non-GCB Subtype Research Articles

Expressions of programmed death-ligand 1 and 2 and phosphorylated protein kinase B in diffuse large B-cell lymphoma and their clinical significances

Objective To investigate the expressions of programmed death-ligand 1 (PD-L1) and PD-L2 and phosphorylated protein kinase B (p-AKT) in diffuse large B-cell lymphoma (DLBCL) patients and their correlations with clinicopathological features and prognosis. Methods A total of 68 paraffin-embedded specimens of DLBCL patients diagnosed in Shanxi Provincial Cancer Hospital with detailed follow-up record from January 2010 to December 2012 were included in the study. The expressions of PD-L1, PD-L2 and p-AKT proteins in DLBCL were detected by using immunohistochemistry (IHC). Results The positive rate of PD-L1 protein in DLBCL patients was 22.1% (15/68), which was related to germinal center B-cell (GCB) subtype or not (χ2=5.591, P = 0.018), clinical stage (χ2=3.969, P = 0.046), international prognostic index (IPI) grades (χ2=4.178, P = 0.041) and treatment remission rate (χ2=6.587, P = 0.010). The positive rate of PD-L2 protein in DLBCL patients was 14.7% (10/68), which was related to extranodal metastasis or not (χ2=6.772, P = 0.009). The positive rate of p-AKT for DLBCL patients was 61.8% (42/68), which was correlated with age (≥60 years old) or not (χ2=6.227, P = 0.013), Eastern Cooperative Oncology Group (ECOG) grades (χ2=4.005, P = 0.045), B symptoms (χ2=10.187, P = 0.001) and treatment remission rate (χ2=4.096, P = 0.043). Univariate survival analysis showed that the overall survival (OS) rate and progression free survival (PFS) rate of PD-L1 protein positive expression group were lower than those of PD-L1 protein negative expression group (both P < 0.05). In the patients with non-GCB subtype, OS rate and PFS rate of PD-L1 protein positive expression group were lower than those of PD-L1 protein negative expression group (both P < 0.05). p-AKT protein positive expression group had poorer OS rate and PFS rate compared to p-AKT negative expression group (both P < 0.05). Correlation analysis showed that PD-L1 protein expression was correlated with PD-L2 and p-AKT proteins expressions (r = 0.380, P = 0.001; r = 0.273, P = 0.025). The prognosis was worse when p-AKT and PD-L1 proteins was co-expressed (P < 0.05). Multivariate analysis suggested high expressions of PD-L1 and p-AKT proteins were independent prognosis risk factors in DLBCL (both P < 0.05). Conclusions The expressions of PD-L1 and p-AKT proteins may be involved in the occurrence and development of DLBCL. Blocking PD-1 and PD-L1 access or combined blocking could provide a promising future for the clinical therapy. Key words: Lymphoma, large B-cell, diffuse; Programmed death-ligand 1; Programmed death-ligand 2; Protein kinase B; Prognosis

Immunohistochemical Subtype and Parameters of International Prognostic Index in the New Prognostic Model of Diffuse Large B-Cell Lymphoma

Aim. To develop an integrated prognostic model of diffuse large B-cell lymphoma (DLBCL) on the basis of immunohis-tochemical tumor subtype and parameters of International Prognostic Index (IPI). Materials &amp; Methods. Out of 104 DLBCL patients in the data base 81 (77.9 %) met the eligibility criteria. Median age was 58 years (range 23-83). All patients were treated with R-СНОР. The creation of overall survival (OS) prognostic model for DLBCL patients was based on machine learning with classification and regression trees. OS was analyzed using Kaplan-Meier method. Survival curves were compared by means of log rank test and hazard ratio (HR). Any test was considered significant if two-sided level of p &lt; 0.05 was reached. Results. Following the developed model three groups of patients were identified: the 1st group of low risk (the combination of low, intermediate-low, and intermediate-high risks according to IPI and GCB subtype); the 2nd group of intermediate risk (the combination of low, intermediate-low, and intermediate-high risks according to IPI and non-GCB subtype); the 3d group of high risk (irrespective of subtype). In the group of low risk (n = 26) 2-year OS during the monitoring period was 100 %. In the group of intermediate risk (n = 34) median OS was not reached, 2-year OS was 74 %, and expected 5-year OS was 68 %. In the group of high risk (n = 21) median OS was 25 months, 2-year OS was 46 %, and expected 5-year OS was 37 % (log rank p &lt; 0.0001). HR calculated for the high-risk group compared with the low- and intermediate-risk groups was 5.1 (95% CI 2.112.1; p = 0.0003). Conclusion. A new integrated system of DLBCL prognosis is suggested which includes IPI risk parameters and immunohistochemical subtype based on Hans algorithm. This prognostic system can be used in clinical practice for DLBCL patient stratification and risk-adapted therapy.

Aggressive B-cell lymphomas—from morphology to molecular pathogenesis

The2016 revised World Health Organization (WHO) classification of lymphoidmalignancies recognizes several distinct entities within the group of diffuselarge B-cell lymphoma (DLBCL) characterized by unique clinical and pathologicalfeatures. Nevertheless, diffuse large B-cell lymphoma, not otherwise specified(DLBCL, NOS) is the most common aggressive B-cell lymphoma. In the last 20 yearsour understanding of the genetic changes and biology of DLBCL has increasedtremendously. According to the 2016 WHO classification, the diagnosis of DLBCL,NOS, should include cell of origin (COO); germinal centre B-cell (GCB) oractivated B-cell (ABC)/non-GCB subtypes, because of their different molecularfeatures, biologic behavior, prognosis and treatment. High-grade B-celllymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements (i.e., double-hit or triple-hit lymphoma, DHL or THL) as well asHGBL, NOS, are two new categories in the 2016 revised WHO classification thatsubstituted the provisional category of B-cell lymphoma, unclassifiable (BCLU)with features intermediate between DLBCL and Burkitt lymphoma (BL), which wasintroduced in the 2008 WHO classification. The pathogenesis and molecularchanges of BL are better understood and led to the recognition of a newprovisional entity called Burkitt-like lymphoma with 11q aberration. In thisarticle, we will review the progress made in the last years within the mostcommonly encountered aggressive B-cell lymphomas, highlighting the betterunderstanding of the underlying disease mechanisms that eventually might be translatedinto more rational and effective therapeutic strategies. Controversial issuesabout fluorescent in situ hybridization (FISH) for the detection of MYC , BCL2 and BCL6 translocations will be addressed, as well as newmolecular techniques used to improve diagnosis and prognostication inaggressive B-cell lymphomas.

