.98 (95% CI: 0.74-1.29); P=0.86]. 3-year PFS was 71% (95% CI: 67-74) in all patients over 60 years and 64% (95% CI: 58-71) in patients over 70 years. 3-year OS was 75% (95% CI: 72-79) and 67% (95% CI: 61-74) in patients over 60 years and over 70 years, respectively. In multivariate analysis including individual factors of the International Prognostic Index (IPI), as well as age as continuous variable, gender, presence of B symptoms, bulky disease, b2-microglobulin higher than 3mg/l and albumin higher than 35 g/l, only age was of independent prognostic significance for OS (P=0.01). Besides the standard IPI and the NCCN-IPI, an elderly IPI (E-IPI; Advani, BJH 2010) and the ABE4 score (Prochazka, PLoS One 2014) have been proposed for better prognostication of elderly DLBCL patients. A detailed comparison of these different prognostic models in our dataset will be presented at the meeting. Conclusion: Outcome and toxicities in DLBCL patients over 60 years treated within the NCRI R-CHOP14 vs 21 trial are comparable to results from other randomised studies investigating R-CHOP14 or R-CHOP21 in elderly DLBCL patients. Our data further support the similar efficacy and tolerability of both R-CHOP variants for first-line treatment of this patient group. Disclosures Cunningham: Amgen: Research Funding; Medimmune: Research Funding; Astra Zeneca: Research Funding; Bayer HealthCare Pharmaceuticals: Research Funding; Merrimack: Research Funding; Merck Serono: Research Funding; Celgene: Research Funding; Sanofi: Research Funding. Pocock:Janssen: Honoraria. Ardeshna:Roche: Honoraria.

Gray Zone Lymphoma (GZL) with Features Intermediate Between Diffuse Large B-Cell Lymphoma (DLBCL) and Classical Hodgkin Lymphoma (cHL): Pathologic Classification and Clinical Outcomes from a Multicenter Consensus Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4145-4145
Author(s):  
Andrew M Evens ◽  
Monika Pilichowska ◽  
Stefania Pittaluga ◽  
Judith Ferry ◽  
Jessica Hemminger ◽  
...  
Keyword(s):  
Tumor Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Relative Rarity ◽  
Relapse Rates ◽  
Large B Cell

