ALBERT

Description: INTRODUCTION The distribution of non-Hodgkin lymphoma (NHL) subtypes varies around the world, but a large and systematic comparative study has not been done. This study is first to evaluate the relative frequencies of NHL subtypes in seven regions of the world. METHODS Five expert hematopathologists classified 4848 consecutive cases of NHL from 25 countries in seven regions, including North America, Central/South America, Western Europe, Southeastern Europe, Southern Africa, the Middle East/North Africa, and the Far East, using the WHO classification. Data from the developed world (North America and Western Europe) was compared to the developing world (all other regions combined). RESULTS Among the 4848 cases reviewed, 4539 (93.6%) were confirmed to be NHL, whereas the other 309 (6.4%) had diagnoses other than NHL and were excluded from further analysis. A significantly higher male to female ratio was found in the developing regions (1.4:1) compared to the developed world (1:1; p

Description: The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P 〈 .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P 〈 .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P 〈 .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P 〈 .001). Extranodal NK/T-cell NHL was also more common in CSA (P 〈 .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.

Description: Key Points Ten cases of an indolent T-cell lymphoproliferative disease of the gastrointestinal tract are reported. It is important to recognize this condition because it can be mistaken for aggressive T-cell lymphoma, which may lead to unnecessary therapy.

Description: Biologic factors that predict the survival of patients with a diffuse large B-cell lymphoma, such as cell of origin and stromal signatures, have been discovered by gene expression profiling. We attempted to simulate these gene expression profiling findings and create a new biologic prognostic model based on immunohistochemistry. We studied 199 patients (125 in the training set, 74 in the validation set) with de novo diffuse large B-cell lymphoma treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or CHOP-like therapies, and immunohistochemical stains were performed on paraffin-embedded tissue microarrays. In the model, 1 point was awarded for each adverse prognostic factor: nongerminal center B cell–like subtype, SPARC (secreted protein, acidic, and rich in cysteine) 〈 5%, and microvascular density quartile 4. The model using these 3 biologic markers was highly predictive of overall survival and event-free survival in multivariate analysis after adjusting for the International Prognostic Index in both the training and validation sets. This new model delineates 2 groups of patients, 1 with a low biologic score (0-1) and good survival and the other with a high score (2-3) and poor survival. This new biologic prognostic model could be used with the International Prognostic Index to stratify patients for novel or risk-adapted therapies.

Description: Key Points Five cases of EBV− PTLD in pediatric recipients of combined liver and small bowel allografts are reported. The lesions were plasma cell neoplasms that resolved completely after minimal treatment.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous disease that is characterized by recurrent translocations and somatic mutations. The prognosis of DLBCL has been associated with clinical features, cell-of-origin (COO) and genetic aberrations. The aim of this study was to determine whether somatic mutations are associated with overall survival (OS) in patients with DLBCL who have been treated with R-CHOP, and whether these mutations can be incorporated into a model to better predict survival. Methods: We identified 340 patients between 2000-2016 from two institutions with a diagnosis of de novo DLBCL treated with R-CHOP. A custom targeted panel with 334 genes which included frequently mutated genes in B-cell lymphoma was used and the captured DNA was sequenced on an Illumina HiSeq 2500. Cases were evaluated by immunohistochemistry (IHC: Hans algorithm; MYC and BCL2 expression), nCounter Nanostring (Lymph2Cx), and FISH analysis for BCL2, BCL6, and MYC rearrangement. OS was estimated using the Kaplan-Meier method. Multivariant modeling of OS was performed incorporating clinical features, IHC, COO by Nanostring, FISH, and mutation status of the most frequently mutated genes (≥5%). LASSO regression was performed to select for significant variables and determine coefficients for these variables and risk scores were calculated based on various fitted models. Concordance C-index was used to assess the discriminatory ability of different models, and three risk groups were determined by stratifying the risk scores in the final model. Results: 199 patients (median age 60 years, M:F ratio 1.4:1) had complete clinical and sequencing data. The germinal center B-cell phenotype (GCB) was more common (69%) than the activated B-cell phenotype (ABC; 26%), and 5% were unclassified by COO. The most frequently mutated genes were KMT2D (31%), CREBBP (21%), and TP53 (20%). Double/triple-hit (DH) lymphomas comprised of 11% of the cases, and 13% were double-protein expressors (MYC and BCL2) only. Significant variables selected by LASSO included factors in the IPI, FISH analysis, and 3 mutated genes (KMT2D, PIM1, and MEF2B). A formula was developed using the individual factors (elevated LDH, age ≥60 years, presence of extranodal sites, stage ≥ 3, male, DH status, and mutations in KMT2D, PIM1, and/or MEF2B. A three risk group model (m3D-IPI) was constructed based on these significant variables and its coefficients were superior in discriminating OS compared to the IPI alone (C-index: 0.830 vs. 0.775; Figures A and B). Within IPI group 3 (Figure C), Lasso 3 (high risk) identified patients that had a poor prognosis (p=0.022). In IPI group 4 (Figure D), Lasso 2 (intermediate risk) identified patients that had a better prognosis (p=0.0074). A simplified risk model using the same variables was also developed by assigning one point for each variable present, and these findings were validated in an independent cohort of DLBCL (Reddy et al, Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell 2017;171(2):481-94). Conclusion: In this study, we incorporated mutation analysis of select genes with clinical risk factors and developed an improved risk model for patients with DLBCL treated with first-line therapy. Disclosures Herrera: Pharmacyclics: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck, Inc.: Consultancy, Research Funding; AstraZeneca: Research Funding; KiTE Pharma: Consultancy, Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Immune Design: Research Funding.