Diagnostic and therapeutic values of interphase fluorescence in situ hybridization in B-cell lymphomas: a clinicopathologic analysis of 604 cases

Objective: To investigate the feasibility and value of interphase fluorescence in situ hybridization (FISH) in the pathological diagnosis, differential diagnosis and therapeutic assessment of B-cell lymphomas. Methods: The cohort included 604 cases of B-cell lymphoma which were collected at West China Hospital from May 2010 to December 2016.And all were subjected to interphase FISH using 11 break apart or fusion probes (MYC, bcl-2, bcl-6, IRF4, MYC/IgH, bcl-2/IgH, CCND1/IgH, IgH, API2/MALT1, p53/ATM, and D13S319/CEP12). Results: The median age of the 604 B-cell lymphoma patients was 47.7 (aged 2-90) years including 372 men and 232 women. All the cases was divided into 463 large B cell lymphomas(LBL) and 141 small B cell lymphomas, and the total interphase FISH positive rate was 59.8% (361/604). Among the 463 LBL, 12.5% (58/463), 9.5% (44/463) and 2.2% (10/463) of cases showed MYC, bcl-6 and bcl-2 gene rearrangements respectively; and 363 diffuse large B cell lymphoma (DLBCLs) were reclassified as germinal center B-cell (GCB) subtype (38.6%, 140/363) and non-GCB subtype (61.4%, 223/363) by Hans algorithm. The rearrangement rates in GCB and non-GCB DLBCL were 45.7%(64/140)and 21.5%(48/223; P=0.001), respectively. Compared to the non-GCB DLBCL, GCB DLBCL showed higher MYC and bcl-2 gene rearrangements (P=0.001). Eleven (2.4%, 11/463) cases had MYC and bcl-6 or bcl-2 gene rearrangement (double-hit lymphoma); one (0.2%, 1/463) case had MYC, bcl-6 and bcl-2 gene rearrangements (triple-hit lymphoma); two (0.4%, 2/463) cases had bcl-2 and bcl-6 gene rearrangements. MYC translocation and MYC/IgH fusion were detected in 94.2%(81/86) and 83.7%(72/86) cases of Burkitt lymphomas. IRF4 rearrangement was detected in two cases of IRF4+ LBCL. Genetic abnormalities were detected in 9/19, 100%(29/29), 30.8%(12/39) and 68.5%(37/54) cases of follicular lymphoma, mantle cell lymphoma, MALT lymphoma and chronic lymphocytic leukemia, respectively. Conclusions: Interphase FISH can rapidly and accurately detect the genetic changes in B-cell lymphomas. Different genetic changes are specifically valuable to the diagnosis, differential diagnosis, prognosis evaluation and treatment guidance of various B-cell lymphomas.

Addition of Rituximab to High-Dose Methotrexate Regimens Improves Complete Response Rates and Median Overall Survival in Non-Germinal Center Primary CNS Lymphoma

Background:Primary central nervous system lymphoma (PCNSL) is a rare type of extranodal non-Hodgkin lymphoma (NHL). Most cases occur in the immunocompetent population. Despite advances in therapy, the prognosis of PCNSL remains poor, with 5-year overall survival (OS) rates at 30-50% (Ferreri 2011). The standard of care treatment regimen includes high-dose methotrexate (HD-MTX), often in combination with other multiagent CNS penetrating chemotherapies. Although the addition of rituximab in systemic aggressive B-cell NHLs has shown improvement in OS, the benefit of this agent in PCNSL has not been confirmed in a prospective dataset (Bromberg 2017). The majority of PCNSLs are classified as diffuse large B-cell lymphomas (DLBCL), and the outcomes based on treatment and cell of origin (germinal center B-cell (GCB) vs. non-GCB subtype) have yet to be fully elucidated. In this review, we report our findings from a series of PCNSL patients based on treatment regimen and cell of origin.Methods:This is a retrospective study of patients with PCNSL diagnosed and treated at the University of Colorado Hospital from 1995 to 2017. Chart abstraction included demographics, DLBCL subtype by Hans algorithm (Hans 2004), treatment details, and outcomes. OS was examined using Kaplan Meier methods, while bootstrap resampling and a z-test was used to compare median survival times across strata. Fisher's exact test was used to determine whether treatment responses were different between those that received treatment withHD-MTX and rituximab versus HD-MTX without rituximab. A significance level of 0.05 was used for all tests. When assessing differences by subtype, treatment type, relapse, and treatment response the data was subset to include only patients without a prior HIV diagnosis.Results:71 patients with PCNSL were identified. 13 patients were HIV positive (the HIV status of 1 patient was unknown). Of the remaining 57 immunocompetent patients, 39 patients were treated with HD-MTX, of which 29 patients received rituximab in combination therapy. The most commonly received regimen was rituximab with methotrexate, procarbazine, and vincristine (R-MPV) (43.6%, 17 of 39). Median age in the HD-MTX subgroup was 65 years, with 83% of patients with KPS>70 at diagnosis. EBV positivity was noted in only 4 of 39 samples (10.2%), while 25 of 39 (64.1%) tested negative; the remaining patients' data was not available.Median OS was 29.9 months for all 71 patients (Figure 1). There was no significant difference in median OS between those with and without HIV (p=0.127).22 of 29 (75.9%) patients in the HD-MTX with rituximab group achieved a complete response (CR) while no patients (0%; 0 of 10) in the HD-MTX without rituximab group achieved a CR. The number of patients with a CR was significantly higher for those that received HD-MTX with rituximab compared to those that received HD-MTX without rituximab (p<0.001).Median OS for HIV negative patients treated with HD-MTX without rituximab (N = 10) was 32.6 months whereas median OS for HIV negative patients treated with HD-MTX with rituximab (N = 29) has not been reached at a median follow up of 33.4 months (range 1.5 - 116.9 months) (Figure 2)Subtyping was available for 23 patients without HIV treated with HD-MTX with or without additional agents. 6 patients had GCB subtype and 16 had non-GCB subtype. Median OS for GCB subtype has not yet been reached, while median OS for non-GCB subtype was 33.4 months (Figure 3). When analyzing data for patients who received HD-MTX and rituximab, median OS for GCB has not been reached, while median OS for non-GCB was 43.8 months (Figure 4).Conclusions:Our review of patients with PCNSL suggests that the addition of rituximab to a high dose MTX-based regimen improves survival although numbers are too small to determine any overarching statistical conclusion. CR rates were significantly higher in patients receiving rituximab in addition to HD-MTX compared to HD-MTX without rituximab. Patients with non-GCB subtype treated with HD-MTX and rituximab had increased median OS compared to median OS of non-GCB patients treated with HD-MTX without rituximab. However, in line with previous data we demonstrated worse outcomes associated with non-GCB subtype compared to GCB subtype. Future research is needed to focus on the characteristics of this subtype of PCNSL to improve outcomes with novel therapeutics. [Display omitted] DisclosuresKamdar:Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b Sadal Study

Single Agent Oral Selinexor Demonstrates Deep and Durable Responses in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL) in Both GCB and Non-GCB Subtypes: The Phase 2b Sadal Study

Epstein-Barr Virus Status in Diffuse Large B Cell Lymphoma Post-Transplant Lymphoproliferative Disorder

BackgroundDiffuse large B cell lymphoma post-transplant lymphoproliferative disorder (DLBCL-PTLD) represents a fatal complication after a solid organ transplant (SOT). Approximately 50% of DLBCL-PTLD can be related to Epstein Barr Virus (EBV) infection. However, the EBV status is not taken into account in the DLBCL-PTLD categorization, although increasing evidence suggests its critical role in biological, clinical and prognostic aspects of the disease. In this single center retrospective study, we compared clinical and histological features, as well as outcomes of DLBCL-PTLDs by EBV status.MethodsThis study focused on patients with SOT who were diagnosed with DLBCL-PTLD at Mayo Clinic (Rochester, MN). Patients were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), between 1989 and 2017. The histology was re-reviewed (RLK) and classified according to the WHO Classification or Tumours of Haematopoietic and Lymphoid Tissues 2017. Cell of origin (COO) was performed by Hans algorithm. EBV RNA in situ hybridization (EBER) was performed. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS).Results148 DLBCL-PTLD were identified. The median age at SOT and at the time of PTLD diagnosis were 50 years (range: 15-71) and 56 years (range: 18-82), respectively. The median time to PTLD diagnosis from SOT was 38 months (range: 1-499). The types of SOT included renal (44%), liver (36%), cardiac (9%), renal/pancreas (5%), pancreas (8%), lung (7%) and multiorgan (4%). 62% were stage III-IV, 30% had elevated LDH and 67% had an IPI >1. 88% of patients presented with extranodal disease, and 16% had involvement of the grafted organ. Eighty-three (56%) cases were EBV positive. The COO information was available on 35 cases. The non-GCB subtype was identified in 24 cases and GCB subtype in 11 cases. The initial treatment was as follows: reduction in immunosuppression (12%), immunosuppression reduction with rituximab (26%), rituximab alone (5%), chemotherapy with or without rituximab (35%). Patients with EBV positive PTLD were more likely to have grafted organ involvement (20% vs. 8%, p=0.047) and late PTLD (occurring after 12 months from SOT - 60% vs. 8%, p<0.001) than patients with EBV negative PTLD. There was no association between EBV status and age, sex, stage, LDH, and extranodal site involvement. At a median follow-up of 80 months (range 9-269), 83 patients (56%) had died. The 5-year survival rate from PTLD diagnosis was 56% (95% CI: 48-65%). The median OS was 85 months (95% CI: 37-148). There was no difference in OS in patients with EBV positive PTLD (median OS=84.7 months, HR=1.21, 95% CI: 0.77-1.92) versus patients with EBV negative DLBCL-PTLD (median OS=85.4 months, p=0.41).ConclusionOur study assessed the impact of EBV status on the presentation and clinical outcome of DLBCL-PTLD in a 148-patient single-institution cohort. 56% of cases were EBV positive. EBV positivity was associated with grafted organ involvement and late PTLD diagnosis. Patients with EBV-negative and EBV-positive disease had similar survival from PTLD diagnosis. DisclosuresMaurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Clinical Characteristics and Outcomes of Chronic Lymphocytic Leukemia Patients with Richter Transformation

Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Most studies on the management of RT were either small retrospective series or early phase non-randomized trials before the era of novel agents. The natural history, prognostication and optimal treatment of patients with RT remain undefined. Here we report the clinical characteristics and outcomes of a large series of RT from a single center. Methods: Biopsy-confirmed RT (limited to non-Hodgkin lymphoma) diagnosed from 4/1993 to 4/2018 were identified from the Mayo Clinic CLL database. Clinical characteristics, treatment information and follow-up data were abstracted by chart review. Overall survival (OS) was defined as time from RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analysis was done in SAS 9.4. Results: A total of 204 patients with CLL who developed RT were identified. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (73%) were male. The median time to transformation was 4.7 years (range 0-34.5). Prior to RT, 68 (33.3%) patients received no treatment for CLL, 109 (53.4%) received chemoimmunotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL. The median lines of CLL therapy prior to RT was 2 (range 0-13). The median age at RT diagnosis was 69 years (range 30-88). Pathology of RT was DLBCL and high grade B-cell lymphoma in 193 (94.6%) and 11 (5.4%) patients, respectively. The median LDH was 306 IU/L (range 99-9000). 62/125 (49.6%) patients had bulky disease (≥ 5 cm), and the median PET SUVmax was 13.9 (range 2.9-30.0). 45/131 (34.4%) patients had del(17p) or TP53 mutation, 12 (9.2%) had del(11q), 21 (16.0%) had trisomy 12, 27 (20.6%) had del(13q), and 25 (19.1%) had normal FISH. The CLL and RT were clonally related in 12/21 (57.1%) patients. For the transformed lymphoma, cell of origin by Han9s algorithm was germinal center B cell-like (GCB) and non-GCB in 31/100 (31.0%) and 69/100 (69.0%) patients, respectively. EBV was positive in 14/52 (26.9%) patients. The median Ki-67 was 80% (range 10-100). Myc and Bcl-2 were positive by IHC in 31/43 (72.1%) and 83/103 (80.6%) patients, respectively; 27/56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18/68 (26.5%), 10/34 (29.4%), and 4/31 (12.9%) patients, respectively; 8/66 (12.1%) were double/triple-hit. The most common first-line treatment (Table 1 notes) of RT was R-CHOP-like regimen (n=114, 65.5%). Other treatments included R-EPOCH-like (n=6, 3.4%), high-intensity chemotherapy (n=15, 8.6%), novel agents (eg, ibrutinib, venetoclax, pembrolizumab; n=19, 10.9%), other chemotherapy (n=12, 6.9%), and palliative therapy (n=8, 4.6%). Response to first-line treatment was CR in 57 (38.0%), PR in 33 (22.0%), SD in 18 (12.0%), and PD in 42 (28.0%) patients. The median OS of the entire cohort after RT diagnosis was 12.0 months. The median OS for patients who received no prior CLL treatment, CIT only or at least one novel agent for CLL were 65.5, 7.3, and 12.0 months, respectively (P Conclusions: Over two thirds of RT were the non-GCB subtype, and about half were Myc/Bcl-2 double expressors. Patients who developed RT without prior CLL therapies had a significantly better OS. In contrast, patients who had received prior CLL therapies had poor outcomes. Myc/Bcl-2 double expressor and MYC/BCL2/BCL6 double/triple hit status had no impact on OS. Disclosures Kenderian:Humanigen: Research Funding; Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding. Kay:Infinity Pharm: Membership on an entity9s Board of Directors or advisory committees; Celgene: Membership on an entity9s Board of Directors or advisory committees; Agios Pharm: Membership on an entity9s Board of Directors or advisory committees; Morpho-sys: Membership on an entity9s Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees; Acerta: Research Funding; Cytomx Therapeutics: Membership on an entity9s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity9s Board of Directors or advisory committees. Parikh:Janssen: Research Funding; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding; Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding. Ding:Merck: Research Funding.

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

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. DisclosuresLeppa: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.

CD47 Expression Defines the Efficacy of Rituximab in Non-Germinal Center B-Cell (non-GCB) Diffuse Large B-Cell Lymphoma (DLBCL)

▪CD47 is an immune-checkpoint protein that binds SIRPa on immune cells to deliver an inhibitory “don't eat me” signal. CD47 is a prominent new target in B-cell malignancies, in which CD47 antibody in combination with the CD20 antibody rituximab (R) is explored in clinical trials. Addition of R to CHOP chemotherapy significantly improves survival of patients with DLBCL, but how CD47 expression contributes to this positive impact of R on patient outcome is currently unclear. Especially in the context of the different cell-of-origin DLBCL subtypes (Germinal Center B-cell (GCB) vs non-GCB DLBCL).We therefore investigated the impact of CD47 expression on rituximab efficacy. We first studied a clinically well annotated transcriptome cohort of 939 DLBCL patients treated with either CHOP or R-CHOP, and we validated these findings in functional in vitro assays. Our analyses showed that overall survival (OS) for patients with high CD47 expression (i.e. above median) is worse compared to patients with low CD47 expression (i.e. below median) after R-CHOP (p=0.001), but not after CHOP treatment (p=0.645). Correspondingly, patients with low CD47 expression benefited most from addition of R to CHOP (HR=0.32, CI:[0.21-0.50], p<0.0001). Non–GCB patients showed a worse survival compared to GCB DLBCL patients after R-CHOP treatment (p<0.0001). Interestingly, with respect to COO classification, high expression of CD47 impacted the OS in non-GCB R-CHOP-treated patients (HR=1.9, CI:[1.14-3.26], p=0.013) but not in GCB DLBCL patients (HR=1.16, CI:[0.68-1.99], p=0.58). Importantly, high CD47 expression was found to determine the worse overall survival of non-GCB versus GCB patients (p=0.0006). No difference in OS was observed between GCB and non-GCB-patients with low CD47 expression (p=0.7662). Pro-phagocytic receptors expressed on DLBCL, i.e. SLAMF7, did not determine outcome upon R-CHOP treatment. In multivariate analysis, high CD47 expression remained significantly associated with poor survival only in non-GCB-patients.We further investigated this differential impact of CD47 in non-GCB and GCB subtypes in vitro. Non-GCB and GCB DLBCL cell lines (n=6) were mixed with allogeneic M1 macrophages and treated with a CD47 blocking antibody, which comprises human IgG4. Results confirmed that macrophage-mediated phagocytosis by R was augmented with CD47-blocking antibody only in non-GCB DLBCL cell lines, and not in GCB DLBCL cell lines. Also, CD47 blocking co-treatment also increased the number of tumor cells ingested per macrophage, with a clear significant increase in phagocytic index in non-GCB cells, but not in GCB DLBCL cells (p=0.001).In conclusion, the patient benefit of addition of R to CHOP is limited by CD47 specifically in non-GCB patients. In addition, we confirmed that CD47-blocking only augmented rituximab-mediated phagocytosis in non-GCB cell-lines. Together, these data suggest that especially non-GCB DLBCL patients with a currently worse prognosis may benefit from CD47-targeted therapy combined with rituximab. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prognostication of Diffuse Large B-Cell Lymphoma By Lympho2Cx Assay and BCL2 and MYC Expression: Application in a Real Life Context of 154 Patients

BACKGROUND: About one third of patients with diffuse large B-cell lymphoma (DLBCL) eventually die from their disease. Thus, it is extremely important to identify powerful and reliable predictive and prognostic markers. In real life patient management, the clinical relevance of the assessment of the Cell of Origin (COO), of MYC and BCL2 protein overexpression, is still not fully clarified. The aim of the study is to evaluate the predictive and prognostic value of COO with Lympho2Cx assay by Nanostring technology and BCL2 and MYC overexpression by immunohistochemistry (IHC), in a real-life context.METHODS: This is a retrospective multicenter study which recruited 154 DLBCL patients treated with R-containing regimen between June 2010 and December 2016 in Modena, Rome (Italy) and Haifa (Israel). All clinical data were recorded at diagnosis and during follow up, including response assessment and survival outcome. COO was determined on formalin-fixed paraffin-embedded diagnostic specimens either by IHC using a panel of antibodies which included CD10, BCL6, MUM1 (i.e. Hans algorithm), or at RNA level with Lymph2Cx assay by Nanostring technology. Expression of MYC and BCL2 was evaluated by IHC. Event free survival (EFS) is defined as the time from diagnosis to the time of last follow-up, or to one of the following events: any response other than complete remission (CR) at the end of therapy or death from any cause. It is assessed by Kaplan-Meier estimates and groups of risk are compared using the log rank test.RESULT: We have currently evaluated the data of 60% (95 out of the 154) of the patients enrolled in the study (Tab 1). After a median follow up of 49 months, EFS is 63% (95CI 51-72%).In univariate analysis, the variables with the greatest impact on the response and on EFS are absolute granulocyte count and BCL2 expression (MYC ongoing). Patients with low IPI showed better survival in comparison with patients with high IPI, but the difference is not statistically significant. By IHC non-GCB subtype was more common than GCB (56% vs. 44%); by Nanostring ABC, GCB and unclassified subtypes were 33%, 50% and 17%, respectively, and K statistics was 0,647, showing a substantial agreement between the results obtained by IHC and by Lympho2Cx assay. No statistically significant differences were observed in EFS among ABC, GCB and unclassified subtypes. However, BCL2 protein overexpression in ABC subtype is associated with shorter EFS.CONCLUSION: Early retrospective studies showed a survival advantage for GCB-type disease. Clinical trial data evaluating the impact of COO determined by GEP on prognosis have shown inconsistent results with 2 studies observing inferior survival of ABC subtype and 2 German studies showing no significant differences in PFS or OS among COO subtypes. Determination of COO by Lympho2Cx is attractive as it is relatively easy and rapid to perform and potentially applicable to clinical practice. However, these preliminary results do not support, at this point, its use as prognostic factor in clinical practice. The analysis of the remaining 59 patients will help to clarify the role Lympho2Cx assay in the context of real life.Table 1. Patients baseline characteristics. DisclosuresTadmor:ABBVIE: Consultancy; ROCHE: Research Funding; JNJ: Consultancy; NOVARTIS: Consultancy; PFIEZER: Consultancy.

High Level of Pre-Treatment C-Reactive Protein-to-Albumin Ratio Predicts Inferior Prognosis in Diffuse Large B Cell Lymphoma

IntroductionDiffuse large B cell lymphoma (DLBCL) is the most common highly aggressive non-Hodgkin lymphoma (NHL) worldwide. The International Prognostic Index (IPI) has been established as a useful prognostic marker, and there have been some proposed markers which could reflect tumor microenvironment including neutrophil, lymphocyte, platelet, serum globulin, ferritin and serum free light chain. C-reactive protein (CRP) is one of the commonly used inflammatory markers, and its clinical relevance has been suggested recently in various malignancies. Serum albumin is a representative marker for nutritional status, and previous studies have presented that hypoalbuminemia might be an indicator of cancer-related inflammation as well. In this point of view, C-reactive-to-albumin ratio (CAR) has been suggested as one of easily-accessible parameters which could be a robust prognostic marker in diverse malignancies such as lung cancer, gastric cancer and colorectal cancer. However, its clinical value has not been assessed in hematologic malignancies. In this study, we evaluated the prognostic effect of CAR in DLBCL.MethodsThis retrospective study included 186 patients who were histologically diagnosed with DLBCL and treated with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) between 2006 and 2018 at National Cancer Center, Korea. One hundred forty one cases were identified whose baseline laboratory values including CRP and albumin were available, and then the medical records were reviewed. To define the appropriate cutoff value of CAR in patients with DLBCL, cutoff finder method was applied which had been suggested by Budczies et al., and the most discriminative point was designated by the value of 0.158. Clinical characteristics and outcomes including response rate, overall survival (OS) and progression-free survival (PFS) were investigated between high and low CAR group. Additionally, the clinical value of CAR was compared to the components of IPI for DLBCL as well.ResultsOf all patients, 73 (51.8%) were classified as high CAR group. Male was 42 (57.5%) in high CAR group and 37 (54.4%) in low CAR group. In terms of IPI, 21 (28.8%) were classified into high IPI (score of 4 or 5) in high CAR group - 6 (8.8%) in low CAR group in comparison. Hans criteria was applied to discriminate germinal center B-cell (GCB) subtype to non-GCB subtype by immunohistochemistry and after 12 patients removed due to missing GCB status, 56 (84.8%) in high CAR group was sorted to non-GCB type - 46 (73.0%) in low CAR group to be compared. The high CAR group showed significantly worse complete response (CR) rates to induction R-CHOP therapy (64.4% vs. 92.6%; p<0.001). Median cycles of induction chemotherapy was 6 in all patients and there was no significant difference between both groups (p=0.824). With a median follow-up of 32.5 months, the high CAR group revealed significantly worse 5-year OS (65.0 vs. 93.5%; p<0.0001) and 5-year PFS (53.5 vs. 80.7%; p<0.0001) (Figure 1). In univariable Cox analysis, high CAR was a statistically significant prognostic factor for both 5-year OS (HR 8.04, 95% CI 2.384-27.139; p=0.001) and 5-year PFS (HR 4.44, 95% CI 2.109-9.341; p<0.001). Along with CAR, all components of IPI was statistically significant for both OS and PFS, except age at diagnosis (HR 1.95, 95% CI 0.908-4.207, p=0.087) for 5-year OS. In multivariable analyses with adjustment for age (>60), stage (III, IV), lactate dehydrogenase (LDH) (>upper normal limit), Eastern Cooperative Oncology Group (ECOG) performance status (>1) and the number of extranodal involvement (>1), high CAR showed statistically significant results for both 5-year OS (HR 4.71, 95% CI 1.175-18.892; p=0.029) and 5-year PFS (HR 2.66, 95% CI 1.122-6.289; p=0.026) (Table 1).ConclusionsIn conclusion, CAR might play an additional role to IPI in prognostication of patients with DLBCL considering the fact that it is simple, objective and easy to obtain. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single-Center Phase IIa Study Evaluating the Safety and Tolerability of Umbralisib and Ibrutinib in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Introduction: Treatment for relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL) remains an unmet medical need despite the recent approval of chimeric antigen receptor T-cell (CAR-T) therapeutic constructs. Many patients will be “too sick to CAR-T” or may have logistical/financial challenges that will not allow this treatment. As a result, non-chemotherapy agents with activity in rel/ref DLBCL require further development to help fill this need. Umbralisib (UMB) is dual PI3K delta/CK-1ε inhibitor that has single agent activity in rel/ref DLBCL with an ORR of 31% [Burris et al. 2018]. Ibrutinib (IBR) is a Bruton Tyrosine kinase (BTK) inhibitor with activity seen in the activated B-cell (ABC) subtype of DLBCL with an ORR of 37% in this subtype [Wilson et al. 2015]. Pre-clinical data (not shown) demonstrated synergistic activity of UMB-IBR against cell lines of both germinal center B-cell (GCB) and non-GCB subtypes of DLBCL. We report results of phase IIa study of the combination of UMB-IBR in rel/ref DLBCL.Methods: Eligible patients (pts) had relapsed or refractory DLBCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. The Hans algorithm defined cell of origin. UMB was dosed at 800 mg daily in AM and IBR 560 mg daily in PM. Treatment stratification was performed on a 1:1:1 design to Cohort A (UMB), B (IBR), or C (UMB+IBR) by consent to optional biopsies, which included optional pre-treatment and day 8 biopsies to assess pre-specified correlative flow cytometric analysis of the B-cell receptor (BCR) pathway. In cohorts A/B the combination was initiated at day 8. A cycle was 28 days. Pts received UMB-IBR for up to 1-year of therapy in the absence of progression disease (PD) or excess toxicity. The primary endpoint was monitoring for cumulative toxicity events (CTEs) occurring during cycles 1-4. A CTE was defined as grade (G) 4 neutropenia or thrombocytopenia, G3 neutropenia or thrombocytopenia last longer than 7 days, G3 non-hematologic toxicity, or any G adverse event which led to a drug hold > 7 days. Consecutive stopping rules for CTEs and efficacy were employed. Secondary endpoints included overall response rate (ORR), complete response (CR) rate, partial response (PR) rate, progression-free survival (PFS), time to response (TTR), and duration of response (DOR).Results: Thirteen pts with rel/ref DLBCL were enrolled. Median age was 71 years (range 27-81) and 9 were male. Median number of prior therapies was 2 [range 1-7] with 8% having undergone prior autologous transplantation. Sixty-two percent were refractory to last therapy. DLBCL subtypes were GCB in 7 and non-GCB in 6 pts. The first 3 pts were enrolled to Cohort C regardless of optional biopsy consent. Cohorts A (n=1) and B (n=1) included pts that consented to optional biopsies. Cohort C (n=11) included the first 3 pts enrolled into the study and those thereafter that did not consent to optional biopsies. Two CTEs were seen: G3 rash and G3 Clostridium difficile (C. diff) diarrhea. No CTEs occurred during cycle 1. Notable serious or recurrent adverse events (SAEs or AEs) of interest occurring across all cycles regardless of attribution included elevated AST/ALT 0% G 3-4 (all G 31%), nausea 15% G 3-4 (all G 54%), and diarrhea 15% G 3-4 (all G 31%). The ORR of the UBR-IBR regimen was 23% with 2 PRs (both GCB) and 1 CR (non-GCB). The pt in CR remains on treatment at 7 months and recovered from a CTE during cycle 4 (C. diff). The median PFS was 3 months [95 % CI 0.85, 3.8]. No patient was taken off study for toxicity and there were no dose reductions necessary.Conclusion: In this phase IIa study of rel/ref DLBCL, the non-chemotherapy regimen of UMB-IBR was well tolerated with only 2 CTEs and limited AEs. The evaluation of CTEs was limited by the rapid PD in many pts seen prior to 4 cycles of therapy. The ORR of the UMB-IBR was modest (23%) and of limited durability in this difficult to treat patient population. Based on limited activity and difficulty in obtaining biopsies for correlative analyses, this study was terminated prematurely. DisclosuresLunning:Portola: Consultancy; Spectrum: Consultancy; Genzyme: Consultancy; Genentech: Consultancy; Juno: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Kite: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Blumel:TG Therapeutics, Inc.: Consultancy. Vose:Epizyme: Honoraria; Seattle Genetics, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Roche: Honoraria; Acerta Pharma: Research Funding; Abbvie: Honoraria; Kite Pharma: Research Funding; Legend Pharmaceuticals: Honoraria; Incyte Corp.: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding.

Primary Diffuse Large B Cell Lymphoma of Thyroid Gland; Germinal Center and Non-germinal Center B Types: Experience of a Single Center

Diffuse large B cell lymphoma (DLBCL) is the most common histological subtype accounting for approximately 70% of primary thyroid lymphoma (PTL) cases. Its prognosis depends on the histology, spread, and the stage of the disease. DLBCL usually displays a better prognosis, but it shows heterogeneity according to the histological subtype. Germinal center B cell (GCB) subtype has a more favorable prognosis than the non-germinal center (non-GCB) subtype. Most of these patients required combined modality management. This study included eight patients with stage I/IIE thyroid DLBCL. Analysis of clinicopathologic features of all PTL patients diagnosed at Cerrahpasa Faculty of Medicine. Pathology reports and slides of patients diagnosed between years of 2000 and 2013 were evaluated. Four of them were GCB and the other four cases were non-GCB type. All patients underwent thyroidectomy. Three of them were treated with chemotherapy and the three patients were treated with chemotherapy followed by radiotherapy. Five patients are presently alive. Due to the fact that PTLs are rare types of tumors, only small case series were published in that field. Increasing the number of cases in the literature for thyroid DLBCL, its histopathologic features will provide a better understanding.

Clinicopathologic implication of PD-L1 and phosphorylated STAT3 expression in diffuse large B cell lymphoma

BackgroundAntitumor immune response of programmed cell death ligand (PD-L1) has shown clinical value not only in Hodgkin lymphoma and EBV-associated lymphomas but also in EBV-negative diffuse large B cell lymphoma (DLBCL) of non-germinal center B cell-like (non-GCB) subtype. Signal transducer and activator of transcription 3 (STAT3) is known to induce PD-L1 in immune cells and its activated form, phosphorylated STAT3 (pSTAT3), is also frequently expressed in non-GCB DLBCL. Herein, we investigated associations between PD-L1 expression/gene alteration, pSTAT3 expression and clinicopathologic variables in EBV-negative DLBCL.MethodsIn 107 cases of DLBCLs with non-GCB subtype (67%; 72/107), GCB subtype (25%; 27/107) and unclassifiable cases (8%; 8/107), we performed PD-L1 and pSTAT3 immunohistochemistry and fluorescence in situ hybridization for PD-L1 gene translocation and copy number gain/amplification.ResultsPD-L1 was expressed in tumor cells (PD-L1t) in 21% (23/107; 30% cutoff), immune cells (PD-L1i) in 36% (38/107; 20% cutoff), and pSTAT3 in tumor nuclei in 41% (44/107; 40% cutoff). PD-L1 gene alteration was observed in 10% (10/102) including translocation in 6% (6/102) and copy number gain/amplification in 4% (4/102). Non-GCB subtype was associated with PD-L1t and pSTAT3 (p = 0.006 and p = 0.042), and tended to have PD-L1 gene alteration (p = 0.058). Tumoral PD-L1 expression without gene alteration (PD-L1t+ GA−) correlated with pSTAT3-positive tumor cell proportions (%) (p = 0.033). In survival analysis, pSTAT3 expression independently predicted shorter PFS in total cohort (p = 0.017) and R-CHOP-treated group (p = 0.007), and in pSTAT3-negative R-CHOP-treated subset, PD-L1 expression in immune cells (PD-L1i) correlated with shorter PFS (p = 0.042).ConclusionsGene alteration and protein expression of PD-L1 and pSTAT3 expression were closely related in DLBCL and constituted features of non-GCB subtype. In addition to known clinical significance of pSTAT3, immune cell expression of PD-L1 (PD-L1i) had also clinical value in pSTAT3-dependent manner. These findings may provide an insight into immunotherapeutic strategy and risk stratification in DLBCL patients.

Inflammation marker ESR is effective in predicting outcome of diffuse large B-cell lymphoma

BackgroundSystemic inflammation has been implicated in cancer development and progression. This study examined the best cutoff value of erythrocyte sedimentation rate (ESR) in diffuse large B-cell lymphoma (DLBCL) patients.MethodsThe relationship between ESR and clinical characteristics was analyzed in 182 DLBCL patients from 2006 to 2017. The log-rank test, univariate analysis, and Cox regression analysis were applied to evaluate the relationship between ESR and survival. An ESR of more than 37.5 mm/hour was found to be the optimal threshold value for predicting prognosis.ResultsESR was associated with more frequent advanced Ann Arbor stage, poorer performance status, elevated lactate dehydrogenase level, the presence of B symptoms, high-risk International Prognostic Index (IPI 3–5), more extranodal involvement (ENI ≥2), non-germinal-center B-cell (non-GCB) subtypes, and more frequent Myc protein positivity. Shorter overall survival (OS) and progression-free survival (PFS) were found for patients with higher ESRs. Multivariate analysis demonstrated that ESR level is an independent prognostic factor of both OS and PFS. In addition, dynamic changes in ESR are valuable in assessing curative effect and predicting disease recurrence.ConclusionHigh ESR in DLBCL patients indicated unfavorable prognosis that may require alternative treatment regimens.

Clinicopathologic features of breast lymphoma in core needle biopsy

Objective: To investigate the clinicopathologic features and differential diagnosis of breast lymphoma in core needle biopsy. Methods: Seventy-two cases of breast lymphoma in core needle biopsy between 2011 and 2016 were extracted from the pathology database of Fudan University Shanghai Cancer Center. The clinicopathologic features were analyzed. The histological diagnosis of the tumors was based on the WHO classifications of tumors of hematopoietic and lymphoid tissues. Immunohistochemistry and molecular methods were performed to detect related antigens and genes. Results: Seventy-one patients were female and one was male. The median age was 54 years. The tumors were located in the right breast in 32 (44.4%) patients and in the left breast in 40 (55.6%) patients. Seven patients had a previous history of lymphoma. Most of the cases presented as a single and painless breast mass. Sixty-three patients received systemic treatment, and nine patients received systemic therapy after excision. The common morphological feature was that single tumor cells infiltrated the stroma, without cohesiveness between tumor cells, and lacking glandular or nested epithelioid structures. The normal ductal and lobular structures of the mammary gland were typically preserved. The tumor cells in some cases were distributed in single rows, and should be differentiated from invasive carcinoma. All cases were positive for LCA, negative for CK. Sixty-eight cases were classified as B-cell lymphoma, including 63 cases (87.5%) of diffuse large B-cell lymphoma (DLBCL; including 3 cases of EBV-positive DLBCL and 60 cases of DLBCL, NOS), two cases of Burkitt lymphoma, one case of mantle cell lymphoma, one case of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue and one case of precursor B lymphoblastic leukemia/lymphoma. The remaining cases included two peripheral T-cell lymphoma (NOS), one extranodal NK/T cell lymphoma, nasal type and one myeloid sarcoma. In 63 cases of DLBCL, 22 cases (34.9%) expressed germinal center B-cell-like (GCB) phenotype and 41 cases (65.1%) showed non-germinal center B-cell-like (non-GCB) phenotype. Conclusions: Core needle biopsy could be the preferred method for diagnosis of breast lymphoma. Diffuse large B-cell lymphoma is the most common histologic type of breast lymphoma, and non-GCB subtype is more frequent than GCB subtype.

Metformin prolonged the survival of diffuse large B-cell lymphoma and grade 3b follicular lymphoma patients responding to first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone: a prospective phase II clinical trial

Background: With the addition of rituximab to chemotherapy, the response rates of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma grade 3b (FL3b) have been significantly improved. However, recurrence remains to be the hinder of long survival of the patients. Metformin is a widely used anti-diabetic agent and has an anti-lymphoma effect through adenosine monophosphate (AMP)-activated protein kinase activation in vitro and in vivo. Methods: We conducted a single center, prospective, single-arm phase II clinical trial of metformin for maintenance therapy in patients with DLBCL or FL3b who achieved complete remission after the first-line treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and analyzed the efficacies of metformin maintenance. Results: The patients received metformin maintenance had significantly better overall survival (OS) than those without metformin maintenance, especially for the diabetic patients. Patients with age >60, elevated serum lactate dehydrogenase (LDH), or International Prognostic Index (IPI) score ≥2 were benefit from metformin maintenance, as well as those with tumor cell expressing Ki67 ≥80%, or with non-germinal center B-cell-like (non-GCB) subtype. In multivariate analysis, age >60, elevated serum LDH and diabetic patients without metformin maintenance were the three independent unfavorable prognostic factors for OS. Conclusions: Metformin could thus be a safe and economic maintenance agent for elderly and high-risk patients not suitable for transplantation.

Differential prognostic impact of GELTAMO-IPI in cell of origin subtypes of Diffuse Large B Cell Lymphoma as defined by the Hans algorithm.

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P=0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype.

Prognostic Significance of High Ki-67 Index and Histogenetic Subclassification in Primary Central Nervous System Lymphoma.

In diffuse large B-cell lymphoma (DLBCL), the germinal center B-cell (GCB) subtype is associated with a better prognosis compared with the nongerminal center B-cell-like (non-GCB) subtype. However, validity of this immunohistochemical subgrouping in primary DLBCL of the central nervous system is unclear. A total 45 cases of primary central nervous system lymphoma (PCNS)/DLBCL were selected, and immunohistochemistries for CD10, Bcl-6, MUM1, and Ki-67 were performed. Each of the cases was subclassified as either GCB or non-GCB based on its immunoprofile. Among clinical and immunologic markers, patients under 70 years of age and who had methotrexate chemotherapy showed a significantly better overall survival (OS). High Ki-67 (ie, a Ki-67 index ≥90%) was an independent prognostic factor for a poor OS in the whole cohort and in the patients with non-GCB subtype tumors (P=0.017, HR=4.267, 95% CI, 1.3-14.0; P=0.031, HR=3.752, 95% CI, 1.3-12.5). Tumors were dominantly non-GCB subtype (41/45, 91.1%); only 4 (8.9%) were GCB subtype. The 2-year OS rates for these groups were 73% and 100%. There was, however, no statistically significant difference between these groups for OS and progression-free survival. The subclassification of PCNS/DLBCL into GCB and non-GCB subtypes did not seem to have a prognostic value. In non-GCB subtype PCNSL patients, high Ki-67 index was an adverse independent prognostic marker that could be used to stratify patients for more suitable management.