Abstract BACKGROUND: GZL (B-cell lymphoma, unclassifiable, with features intermediate between DLBCL andcHL) was first described in 2005 and included in the 2008 WHO classification. The majority of cases present withmediastinal disease and share features withcHL and primarymediastinal large B-cell lymphoma (PMBCL). Non-mediastinal lymphomas with similar features have also been reported. Due to the relative rarity and the diagnostic complexity of this disease, data on GZL are limited and further description of this entity is desired. METHODS: Clinical data from cases originally diagnosed as GZL were collected from 15 academic centers across the United States and Canada (Evens et al. Am J Hematol, 2015). In an attempt to further characterize the diagnostic features and clinical correlations, 73 cases (including 62 cases from the aforementioned series and 11 subsequently collected cases) were obtained and submitted for central pathology review using criteria of the 2016 revisedWHO classification. All diagnostic samples were evaluated with a panel comprising CD20, CD79a, PAX5, OCT2, BCL6, MUM1, CD30, CD15, CD3 and EBV by in situ hybridization (EBER). Beyond the tumor cellimmunoprofile, diagnostic criteria included: tumor cell density and morphology, necrosis, and the microenvironment. Five cases were rejected for insufficient material/technical issues. Collectively, 68 cases were evaluated by 5 experthematopathologists and consensus diagnosis was reached at multi-headed scope review. Additionally, clinical data were obtained to analyze patient (pt) characteristics and disease outcomes. RESULTS: Of 68 cases given an original diagnosis of GZL from academic institutions, only 26 cases (38%) were confirmed as GZL on consensus review. Pt characteristics of these 26 GZL cases included: 15M/11F; median age 37 years (range 19-72); 42% B symptoms; 61% anemia; 35% increased LDH; and 33% with hypoalbuminemia. 11/26 (42%) biopsies were mediastinal in origin, and in an additional 4 cases, a mediastinal mass was present clinically; 11 (42%) had only peripheral lymphadenopathy/disease (ie, non-mediastinal). 60% of pts had stage I/II disease with 16% having stage IV. GZL cases were characterized by high tumor cell density and paucity of a mixed inflammatory background (both contrary as seen in cHL). The immunohistochemical profiles of the 26 consensus GZL cases are noted in the Table. Notably, only 1 GZL case was EBV positive. 42/68 (62%) of the original cases were reclassified as follows: nodular sclerosis (NS)cHL, n=27 [n=10 of which werecHL, NS grade 2 (cHL-NS2)] and one lymphocyte-richcHL (LRCHL), n=1; DLBCL NOS, n=4; PMBCL, n=2; nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), n=3; EBV positive LBCL, n=3; and B-cell lymphoproliferative disorder, n=1. Most cases ofcHL diagnosed as GZL had strong CD20 expression. Further, cHL-NS2 was often misdiagnosed as GZL usually due to confluent growth of lacunar cells. Clinically, therapy received and outcomes were available for 25 of 26 of the aforementioned consensus GZL cases; the overall response rate (ORR) for these consensus confirmed GZL cases was 64% (complete remission (CR) 48%) with 28% ofpts experiencing primary refractory disease to frontline therapy. Relapse rates by primary chemotherapy regimen for thesepts were: ABVD 5/6 (83%); CHOP 7/17 (41%); and EPOCH 1/2 (50%). Among consensus GZLpts with relapsed disease, 71% underwent autologous SCT. With a median follow-up of 40 months, the 3-year PFS was 44% with 3-year OS of 90% for the consensus GZL pts. Among all other cases that were reclassified to a non-GZL diagnostic entity, the ORR was 75% (CR 67%) with 3-year PFS and OS rates of 52% and 80%, respectively. This included a relapse rate of 86% amongpts with cHL-NS2. CONCLUSIONS: Accurate diagnosis of GZL remains challenging. Relative rarity of the cases and overlap withcHL, especially thecHL-NS variant with lymphocytic depletion and confluent lacunar cells (also known as cHL-NS2), contribute to this difficulty. Diagnosis should be based on integration of architectural, cytological andimmunophenotypic features. In addition, relapse rates are high with standard chemotherapy regimens, especially ABVD-based therapy. Enhanced biologic understanding and improved therapeutic strategies are needed for GZL. Disclosures Evens: Takeda: Other: Advisory board. Abramson:Abbvie: Consultancy; Gilead: Consultancy; Seattle Genetics: Consultancy; Kite Pharma: Consultancy. Fenske:Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria; Seatle Genetics: Honoraria. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board. Blum:Pharmacyclics: Research Funding.

scholarly journals Safety of Axicabtagene Ciloleucel CD19 CAR T-Cell Therapy in Elderly Patients with Relapsed or Refractory Large B-Cell Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 96-96 ◽  
Author(s):  
Dahlia Sano ◽  
Loretta J. Nastoupil ◽  
Nathan H. Fowler ◽  
Luis Fayad ◽  
F. B. Hagemeister ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Age Groups ◽  
B Cell Lymphoma ◽  
Advisory Committees ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Large B Cell