Description: Abstract 2710 Introduction Recent refinement in B-cell lymphoma classification by the WHO in 2008 has defined an entity that exists in the gray zone between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Varying in morphology, immunohistochemical, or genetic features, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (Intermediate DLBCL/BL) has been reported to have a poor clinical outcome. We aim to describe the clinical factors affecting outcomes and compare therapy response in a representative population. Methods A retrospective search of the Nebraska Lymphoma Study Group Registry from 1983–2009 meeting the diagnostic criteria for Intermediate DLBCL/BL yielded clinical data at presentation, follow-up, and treatment information. Treatments were grouped as CHOP-like +/− Rituximab (R) vs. intensive regimens (e.g. CODOX-M +/− R, R-EPOCH). Diagnostic slides were re-reviewed to verify the diagnosis. Probabilities of progression-free survival (PFS) and overall survival (OS) were approximated using Kaplan-Meier method. Cox proportional regression analysis was used to evaluate the clinical variables associated with risk of treatment-failure and death. Results Our cohort of 63 patients had a median age of 69 (19–93), male sex in 49%, a Karnofsky performance status of at least 80 at time of diagnosis in 73%, an elevated serum lactate dehydrogenase (LDH) in 62%, and stage IV disease in 46%. International Prognostic Index (IPI) scores were low in 38%, low-intermediate in 27%, high-intermediate in 24% and high in 11%. The probability of PFS at 5 and 10 years was 25% (95% CI 15–37%) and 10% (95% CI 4–21%) respectively, with a median time to treatment-failure of only 5.7 months. The 5 and 10 year probability of OS was 32% (95% CI 21–44%) and 20% (95% CI 10–32%) respectively, with a median survival of 10.4 months. Univariate regression analysis showed the following factors to be associated with an increased risk for treatment-failure: Ann Arbor stage IV disease (HR 2.49, 95% CI 1.33–4.68); elevated LDH (HR 1.85, 95% CI 1.02–3.37) and having at least 2 extra-nodal sites (HR 2.12, 95% CI 1.12–4.04). The following factors were associated with an increased risk of death: elevated LDH (HR 2.03, 95% CI 1.08–3.81), stage IV disease (HR 1.88, 95% CI 1.00–3.45), and having at least 2 extra-nodal sites (HR 2.26, 95% CI 1.15–4.40). The IPI scores of low-intermediate, high-intermediate, and high risk were associated with treatment-failure (HR 2.01, 95% CI 1.00–4.11; 4.62, 95% CI 2.11–10.14; 6.11, 95% CI 2.31–16.17) respectively, and death (HR 2.57, 95% CI 1.23–5.37; 3.13, 95% CI 1.41–6.94; 8.30, 95% CI 3.07–22.43) respectively. The median OS of patients who received CHOP/CHOP-like regimens +/− R was 8.7 months, whereas those who received a more intensive regimen +/− R was 45 months (p=0.38). The median PFS was 5.4 months for CHOP/CHOP-like regimens +/− R and 52.3 months for a more intensive regimen (p=0.08) (Fig.1).Figure 1.Progression free survival intensive versus CHOP/CHOP-like regimens +/− Rituximab, p=0.08Figure 1. Progression free survival intensive versus CHOP/CHOP-like regimens +/− Rituximab, p=0.08 Summary Our analysis confirmed poor clinical outcome with stage IV disease, elevated serum LDH, at least 2 extra-nodal sites at presentation, or worse IPI score. There was a better outcome with intensive chemotherapy regimens. This study underscores the importance of early identification and proper treatment choice. Disclosures: No relevant conflicts of interest to declare.