Abstract Background Axicabtagene ciloleucel (axi-cel) is an autologous CD19-specific CAR T-cell therapy product that was FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after at least two lines of systemic therapy. In the pivotal ZUMA-1 study, the best overall response (ORR) and complete response (CR) rates observed in 108 patients treated with axi-cel were 82% and 58%, respectively. At a median follow-up of 15.4 months, 42% of the patients remain in ongoing response (Neelapu et al. N Eng J Med 2017). Analysis of efficacy outcomes in patients <65 years (N=81) and ³65 years (N=27) showed that the ORR and ongoing response at 12 months were comparable between the two subgroups (Neelapu et al. N Eng J Med 2017). Whether the safety is also comparable between the two subgroups is unknown. Here, we report safety outcomes in elderly patients (³65 years) with large B-cell lymphoma treated with axi-cel at our institution. Methods We retrospectively analyzed and reviewed the data from patients treated with axi-cel at our institution. Patients had a diagnosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and transformed follicular lymphoma (TFL). Patients were treated with conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days followed by axi-cel infusion after 2 days of rest at a dose of 2 x 106 CAR+ T cells/kg body weight. Patients were monitored for toxicities for at least 7 days in the hospital after CAR T infusion and those who had at least 30 days of follow-up after axi-cel were considered to be evaluable for safety. Cytokine release syndrome (CRS) and neurological toxicity termed as CAR-related encephalopathy syndrome (CRES) were graded according to the CARTOX grading system (Neelapu et al. Nat Rev Clin Oncol 2018). Results A total of 61 patients with relapsed or refractory large B-cell lymphoma who received axi-cel at our institution were included. Of these, 44 (72%) patients were <65 years of age and 17 (28%) patients were ³65 years of age. The baseline characteristics of the patients are summarized in Table 1. ORR and CR rates at Day 30 were comparable between the two groups. CRS was common in both groups and was observed in 83% and 91% of the patients in the older and younger age groups, respectively. But most CRS events were grade 1-2. Grade 3 or higher CRS was observed in 18% vs. 11% in the older vs. younger age groups (P=0.67). One patient with a history of autoimmune disease in the elderly group died of hemophagocytic lymphohistiocytosis (HLH). CRES was observed in 58% and 71% of the patients in the older and younger age groups, respectively. Grade 3 or higher CRES was observed in 29% vs. 39% in the older vs. younger age groups (P=0.58). Median hospitalization period for axi-cel CAR T-cell therapy was comparable between the two groups. Conclusions Our results suggest that response rates are comparable between the elderly and younger age groups at day 30 after axi-cel therapy. Importantly, toxicities due to CRS and/or CRES after axi-cel CD19 CAR T cell therapy are comparable between the elderly (³65 years) and younger (<65 years) patients with relapsed or refractory large B-cell lymphoma. Table 1 Table 1. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Janssen: Research Funding; Juno: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria. Fowler:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Samaniego:ADC Therapeutics: Research Funding. Wang:Kite Pharma: Research Funding; Acerta Pharma: Honoraria, Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics: Honoraria, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MoreHealth: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Neutrophil-to-Lymphocyte Ratio Is Prognostic in Patients with Diffuse Large B-Cell Lymphoma: A Study from the Latin American Group of Lymphomas (GELL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2987-2987
Author(s):  
Brady E. Beltrán ◽  
Victoria Otero ◽  
Marialejandra Torres Viera ◽  
Camila Peña ◽  
Myriam Lucía Rodriguez ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factor ◽  
B Cell ◽  
Latin American ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Entire Group ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: Diffuse large B-Cell Lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world. The IPI score is a powerful risk-stratification tool in patients with DLBCL. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with DLBCL in Asia, Europe and USA. The GELL is a recently formed group for the study of lymphomas in Latin America composed by large institutions from eleven countries. The aim of this study was to evaluate whether the NLR is a prognostic factor in Latin American patients with DLBCL. Methods: We included patients with a pathological diagnosis of DLBCL who were diagnosed and treated at our institution between 2012-2013. IRB approval was obtained prior to research, and pathological samples were reviewed by hematopathologists at each of the participating institutions to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. The NLR was calculated by dividing the absolute neutrophil by the absolute lymphocyte count and dichotomized in NLR≥4 and NLR<4. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate Cox models were fitted to evaluate hazard ratios (HR) for overall survival (OS). Results: A total of 329 patients with a diagnosis of DLBCL were included in this analysis. The median age at diagnosis was 64 years (range 18-83 years) with a slight female predominance (54%). Clinically, 59% of patients were 60 or older, 34% had ECOG >1, 29% had elevated LDH, and 70% had extranodal disease; 49% had early stage and 51% had stage III and IV. The IPI score was low risk in 36%, low-intermediate in 25%, high intermediate in 22% and high risk in 17%. 41% of patients had NLR ≥4. 89% of patients received standard R-CHOP, 2% received R-miniCHOP and 9% received other regimens. The overall response rate as 83%; 69% had complete response and 14% had partial response. The median follow-up for the entire group was 5 years (95% CI 4.9-5.4 years). The 5-year overall survival (OS) rate for the entire group was 65%. The 5-year OS rates for patients with NLR ≥4 and <4 were 59% and 71%, respectively (p=0.008). Patients with low, low-intermediate, high-intermediate and high IPI scores had 5-year OS rates of 80%, 65%, 56% and 45%, respectively (p<0.001). In the multivariate analysis, advanced stage (HR 3.1, 95% CI 1.9-5.0; p<0.001), LDH level (HR 2.2, 95% CI 1.2-4.2; p=0.016) and NLR ≥4 (HR 1.7, 95% CI 1.1-2.6; p=0.03) were statistically independent factors associated with worse OS. NLR ≥4 was an adverse prognostic factor after adjusting for IPI score (HR 1.7, 95% CI 1.1-2.6; p=0.01). Conclusion: The NLR appears as a novel and easy to use prognostic factor for OS, independent of the IPI score, in previously untreated Latin American patients with DLBCL. Our findings support the need for validation of the NLR in larger retrospective or prospective studies in patients with DLBCL. Figure. Figure. Disclosures Chiattone: Janssen: Honoraria, Research Funding. Castillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Genentech: Consultancy.

scholarly journals EZH2 Upregulation Is Associated with Unfavorable Prognosis in Diffuse Large B-Cell Lymphoma through Potential RUNX3 Downregulation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5301-5301
Author(s):  
Denise Peker ◽  
Samara Roman-Holba ◽  
Yuri Kwon ◽  
Jennifer Gordetsky ◽  
Amitkumar Mehta ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rna Expression ◽  
Large B Cell Lymphoma ◽  
Group 3 ◽  
Group 2 ◽  
Large B Cell ◽  
Group 1

Abstract Introduction: The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in apoptosis, angiogenesis, cell migration and invasion. Putative tumor suppressor activity of RUNX3 has been presented extensively in the literature, particularly in solid epithelial tumors and recently in lymphoma with loss of expression favoring tumorigenesis and/or prognosis, but its role in diffuse large B-cell lymphoma (DLBCL) has not been studied. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. RUNX3 downregulation due to EZH2 upregulation has been shown in various solid tumors. In the present study, we investigated the EZH2 and RUNX3 RNA expression status in DLBCL and its impact on clinical outcome. Methods: A retrospective chart review was performed and 169 cases of DLBCL treated with chemoimmunotherapy between 2003 and 2013 were included. Immunodeficiency- or EBV-associated and MYC+ LBCL were excluded. Archived formalin-fixed-paraffin-embedded tissue samples were retrieved and RNA was extracted using commercially available kits. We correlated the RNA expression levels for EZH2 and RUNX3 in various sites using quantitative real-time PCR (Taqman assay) and custom designed primers for each gene. Control samples included three benign lymph nodes free of a neoplastic process. Results: We identified 66 cases of DLBCL, including25 nodal DLBCL and 41 extranodal DLBCL, with sufficient RNA extracted. Extranodal locations included testis (n=12), orbit (n=6), primary central nervous system (n=5), bone (n=3), breast (n=2) and viscera (n=13). The median age was 64 years (range 29- 81 years) with a female to male ratio of 0.4 (F=20 and M=46). Median overall survival (OS) was 28 months (1-156 months). Immunophenotypic subtype based on cell-of-origin using Hans algorithm was available in 63 cases; 34 cases were germinal center B-cell (GCB) type while 29 were non-GCB type. Treatment data was available in 63 cases and all patients received R-CHOP as initial therapy except three patients who died shortly after diagnosis. Forty-four cases showed higher expression of EZH2 and RUNX3 when compared to normal lymph nodes (p < 0.05). Nineteen out of 44 cases showed increased EZH2 and decreased RUNX3 expression (Group 1) while EZH2 expression was lower than RUNX3 in the remaining cases (Group 2). The remaining 22 DLBCL cases did not show significant correlation for expression (Group 3). Overall survival was significantly low in Group 1 compared to Group 2 and Group 3 (p =0.030 and p=0.026, respectively). There was no difference for OS between Groups 2 and 3 (p>0.05) (Figure 1). Conclusions: Our results showed that decreased RUNX3 RNA expression is associated with EZH2 overexpression and poses an adverse prognostic factor in DLBCL. Larger studies are needed to establish the prognostic and therapeutic utility of EZH2 and/or RUNX3. Disclosures Mehta: Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Roche Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Forero:University of Alabama at Birmingham: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

scholarly journals Molecular Characteristics of Diffuse Large B-Cell Lymphoma and Correlation with Baseline Metabolic Tumor Volume (MTV), Interim Positron Emission Tomography (iPET) and Outcome in the PETAL Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4188-4188
Author(s):  
Julia Richter ◽  
Andreas Hüttmann ◽  
Jan Rekowski ◽  
Christine Schmitz ◽  
Selina Gärtner ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Diagnostics ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Emission Tomography ◽  
Large B Cell Lymphoma ◽  
Positron Emission ◽  
The Relationship ◽  
Large B Cell

Abstract Introduction: Treatment results in diffuse large B-cell lymphoma (DLBCL) are heterogeneous. Established risk models like the International Prognostic Index (IPI) and molecular lymphoma features such as MYC translocations and the cell of origin (COO) subtype are prognostic of outcome. A positive iPET scan after 2 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has recently been shown to predict poor outcome independent of the IPI (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial [PETAL]; Dührsen et al., J Clin Oncol 36:2024, 2018). Another PET-derived parameter of potential prognostic significance is baseline MTV. This retrospective analysis of lymphoma biopsies from the PETAL trial investigated the relationship between molecular lymphoma features and PET parameters. Methods: Available lymphoma specimens were analyzed for COO by immunohistochemistry employing the Hans-classifier (HC) and by gene expression (GE) using the HTG EdgeSeq System (HTG Molecular Diagnostics). MYC and BCL2 and/or BCL6 translocations ("double-hit" [DH]) were assessed by fluorescence in situ hybridization (FISH). MTV was determined applying the 41% SUVmax segmentation method, and iPET was evaluated using the deltaSUVmax method. Association between iPET result and molecular lymphoma features was assessed by risk ratios (RR). Survival curves of time-to-event endpoints were compared using hazard ratios (HR) from Cox regression and the log-rank test. Results: Of 609 DLBCL patients treated in the PETAL trial, 63 had a positive iPET. 134 of 267 DLBCL biopsies available for HC analysis (50.2%) were classified as non-germinal center B-cell (non-GCB) and 133 (49.8%) as GCB. COO analysis by GE revealed an activated B-cell (ABC) type in 122 (51.1%) and a GCB type in 102 (42.7%) of 239 available biopsies (n=7 [2.9%] unclassified, n=8 [3.3%] failed quality control). Concordance between HC and GE was found in 165 of 197 biopsies studied by both methods (83.8%). MYC breaks were found in 27 (10.7%) and MYC amplifications in 48 (19.0%) of 253 cases studied by FISH. A DH lymphoma was diagnosed in 16 of 253 cases (6.3%). Complete information on HC, GE and DH status was available for 170 cases. The relationship is depicted in figure 1. COO classification by either HC or GE was not correlated with baseline MTV, iPET result, event-free (EFS) survival or overall (OS) survival. By contrast, DH status was correlated with positive iPET (RR 2.30 [95% CI, 0.76 to 6.96]) and inferior outcome as shown in figure 2 (EFS: HR 2.04 [95% CI, 1.02 to 4.07]; p=.044; OS: HR 3.00 [95% CI, 1.34 to 6.71]; p=.007). There was no correlation between DH status and MTV. iPET-positive DLBCL harbored MYC breaks more frequently than iPET-negative DLBCL (RR 3.29 [95% CI, 1.40 to 7.77]). A similar trend was observed in 72 cases tested for BCL2 breaks (RR 1.30 [95% CI, 0.44 to 3.84]) and 74 cases tested for BCL6 breaks (RR 1.85 [95% CI, 0.59 to 5.80]). Conclusion: HC and GE showed good concordance with respect to COO classification, but COO was not correlated with MTV, iPET, EFS or OS. By contrast, MYC-rearranged lymphomas with or without BCL2 or BCL6 breaks were statistically significantly associated with a positive iPET, and DH lymphomas were correlated with poor outcome. Yet, the unfavorable prognosis of iPET-positive DLBCL cannot solely be explained by MYC translocations because most iPET-positive lymphomas lacked this genetic anomaly. Our results strengthen the role of iPET as a prognostic tool, independent not only of IPI, but also of COO status and MYC translocation. Disclosures Richter: HTG Molecular Diagnostics, Inc.: Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Gärtner:HTG Molecular Diagnostics, Inc.: Employment. Duehrsen:Amgen: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Amgen: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

scholarly journals Genomic Characterization of Diffuse Large B-Cell Lymphoma Transformation from Nodular Lymphocyte Predominant Hodgkin Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1486-1486
Author(s):  
Joo Y. Song ◽  
Caoimhe Egan ◽  
Alyssa Bouska ◽  
Weiwei Zhang ◽  
Qiang Gong ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
Immune Surveillance ◽  
B Cell Lymphoma ◽  
Pi3k Pathway ◽  
Large B Cell Lymphoma ◽  
Frequent Mutations ◽  
Large B Cell

Introduction: Transformed nodular lymphocyte predominant Hodgkin lymphoma (tNLPHL) with a typical diffuse large B-cell lymphoma (DLBCL) pattern is rare and not well studied by genomic analysis. We employed next generation sequencing and copy number analysis (CNA) to examine the pathogenesis of these tumors. Methods: We identified 19 cases of tNLPHL with DLBCL morphology and sheet-like growth from three institutions. NLPHL preceded transformation in 5 patients and was concurrent with transformation in 11. All cases of tNLPHL were sequenced using a targeted sequencing panel of 356 genes that included commonly mutated genes associated with lymphoma. We had 8 cases with matched germline DNA. We also performed CNA using Oncoscan on 18 cases of tNLPHL. Library preparation with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to three large series of de novo DLBCL. Results: The CNA showed frequent gains in REL and loss of CDKN2A. Mutation analysis showed frequent mutations of genes associated with the PI3K pathway such as SGK1 (26%), ZFP36L1 (16%), PIK3R1 (11%), and IL7R (11%), the NF-kB pathway such as CARD11 (21%), JUNB (21%), BCL10 (11%), NFKBIA (11%), TNFAIP3 (11%), histone/DNA modification such as KMT2D (26%), EP300 (21%), TET2 (11%), TET3 (11%), and the NOTCH pathway such as NOTCH2 (16%), NOTCH1 (1 case), CTBP2 (11%). Mutations in genes involved in immune surveillance and TP53 abnormalities were infrequent. Compared to de novo DLBCL, mutations in IL7R (10.5% vs 0.6%, p=0.03), JUNB (21% vs 4.2%, p=0.01), and SMARCAL1 (11% vs 0%, p=0.01) were significantly higher in tNLPHL than in germinal center B-cell (GCB) subtype of DLBCL. Conclusion: The mutational spectrum of tNLPHL resembles the DLBCL Cluster 4 of Chapuy et al (Nat Med, 2018), which were primarily GCB-DLBCL with frequent mutations in the PI3K pathway (SGK1), NF-kB pathway (CARD11, JUNB), and histone modification. The mutational spectrum is also distinctive in having frequent mutations that are not often seen together in DLBCL, such as TET2, JUNB and NOTCH2. Distinct from transformed follicular lymphoma, TP53 abnormalities and mutations affecting immune surveillance are uncommonly observed. This study provides new insights into the biology of tNLPHL and may highlight potential targets for therapy in the future. Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding.

scholarly journals Young High Risk Patients with MYC/BCL2 Double Hit Lymphoma, BCL2+ and/or Germinal Centre B-Cell like Diffuse Large B-Cell Lymphoma Benefit from Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis: Analysis of Data from the Nordic Lymphoma Group CRY-04 and Chic Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2955-2955 ◽  
Author(s):  
Sirpa Leppa ◽  
Judit Jørgensen ◽  
Leo Meriranta ◽  
Klaus Beiske ◽  
Jan M.A. Delabie ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Dose Dense ◽  
In The Beginning ◽  
Large B Cell

Abstract Background. Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these trials to compare clinical outcome and biological prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) versus at the end (CRY-04) of therapy. Patients and methods. In CRY-04 study, patients were treated with six courses of R-CHOEP14 followed by HD-Mtx and HD-Ara-C. In CHIC trial, treatment started with two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP-14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. For the correlative studies, formalin fixed paraffin embedded pretreatment tumor samples were analyzed by fluorescent in situ hybridization for BCL2 and c-MYC breakpoints and by immunochemistry for CD10, BCL6, MUM1, MYC and BCL2 expression. Germinal center B-cell-like (GCB)/non-GCB) subclassification was performed according to Hans algorithm. Results. Among 303 patients enrolled in the trials (CRY-04, n=160 and CHIC, n=143), 295 (CRY-04, n=154 and CHIC, n=139) were evaluable for baseline characteristics and outcome. Median age (54 and 56 years, p=0.222), male/female ratio, stage, and aaIPI scores were comparable in the two cohorts. CHIC regimen improved outcome over CRY-04; the findings included 4-year estimates of PFS (81% vs 66%, p=0.003), OS (83% and 79%, p=ns) and cumulative incidence rates of CNS progression (2.4% and 5.0%, p=ns). Treatment with the CHIC regimen reduced the risk of systemic progression (aaIPI adjusted RR=0.489, 95%CI 0.308-0.777, p=0.002). PFS benefit with CHIC over CRY-04 was observed across pre-specified subgroups, and particularly in patients less than 60 years old (p=0.008). In the entire study population, dual protein expression (DPE) of BCL2 and MYC was the only parameter to be significantly correlated with a worse PFS (4-y PFS 77% vs 50%, p=0.024; RR=2.300, 95% CI 1.088-4.860, p=0.029). Neither any single immunohistochemical marker nor the GCB/non-GCB subtype or MYC/BCL2-translocations significantly affected outcome. However, when treatment interaction was tested, MYC/BCL2 double hit status (DHL; 13%) predicted poor outcome among patients treated with CRY-04 regimen compared with patients who received CHIC regimen (4-y PFS; 38% vs 78%, p=0.086). GCB subtype and BCL2 positivity were also associated with better outcome in the CHIC cohort (4 y PFS; 63% vs 84%, p=0.011 and 61% vs 80%, p=0.007, respectively), whereas there were no significant survival differences between these regimens among the patients with non-GCB subtype, BCL2 negative DLBCL or DPE lymphomas. Conclusions. Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. The survival benefit related to CHIC regimen over CRY-04 is due to better systemic control of the disease, and at least partly linked to improved survival among patients with GCB subtype, BCL2 positivity and DHL. Disclosures Leppa: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding.

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