Description: Background: In diffuse large B-cell lymphoma (DLBCL), the presence of MYC and BCL2 and/or BCL6 translocations, so-called double-hit lymphoma (DH), has been associated with an aggressive clinical course. Recently, it was reported that gene expression profiling (GEP) could also identify cases with the biological and clinical characteristics of DH lymphoma, including some without the requisite translocations (DHITsig-positive cases)1. The purpose of this study was to develop a molecular subtyping schema for germinal center B-cell type (GCB) DLBCL using genomic studies such as fluorescence in situ hybridization (FISH) cytogenetic analysis, GEP, and mutation analysis to risk-stratify patients with GCB DLBCL. Method and Results: We performed a detailed genomic analysis of 87 cases of de novo GCB DLBCL to identify characteristics that are associated with survival in those treated with R-CHOP. The cases were extensively characterized by combining the results of immunohistochemistry, cell-of-origin GEP (Nanostring), DH GEP (DLBCL90)1, FISH cytogenetic analysis for DH lymphoma, copy number analysis (CNA), and targeted deep sequencing using a custom mutation panel of 334 genes. These studies were used to divide the cases into four groups. GCB1: DHITsig-positive with TP53 inactivation (DHIT+TP53): DLBCL with TP53 mutations and/or deletions has a poor prognosis in patients treated with R-CHOP. We found 7 cases (8% of all cases) of GCB DLBCL that were DHITsig-pos with TP53 abnormalities. By FISH analysis, two cases had a triple-hit (TH), one was DH with MYC/BCL2, and 2 cases had a MYC translocation only. Cases in GCB1 had the worst overall survival (OS; Hazard Ratio (HR)=9.2, P=0.0018) and shortest progression-free survival (PFS; HR=6.1, P=0.002) compared to other groups (Figures 1 A/B). However, cases with TP53 abnormalities that were DHITsig-neg did not have the same poor survival. GCB2: DHITsig-positive (DHITsig-pos): The other 8 cases (9%) who were DHITsig-pos from the DBLCL90 GEP but lacked TP53 abnormalities showed a predilection (88%) for having an EZH2 mutation and/or BCL2 translocation (EZB of Schmitz et al2). These cases also had a high frequency of MYC mutations (63%) but lacked mutations in SGK1 and had a low frequency of mutations in linker histone genes (e.g. HIST1H1E). By FISH analysis, 3 cases were DH lymphoma with MYC/BCL2, 2 cases were TH lymphoma, and 1 case had a MYC translocation only. Typically DHITsig-pos cases have a poor OS when compared to DHITsig-neg cases1, however this group demonstrated good survival in our study, after removing the cases with TP53 abnormalities. GCB3: DHITsig-negative and EZH2 mutation and/or BCL2 translocation (EZB-like): We had 28 cases (32%) that were DHITsig-neg and had an EZH2 mutation and/or BCL2 translocation. These were categorized as EZB-like with some overlapping features with the DLBCL in Cluster 3 of Chapuy et al3. The survival of this group was intermediate compared to the other groups (Figures 1A/B). GCB4: DHITsig-negative and not EZB-like (GCB Other): The largest group of cases (51%) were DHITsig-neg and lacked EZH2 mutations and BCL2 translocations. These cases had frequent mutations in SGK1 (16%) and histone modifying genes (50%), as well as TET2 mutations (25%). These cases have similarities to Cluster 4 of Chapuy et al3 and the ST2 group from Wright et al4. The survival of this group was excellent (Figures 1 A/B). These groups were validated in an independent cohort of 188 cases of GCB DLBCL4 (Figures 1 C/D). Conclusions: We have identified four distinct biologic subgroups of GCB DLBCL with different survival rates, and with similarities to the genomic classifications from recent large retrospective studies of DLBCL. Patients with the DH signature but no abnormalities of TP53 (GCB2), and those lacking EZH2 mutation and BCL2 translocation (GCB4), had an excellent prognosis. However, patients with an EZB-like profile (GCB3) had an intermediate prognosis, whereas those with TP53 inactivation combined with the DH signature (GCB1) had an extremely poor prognosis. We propose this as a practical schema to risk-stratify patients with GCB DLBCL. This schema provides a promising new approach to identify high-risk patients for new and innovative therapies. Figure 1 Disclosures Herrera: AstraZeneca: Research Funding; Karyopharm: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Pharmacyclics: Research Funding. Zain:Kyowa Kirlin: Research Funding; Mundai Pharma: Research Funding; Seattle Genetics: Research Funding. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Kwak:Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; CJ Healthcare: Consultancy; Sellas Life Sciences Grp: Consultancy; Enzychem Life Sciences: Membership on an entity's Board of Directors or advisory committees; Antigenics: Other: equity; InnoLifes, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pepromene Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Xeme Biopharma/Theratest: Other: equity; Celltrion, Inc.: Consultancy. Scott:NIH: Consultancy, Other: Co-inventor on a patent related to the MCL35 assay filed at the National Institutes of Health, United States of America.; Roche/Genentech: Research Funding; Celgene: Consultancy; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoString, Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding.