Indolent Subtypes Research Articles

The Investigation of Hepatitis Virus Infection in Different Subtypes of B-Cell Non Hodgkin Lymphoma in China: High Infection of Both HBV and HCV in Splenic Marginal Lymphoma

Background: The hepatitis virus infection is considered as one of the important pathogens in the pathogenesis of lymphomas. But the divergence of hepatitis infection between aggressive and indolent B cell Non-Hodgkin Lymphoma (B-NHL) has rare been investigated and dates for the subtypes of different lymphomas are limited too.Methods: 733 new diagnosed indolent B-NHL patients and 148 aggressive B-NHL patients from January 1994 to January 2014 at institute of Hematology&Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College were retrospectively investigated. The data of general population were from large scale of national epidemiological survey in China.Results: Compared with general population, the HCV positive rate was significantly higher in the whole B-NHL group and the indolent group (1.8% vs 0.4%, 1.9% vs 0.4% respectively, both p=0.000). While it had no significant difference in the aggressive group (1.35% vs 0.4%, p=0.068). The HCV-positive patients was similar in the indolent group and the aggressive one (1.9% vs 1.35%, P=0.639). In different indolent subtypes , the HCV-Ab positive rate of CLL WM SMZL HCL, NMZL group was significantly higher than the general population. The HBs-Ag positive rate in the whole B-NHL group and the aggressive group was 9.0% and 14.2% respectively, which was significantly higher than the general population (9.0% vs 7.2%, p=0.044; 14.2% vs 7.2%, p=0.001). While it had no significantly difference between the indolent group and the general population (7.9% vs 7.2%, p=0.548).However, in the indolent B-NHL subtypes, the SMZL group had the highest HBs-Ag positive rate, which was significantly higher than the general population (18.8% vs 7.2%,p=0.002).Conclusion: The hepatitis virus infection rate varied from different subtypes of lymphoma. In different indolent B-NHL subtypes, SMZL had the highest HBs-Ag and anti-HCV positive rate, which were significantly higher than the general population and other B-NHL. This result may suggest that the infection of hepatitis virus may play an etiologic role in SMZL. DisclosuresNo relevant conflicts of interest to declare.

Routine Blood Investigations Have Limited Utility in Routine Surveillance of High-Grade Lymphomas (HGL) in Remission after First-Line Therapy

BackgroundPatients with HGL achieving complete remission (CR) after first-line combination chemotherapy undergo regular surveillance to detect early signs of relapse. As follow-up imaging is associated with increased radiation-related risk and minimal benefit in asymptomatic (aSx) patients, imaging as surveillance is no longer routine. (Eichenauer Ann Oncol 2014, Tilly Ann Oncol 2015) Regular laboratory testing (Labs) still feature in internationally-recognised surveillance guidelines (eg NCCN), despite limited evidence in the modern era for their use in relapse detection. Studies conducted prior to modern imaging (PET/CT) and use of rituximab suggested LDH and ESR may be useful, and more recently the absolute lymphocyte count (ALC) and lymphocyte-monocyte ratio (LMR) have shown promise in small series (Weeks JCO 1991, Henry-Amar Ann Int Med 1991,Wei Leuk Lymph 2015, Porrata Leukemia 2010). However large scale data are lacking hence there is no consensus on the value and optimum frequency of specific laboratory parameters for use in routine surveillance of HGL.MethodsWe conducted a retrospective analysis of patients with histologically-proven cHL, DLBCL, T-cell lymphoma or Burkitt lymphoma receiving curative-intent treatment over a 15-year period. Eligible patients were aged≥16years, in CR for ≥3 months & had >12months follow-up. Primary CNS lymphoma, HIV-associated lymphomas and transformation from indolent subtypes were excluded. Data were collated from patient records. Laboratory results were considered abnormal if a) FBE, ALC, neutrophil count, absolute monocyte count (AMC), ESR or LDH fell outside local laboratory normal limits b) the derangement was not present previously and c) could not be explained by a concurrent medical condition. Abnormal Lab results were investigated at clinician discretion. Labs were evaluated based on their independent ability to detect relapse within 3 months of confirmation. Kaplan-Meier method was used for survival analysis and compared by the log-rank test between groups.ResultsBetween 2000-2015, 346 eligible patients underwent 3048 outpatient visits. Median follow-up was 30 months (range 3-184). Labs were performed at 90% of appointments: FBE in 99.7%, LDH in 78% (of NHL), ESR in 38% (of HL) with abnormalities in 26%, 12% and 16% respectively. Fifty-five patients relapsed (16%). Routine Labs detected aSx relapse in 3/55 (5%); routine imaging detected 9/55 relapses (16%) and clinical symptoms/signs lead to diagnosis of relapse in 43/55 (78%; 19/43 were unscheduled visits). Unscheduled appointments due to patient-reported symptoms (3% of all visits) showed a significantly stronger association with relapse than scheduled visits (OR 50.4, p<0.001).Table 1 presents sensitivity, specificity, PPV and NPV of Labs, demonstrating in particular a low PPV and high NPV. ALC, AMC and LMR were very poor markers for relapse, with area under the curve of 0.517, 0.529 and 0.576 respectively. In addition, an abnormal Lab result prompted a change in management for only 16% of aSx patients, (37 imaging, 38 repeat Labs, 22 earlier scheduling of next review), compared to 59% with symptoms/signs. In 43 episodes, abnormal Labs lead to further investigations which were subsequently negative (25 imaging, 6 biopsies, 11 repeat Labs).There was no significant difference in OS between patients who had Labs performed ≥3 months prior to documented relapse versus patients who did not (p=0.88, figure 1).ConclusionAlthough normal Lab results have a high NPV for relapse, most HGL relapses are detected by patient-reported symptoms, often at unscheduled visits. Abnormal Labs in aSx patients infrequently trigger a change in management. Routine Labs rarely detect relapse in aSx patients with HGL in CR after primary curative-intent chemotherapy, demonstrate unacceptably poor performance characteristics, have no impact on survival and have limited value in routine surveillance. [Display omitted] [Display omitted] DisclosuresHawkes:BMS: Other: travel expenses, Research Funding; Takeda: Other: travel expenses; Merck Serono: Research Funding.

Prognostic Significance of Serum LDH in B Cell Chronic Lymphoproliferative Disorders: A Single-Institution Study of 829 Cases in China

Background: B-cell chronic lymphoproliferative disorders (B-CLPD) comprise several indolent lymphoma subtypes with similar characteristics but also difference and heterogeneity. Several prognostic systems had been established for separate subtypes, such as Rai/Binet stage system for CLL, FLIPI for follicular lymphoma. Here, we want to explore the prognostic role of some common clinical characteristics in each lymphoma subtype, such as serum LDH.Materials and methods: The clinical data of 829 patients with B-CLPD including clinical features, LDH expression level, cytogenetic abnormalities and therapeutic outcome were analyzed retrospectively in department of lymphoma & myeloma, Institute of hematology & Blood disease hospital from April 1990 to August 2013, and the prognosis of B-CLPD patients with different expression levels of LDH was compared, including overall survival (OS) and progression-free survival (PFS) rates.Results: 829 patients were divided into three groups, including 426 (51.4%) patients with chronic lymphocytic lymphoma (CLL), 307 (37.0%) patients with non-CLL B-CLPD and 96 (11.6%) patients with BLPD-U. Elevated serum LDH at diagnosis was detected in 112 (26.3%), 85 (27.7%) and 23 (24.9%) of CLL, non-CLL B-CLPD and BLPD-U group, respectively. Patients with elevated LDH B-CLPD had poorer 5-year overall survival rate (CLL: 63.8% vs 83.0%; non-CLL B-CLPD: 62.2% vs 78.1%; BLPD-U: 47.4% vs 88.6%) and 5-year progression-free survival rate (CLL: 52.0% vs 78.2%; non-CLL B-CLPD: 40.8% vs 75.6%; BLPD-U: 48.9% vs 89.5%) than LDH normal patients. Univariate analysis showed that LDH expression, hemoglobin level, platelet count, B symptoms, P53 deletion were prognostic factors for CLL patient survival, while LDH expression, platelet count, albumin level affected non-CLL B-CLPD patient survival significantly and LDH expression, albumin level, ECOG PS scores for BLPD-U patient survival. Multivariate analysis showed that elevated LDH was an independent significant prognostic factor for overall survival (P<.001) and progression-free survival (P<.001) in all three groups.Conclusions: Based on these data, we conclude that elevated serum LDH at diagnosis is an unfavorable prognostic factor in patients with B-CLPD. DisclosuresNo relevant conflicts of interest to declare.

More Somatic Mutations Including Those in the Aid-Motif with High-Risk, Histologically Non-Transformed Follicular Lymphomas

Follicular lymphoma (FL) is the most prevalent among indolent subtypes of non-Hodgkin lymphomas. While the histologic transformation associates with disease aggressiveness in variant FL, a minor population of non-transformed FL patients also shows a shorter period for disease control despite the use of rituximab (Rit) immunochemotherapy. In this study, we investigated the clinical and genetic features of high-risk non-transformed FL. With the median follow-up period of 61 months for 103 consecutively treated patients with histologically non-transformed FL including 85 patients treated with the first-line Rit-containing therapies and 18 with watch and wait, the 5-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 93.3% and 54.4%, respectively. Chemotherapy was initiated according to the GELF criteria. Although neither FLIPI nor FLIPI2 sufficiently predicted the risks for either OS or PFS, the presence of two extranodal involvements, including peripheral blood (PB) (N=7, p=0.006) and/or bone (N=6, p=0.007), at diagnosis were found to be significantly associated with poor PFS, but not OS, in our cohort. Indeed, 13 high-risk patients with PB and/or bone involvements at diagnosis showed a significantly shorter median PFS of 27.2 months compared with that of the 90 standard-risk patients, who have not yet reached the median (p<0.001). Other factor, including age, performance status, disease stage, histologic grade, laboratory tests etc., showed no prognostic impact in our cohort. Next, to determine the genetic characteristics of the high-risk subset of FLs, we randomly selected 14 FLs, including 5 high- and 9 standard-risk FLs according to our disease-risk criteria, and performed whole exome sequencing analysis of 14 tumor samples at diagnosis with matched germline samples. The mean numbers of total mutated genes in the high-risk and in the standard-risk groups were 190 and 138 (p=0.04), respectively, and the mean numbers of genes with non-synonymous mutations were 52 and 39 (p=0.06), respectively. To investigate the consequence of multiple mutational processes, we analyzed the profiles of substitution subtypes including flanking bases in the mutated genes and identified a CG>TG substitution to be the most common mutational signature, while there was no difference with regard to the composition of the signature between the high- and standard-risk FLs. "Kataegis", a pattern of clustered hypermutations, was observed mostly in the target motif of activation-induced cytidine deaminase (AID), recurrently on chromosome 2p12 (involving the IGK locus), 14q32 (IGH), 18q21 (BCL2), 21p11, and 22q11 (IGLL). The mean number of C>T mutations in the AID-motif was significantly increased in the high-risk FLs over that in the standard-risk FLs (17 vs. 11, p=0.02), whereas there was no difference in the mean number of mutations in the target motif of APOBEC, which is considered to be the major driving agent responsible for kataegis in various solid cancers, between the two risk groups (8 vs. 7, p=0.49). For functional assessment of mutated genes, CREBBP and TNFRSF14 mutations were identified as the driver mutations of FL regardless of the disease risk using background mutation rate analysis. Hypergeometric test on all of the non-synonymous mutated genes from 14 FLs resulted in 71 significantly enriched gene ontologies (GOs), including the terms "cell development and differentiation", "regulation of cell death", "immunity mediated by lymphocytes, including B cells", "hematopoiesis", and "differentiation of leukocytes, including lymphocytes". In addition, pathway analysis demonstrated that mutated genes were enriched in the Notch and B cell receptor signaling pathways. However, we were not able to identify GOs or signaling pathways specific to the high-risk FL patients that could explain the different outcomes of the disease. Non-synonymous mutations in the high-risk FLs were found in genes, such as MEF2B and FUBP1, and were suggested to be associated with cancer aggressiveness, but not with the AID pathway. Overall, our results suggested that genomic instability, which allows for the emergence of distinct mutations not only by kataegis due to AID activity but also by additional mechanisms that increase mutations, underlies development of the high-risk phenotype in FLs. DisclosuresKuroda:Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Astra Zeneca: Research Funding; Janssen: Honoraria.

Dynamics of Soluble B-Cell Activation Markers sCD27 and sCD30 and Risk of B-Cell Lymphoma: A Prospective Study Using Repeated Plasma Samples Donated up to 25 Years Pre-Diagnosis

Background: We studied changes in blood concentrations of the soluble B-cell activation markers sCD27 and sCD30 in relation to future lymphoma risk, by investigating repeated pre-diagnostic plasma samples from the same individuals. High levels of sCD27 and sCD30 have been associated with lymphoma risk in previous prospective studies based on a single pre-diagnostic blood sample per participant. These studies, however do not inform about the dynamics of the marker-disease association on an individual level hampering its interpretation and potential use in lymphoma diagnostics and disease monitoring.Methods: In the Northern Sweden Health and Disease Study cohort we identified 170 individuals who had donated two pre-diagnostic blood samples and subsequently developed B-cell lymphoma. Blood samples were donated 13.2±4.4 and 5.5±4.0 years (mean±SD) prior to diagnosis, respectively. Cancer-free controls from the same cohort were individually matched to cases on a 1:1 ratio on sex, age and blood draw dates. We investigated associations between lymphoma risk by subtypes and marker concentrations; as measured separately at baseline, at time of the repeated sample, as well as the association with rate of change (slope) while adjusting for the baseline marker concentration.Findings: We observed strong associations between B-cell lymphoma risk and sCD27 and sCD30 concentrations, both at baseline and at time of the repeated blood sample. Associations were evident in samples collected up to 25 years before diagnosis. Blood concentrations of sCD27 and sCD30 increased significantly closer to diagnosis among future B-cell lymphoma cases, while they remained temporally stable among controls. Modeling measures of baseline and slope simultaneously with multivariable conditional logistic regression to estimate odds ratios (ORs), revealed significant associations between both slope and baseline measures and lymphoma risk; sCD27 (ORBaseline=7.2, Ptrend=2.8 x 10-4; ORSlope=2.8, Ptrend=2.2 x 10-4), and sCD30 (ORBaseline=2.9, Ptrend=3.7 x 10-4; ORSlope=2.9, Ptrend=0.001) (ORs 4th vs. 1st quartile; P for linear trend based on median values of analyte quartiles used as a continuous variable). Subtype specific analyses showed that the association between lymphoma risk and slope was restricted to indolent subtypes and mainly driven by chronic lymphocytic leukemia; sCD27 (ORSlope=6.7, Ptrend=1.3 x 10-5), and sCD30 (ORSlope=5.9, Ptrend=4.8 x 10-5), while associations with baseline marker concentration were evident among different subtypes, including diffuse large B-cell lymphoma.Interpretation: B-cell lymphoma risk seems to be influenced by increased sCD27 and sCD30 blood concentrations more than two decades before diagnosis. Increased concentrations of these B-cell activation markers among different future lymphoma subtypes early in life may reflect a constitutional predisposition, suggesting a role of B-cell activation in lymphoma development at early stages across subtypes. The observed increase of sCD27 and sCD30 concentrations closer to diagnosis however, seems to be subtype-specific and restricted to indolent lymphoma cases. Therefore, these markers may reflect early progression of undiagnosed disease and could potentially be utilized to improve lymphoma diagnostics and disease monitoring in indolent lymphoma. DisclosuresNo relevant conflicts of interest to declare.

What Is the Cost of Disease Progression Among Patients with Indolent or Aggressive Non-Hodgkin Lymphoma (NHL)?

Background: The natural histories of aggressive and indolent NHL vary in terms of the timing and pattern of disease progression. However, little is known about the impact of progression of disease (PD) on costs, and in particular how this differs between aggressive and indolent subtypes of NHL. This study examined patterns of care and outcomes for patients with aggressive and indolent NHL, and the impact of PD on health care costs.Methods: To identify cases of NHL, this retrospective studyused medical and pharmacy claims from a large national US health plan to identify commercially insured and Medicare Advantage (MA) patients age ≥18 years from 1/2007 - 8/2014 with ≥2 medical claims for NHL based on ICD-9-CM diagnosis codes. Patients were divided into cohorts of aggressive (AGG) NHL and indolent (IND) and based on diagnosis codes. Patients were required to have ≥1 claim for systemic anti-cancer therapy, with the index date being defined as the first observed claim for such therapy. Continuous enrollment in the health plan for 6 months prior to (baseline period), and ≥6 months after, the index date (variable follow-up period) was required; patients with <6 months of follow-up due to death were included. An algorithm to identify line of therapy (LOT) periods was implemented. PD was defined as: start of a second LOT, receipt of hospice care (based on procedure or revenue codes) or death (based on Social Security Administration death data). Health care costs were calculated over 6-month periods of follow-up (6, 12, 18, 24 months), with costs calculated for pharmacy, inpatient hospital, ambulatory, and other sites of service.Results: A total of 1,197 AGG and 2,454 IND patients met study criteria. Progression was experienced by 40.6% of AGG and 49.4% of IND patients respectively during the entire study period; 6-month progression was 18.9% (AGG) and 18.5% (IND). Compared to patients without PD during the study period, patients who progressed had higher average costs over each time period: in the first 6-months, costs were $138,957 PD vs. $108,607 for non-PD among AGG, and $114,644 PD vs. $80,873 for non-PD among IND (Figure, Table). Similarly, total costs for PD were higher than non-PD over 12, 18, and 24 months (Figure). Costs by site of service were higher for PD patients compared to non-PD patients among both the AGG and IND groups, particularly for inpatients costs; the table shows costs by site of service for the first 6 months, and results were similar over 12, 18, and 24 months. A higher proportion of AGG patients died compared with IND patients. Approximately one third of patients who died used hospice services among AGG and IND, and of these, 90.1% of AGG and 91.3% of IND used 3 or more days of hospice care.Conclusion: Among both aggressive and indolent NHL populations, costs were higher for patients with progressive versus without progressive disease, and increased over longer follow-up time. Patients with aggressive NHL had higher costs compared with patients with indolent NHL for both progressive and non-progressive disease. This study is the first to quantify systematically the cost of progression in NHL, both indolent and aggressive, and can inform efforts to improve value-based care, taking into account costs not just of therapy, but of subsequent progression. [Display omitted] [Display omitted] DisclosuresEngel-Nitz:Optum: Employment, Other: UnitedHealth Group stock. Dacosta Byfield:UnitedHealth Group: Equity Ownership; Optum: Employment. Bancroft:Optum: Employment, Other: UnitedHealth Group stock. Amy:Optum: Employment, Other: UnitedHealth Group stock. Reyes:Genentech: Employment; Roche: Equity Ownership.

Impact of oviductal versus ovarian epithelial cell of origin on ovarian endometrioid carcinoma phenotype in the mouse.

Endometrioid carcinoma (EC) is a relatively indolent ovarian carcinoma subtype that is nonetheless deadly if detected late. Existing genetically engineered mouse models (GEMMs) of the disease, based on transformation of the ovarian surface epithelium (OSE), take advantage of known ovarian EC driver gene lesions, but do not fully recapitulate the disease features seen in patients. An EC model in which the Apc and Pten tumour suppressor genes are conditionally deleted in murine OSE yields tumours that are biologically more aggressive and significantly less differentiated than human ECs. Importantly, OSE is not currently thought to be the tissue of origin of most ovarian cancers, including ECs, suggesting that tumour initiation in Müllerian epithelium may produce tumours that more closely resemble their human tumour counterparts. We have developed Ovgp1-iCreERT2 mice in which the Ovgp1 promoter controls expression of tamoxifen (TAM)-regulated Cre recombinase in oviductal epithelium - the murine equivalent of human Fallopian tube epithelium. Ovgp1-iCreERT2 ;Apcfl/fl ;Ptenfl/fl mice treated with TAM or injected with adenovirus expressing Cre into the ovarian bursa uniformly develop oviductal or ovarian ECs, respectively. On the basis of their morphology and global gene expression profiles, the oviduct-derived tumours more closely resemble human ovarian ECs than do OSE-derived tumours. Furthermore, mice with oviductal tumours survive much longer than their counterparts with ovarian tumours. The slow progression and late metastasis of oviductal tumours resembles the relatively indolent behaviour characteristic of so-called Type I ovarian carcinomas in humans, for which EC is a prototype. Our studies demonstrate the utility of Ovgp1-iCreERT2 mice for manipulating genes of interest specifically in the oviductal epithelium, and establish that the cell of origin is an important consideration in mouse ovarian cancer GEMMs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Quality of Life is Similar between Long-term Survivors of Indolent and Aggressive Non-Hodgkin Lymphoma

ABSTRACTDifferences in quality of life (QOL) of long-term survivors of aggressive or indolent subtypes of non-Hodgkin lymphoma (NHL) have not been frequently evaluated. We assessed these differences by analyzing results of a large QOL survey of long-term NHL survivors. We hypothesized that the incurable nature of indolent NHL would relate to worse QOL in long-term survivors while the potentially cured long-term survivors of aggressive lymphoma would have better QOL. We found that QOL was similar between the two groups. Results suggest that patients with indolent NHL are coping well with their disease, yet experience some overall feelings of life threat.

Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial

Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population. In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients. Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related. Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy. F Hoffmann-La Roche Ltd.

Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms

The Polycomb repressive complex-2 members (EZH2, EED, SUZ12 and EZH1) are important regulators of haematopoiesis, cell cycle and differentiation. Over-expression of EZH2 has been linked to cancer metastases and poor prognosis. Detailed information on the expression of other members in normal and neoplastic lymphoid tissue remains to be elucidated. Immunohistochemical and immunofluorescent analyses of 156 samples from haematopoietic neoplasms patients and 27 haematopoietic cell lines were used. B-cell neoplasms showed a significant over-expression of EZH2, EED and SUZ12 in the aggressive subtypes compared to the indolent subtypes and normal tissue (p= 0.000-0.046) while expression of EZH1 was decreased in mantle cell lymphoma compared to normal tissue (p= 0.011). T/NK-cell neoplasms also showed significant over-expression of EZH2, EED and SUZ12 (p= 0.000-0.002) and decreased expression of EZH1 (p= 0.001) compared to normal cells. EZH2 and EZH1 have opposite expression patterns both in normal and neoplastic lymphoid tissues as well as an opposite relation to Ki-67. These results were supported by western blotting analyses. Immunofluorescent staining revealed a difference in the intracellular localisation of EZH1 compared to other members. These evidences suggest that EZH2 and EZH1 are important in the counter-balancing mechanisms controlling proliferation/resting of lymphoid cells. The disruption of the balanced EZH2/EZH1 ratio may play important roles in the pathogenesis of lymphomas.

Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression.

Follicular lymphoma, the most common indolent subtype of non-Hodgkin lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from the time of diagnosis. However, in 20% to 60% of follicular lymphoma patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of follicular lymphoma transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of follicular lymphoma transformation, we performed systematic analysis of a B-cell-specific regulatory model exhibiting follicular lymphoma transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small-molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to follicular lymphoma transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies.

Hepatitis C virus-associated B-cell non-Hodgkin's lymphomas: what do we know?

Epidemiological studies have shown an increased risk of developing B-cell lymphomas in patients with chronic hepatitis C virus (HCV) infection. There is, however, a great geographic variability and it remains unclear whether additional environmental and genetic factors are involved or whether the international discrepancies represent simply a consequence of the variable prevalence of HCV infection in different countries. Other confounding factors may affect the comparability of the different studies, including the method of HCV assessment, the selection of normal controls, the lymphoma classification used and the year of publication. The most convincing evidence for a causal relationship comes from the observation, mainly limited to some indolent subtypes, of B-cell lymphoma regressions after successful HCV eradication with antiviral treatment. Yet, the molecular mechanism of HCV-induced lymphomagenesis are mainly hypothetical. According to most plausible models, lymphoma growth is a consequence of continuous antigenic stimulation induced by the chronic viral infection. This review will summarize the current knowledge on HCV-associated lymphomas and their management.

Prognostic Markers in Cardiac Non-Hodgkin Lymphoma: A Retrospective Review

Introduction: Cardiac involvement by Non-Hodgkin lymphoma (NHL) occurs by several distinct mechanisms: primary extra-nodal disease, direct extension, hematogenous or lymphatic spread. While it is not an uncommon autopsy finding, it is rarely deemed to be clinically significant. By contrast, extranodal involvement by NHL is associted with inferior outcomes. Here we performed a retrospective review of 91 published cases of NHL with biopsy-proven cardiac disease to evaluate its clinical significance and impact on outcomes.Methods: A literature search using Pubmed was performed between 1990 and 2015. Inclusion criteria were biopsy proven lymphoma, age greater than or equal to 18, no history of bone marrow transplant and direct involvement of the pericardium and or myocardium. Survival data was only analyzed from patients without HIV/AIDS. Log-rank (Mantel-Cox) test was used to calculate survival. Age comparisons were calculated using an unpaired t-test with a two-tailed p-value and one-way ANOVA.Results: Ninety-one cases met inclusion criteria for the review. The mean age was 55 years (range 19-90 years). Patients with Burkitt lymphoma and HIV/AIDS were younger (p=0.016). Of patients with pathological evidence of cardiac involvement, diffuse large B-cell lymphoma (DLBCL) was the most common NHL subtype (52% of cases), followed by T-cell lymphoma (16%), Burkitt Lymphoma (8%) and small lymphocytic lymphoma (SLL, 6%). Chest pain was the most frequent presenting symptom (Table).TableN=91 (%)Age: 18-60 >60 (60-90)48 (53) 43 (47)Sex: Male Female60 (66) 31 (34)Lymphoma type: Burkitt SLL DLBCL Follicular T-Cell Not specified8 (9) 6 (7) 52 (57) 2 (2) 15 (16) 8 (9)Treatment: Chemotherapy Chemo and radiation Radiation Surgery None Unreported25 (28) 6 (6) 1 (1) 4 (4) 11 (12) 44 (49)HIV/AIDS: Infected Non-infected17 (19) 74 (81)Presenting clinical syndrome: Arrhythmia Chest pain CHF/Dyspnea Constitutional symptoms SVC syndrome Heart Block Stroke Sudden Death Other Unreported2 (2) 10 (12) 31 (34) 6 (7) 4 (4) 4 (4) 3 (3) 3 (3) 8 (9) 20 (22)Forty-eight patients had primary cardiac lymphoma, which was defined as de novo lymphomatous involvement confined to the myocardium and/or pericardium, 41 patients had secondary disease and two were indeterminate. Patients with primary cardiac lymphoma were older (60 years, 95% CI, 55-59 years, versus 50 years, 95% CI, 47-53 years, p=0.006).Survival data were available for 54 patients. Of note, ~50% of patients did not receive therapy. Median survival was 3 months for all patients. The median survival of patients with T-cell lymphoma was 2 months, versus 4 months in the B-cell lymphoma subgroup (p=0.20). The median survival of patients with indolent B-cell lymphoma (SLL) was 37.5 months versus 4 months in patients with aggressive lymphoma (DLBCL and Burkitt, p=0.77). We found that female sex was associated with a trend towards improved outcome (median survival of 12 versus 3 months, p=0.63). Furthermore, patients diagnosed with primary (de novo) cardiac lymphomas also had better survival, 4 versus 2 months (p=0.23), possibly reflecting the more aggresive nature of relapsed disease.On further analysis, patients who were alive one month after diagnosis had a median survival of 18 months versus 3 months for all patients in this cohort (p=0.032). Furthermore, patients with primary B-cell lymphoma had superior survival to patients with T-cell lymphoma and/or secondary disease (median survival not reached vs 2.5 months, p=0.027). We also found that patients who received chemotherapy had a median survival of 18 months versus 1 month for those who did not (p=0.003).Discussion: Symptomatic cardiac involvement by NHL is rare. While it appears to be more common in DLBCL, it is seen across multiple indolent and aggressive NHL subtypes and is more common in men, typically presenting in the 6th decade of life. The outcomes of patients with NHL with cardiac involvement are poor, particularly among those with aggressive subtypes. However, patients who are candidates for chemotherapy and who survive beyond one month, particularly those with de novo (primary) cardiac B-cell lymphoma, are more likely to achieve long-term survival. Pathological lymphomatous involvement of cardiac tissue needs to be considered as part of differential diagnosis during work-up of patients with NHL. DisclosuresNo relevant conflicts of interest to declare.

Adult T-Cell Leukemia/Lymphoma: A Clinical and Epidemiological Analysis at the Medicine School of Sao Paulo University

Background: Adult T-cell leukemia/lymphoma (ATLL) is a rare disease described in Japan in 1977 and associated with human T-cell leukemia virus 1 (HTLV-1) infection. It is classified into four subgroups [1]: smoldering and chronic forms which are considered indolent and acute and lymphoma subtypes that present an aggressive behavior and short overall survival (OS) despite the treatment. Here, we describe an ATLL experience at a reference cancer treatment institution in Sao Paulo, Brazil.Methods: We retrospectively analyzed 29 ATLL patients who were attended from June/2006 to June/2015 at the Medicine School of Sao Paulo University, Brazil. ATLL was classified according to Shimoyama criteria [1] and Levine score [2] was used to estimate the probability of ATLL diagnosis. All patients were HTLV-1+. In the leukemic subtypes of ATLL, the neoplastic cells were CD3+/CD4+/CD8- or CD3+/CD4-/CD8- along with CD25+ and lack of CD7 expression. In the lymphoma type all patients showed a peripheral T cell lymphoma on their tissue biopsy. Statistical analysis was performed using GraphPad Prism Version 5.0 software.Results: Table 1 shows the clinical characteristics of patients on diagnosis. Acute ATLL was associated with higher Levine's score. The average age on diagnosis was 48.82 years old (18.69-74.26). Our data is in accordance with previous Brazilian studies that showed lower average age on diagnosis. This could be related to earlier infection, intrinsic characteristics of virus strains circulating in Americas or host immune particularities. There was confection with B hepatitis, C hepatitis and HIV in three, two and one case, respectively. Forty-five per cent of the patients had skin lesions and eight patients presented central nervous system disease (4 of acute ATLL). No patient had concomitant HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis.In our practice, smoldering ATLL was usually held in a watchfull-waiting approach. All six chronic ATLL patients were treated with interferon alpha and zidovudine (IFN+AZT) first-line. Progression-free survival (PFS) was 36.06 months and 12.4 months for smoldering and chronic subtypes, respectively. Acute and lymphoma subtypes had been treated with polichemotherapy, usually with CHOEP regimen (vincristine 1,4 mg/m2 i.v D1, doxorubicin 50mg/m2 i.v D1, cyclophosphamide 750mg/m2 i.v D1, etoposide 750 mg/m2 i.v D1, dexamethasone 20 mg i.v on day 1, prednisone 100 mg days 2 to 5) first-line. Overall average survival for lymphoma ATLL was 11.57 months, shorter than previous reports (average of 16 months, 86% treated with CHOP regimen [3]; survival of 19.7 months LSG15 protocol [4]). Eleven in 15 patients with acute ATLL had died after an average of 8.5 months (2.3 - 15.5) after the diagnosis. Overall survival for all subtypes was 15.17months (fig 1A), and 59.03; 44.47; 11.75 and 5.8 months (p= 0.0634) for smoldering, chronic, lymphoma and acute subtypes, respectively (fig 1B).Conclusion: We found an OS of 5.8 months for acute ATLL treated with chemotherapy as first-line, which is comparable to literature (average survival of 6 months [3]) but shorter than those patients treated with first-line IFN+AZT (average survival of 9 months [3]). In our setting it is still scarcely available trioxide arsenic and clinical trials for ATLL, and allogenic transplant related to mortality is still high. We are therefore changing our practice according to recent recommendations and aiming to treat leukemic ATLL first-line with higher tolerated doses of IFN+AZT to improve our survival curve.

Treatment Outcomes in Relapsed/Refractory Adult T-Cell Lymphoma/Leukemia and Role of CNS Prophylaxis: A New York City Hospital Experience

Background:Adult T-cell leukemia/lymphoma (ATLL) is a rare and aggressive peripheral T-cell neoplasm characterized by clonal human T-cell lymphotropic virus type-1 (HTLV-1) proviral DNA integration with host T lymphocytes.It presents as aggressive (acute/lymphomatous) or indolent (chronic/smouldering) subtypes. The aggressive subtypes have median survival of 6-13 months despite aggressive chemotherapy regimens. Presently, there is no established therapy for patients with relapsed/refractory disease. The data on efficacy of traditional chemotherapy agents in this setting is scant. In the last 6 years, 4 new drugs have been approved by US Food and Drug Administration for patients with relapsed/refractory peripheral T cell lymphoma (PTCL): pralatrexate and 3 histone deacetylase (HDAC) inhibitors (romidepsin, belinostat, vorinostat). Treatment approaches for PTCL are often applied to ATLL, as there is little data available for this subtype. However, none of the HDAC inhibitor trials included ATLL patients and there was only one patient in the pivotal PROPEL study for pralatrexate. The prevalence of CNS disease in the aggressive subtypes varies from 3 to 50 % and the efficacy of intrathecal chemotherapy is not known.Methods:To investigate the therapeutic benefit of second-line therapy and prophylactic intrathecal therapy, we reviewed all patients with ATLL at King's County Hospital between 2006 and 2014. Individual chart review was performed to report clinicopathologic features and treatment outcomes. SPSS was used for statistical analysis.Results:Fifty five patients were identified between January 2006 and December 2013 including 33 (60%) females and 22 (40.0%) males with a median age of 54 years (range, 31-78 years). All patients had immigrated to the United States from the Caribbean or South America. Median follow-up period was 6.6 months (0.4-124). Forty four patients were dead, 5 were alive and 6 were lost to follow-up at the time of analysis. Stage distribution was 26%, 51%, 16%, 6% for stage I, II, III and IV respectively. Forty three patients (78.2%) received etoposide/prednisone/vincristine/cisplatin/adriamycin (EPOCH) for first-line therapy. Twenty nine patients received second-line chemotherapy: gemcitabine/oxaliplatin, iphosphamide/cisplatin/etoposide (ICE), romidepsin, pralatrexate and high dose methotrexate. Median progression free survival was 6.8 weeks (range 1.6-72). No complete responses were seen. Partial response was seen in 9 (n=29) patients (31%). Median duration of response was 20.8 weeks (range 9.1-40). Three (5%) patients had CNS involvement at presentation. Prophylactic intrathecal therapy with methotrexate (IT MTx) 12 mg Q14 days was given to 21 patients (40.3%). CNS relapse was seen in 3 (14.2%) patients who received IT MTx and 6 (19.4%) patients who did not receive intrathecal chemotherapy. All patients with CNS relapse also had peripheral relapse.Conclusion:ATLL is a rare and difficult disease to manage. In our experience of relapsed/refractory ATLL, patients appear to have modest response rate to a second-line chemotherapy and these responses are not long lasting. In our patient population, risk of CNS disease at presentation was low (5%) but the incidence approaches 17.3% at the time of relapse. Administration of prophylactic intrathecal methotrexate showed a trend towards reducing the incidence of CNS disease although the results were not statistically significant. DisclosuresNo relevant conflicts of interest to declare.

Treatment of adult T-cell leukaemia/lymphoma: is the virus a target?

To discuss current understanding of the mechanisms of human T-lymphotropic virus type-1 (HTLV-1) tumorigenesis and current and potential treatment strategies for adult T-cell leukaemia/lymphoma (ATL), an aggressive malignant disease of CD4 cells caused by HTLV-1. Treatment of the aggressive subtypes of ATL remains inadequate, with little improvement in overall survival in the 30 years since HTLV-1 was discovered. Detailed analysis of the clonal expansion of HTLV-1 has provided new insight into pathogenesis. Most HTLV-1-infected cells, including ATL, express CCR4 which can be targeted. Reports of antitumour effects with allogeneic bone marrow transplantation provide a rationale for novel immunotherapy approaches. Progress has been made in the indolent subtypes of ATL with the use of 'antiviral' therapies. ATL has poor prognosis. There is a major, urgent, unmet clinical need to identify HTLV carriers who will develop ATL to develop biomarkers of transforming disease and disease progression and to provide novel treatment approaches within the context of clinical trials. Several strategies now include putative or actual antiviral therapy. Potentially, the risk of ATL would be reduced by eliminating some or all infected clones. HTLV-1 infection, and hence ATL, can be prevented by antenatal HTLV-1 screening.

Abstract A16: Master regulators of transformation of follicular lymphoma to diffused large B-cell lymphoma in patients defined by expression and activity of MYC

Abstract Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin's lymphoma with relatively long overall survival rate where median survival ranges from 6 to 10 years from the time of diagnosis. FL is a consequence of malignant transformation of germinal center (GC) derived B-cells and is associated with the translocation t(14;18)(q32;q21) resulting in overexpression of BCL2. FL transforms to more aggressive form of lymphoma, Diffused Large B-Cell lymphoma (DLBCL), with very high frequency (20-60% cases) causing the dramatic decrease in median survival rate to about 1.2 year from transformation. Several abnormalities were associated with transformation, such as alterations in TP53, MYC and BCL6, inactivation of p15 and p16, or amplification of REL, however they were observed only in a fraction of transformed lymphomas and the precise mechanism of transformation is still unknown. In the past, we have used a computational algorithm, called Master Regulator Inference algorithm (MARINa) which infers genes causally responsible for rendering a specific phenotype by interrogating cell context specific regulatory networks using gene signatures of disease progression. MARINa has been extensively validated at the experimental level leading to discovery of novel regulatory genes and mechanisms of disease progression in different cellular contexts. In this study, we applied MARINa algorithm to infer master regulators (MRs) of FL transformation to DLBCL using expression profiles from patient's biopsies at the time of FL diagnosis and subsequent biopsies at the time of transformation (1). Gene expression profile (GEP) analysis revealed two subtypes among the patients diagnosed with transformed FL, one with “high activity MYC” and another with “low activity MYC”. We performed MR analysis for both groups separately and found that MRs with high activity in one group were associated with low activity in the other group. In “high activity MYC” group we identified FOXM1, TFDP1, ATF5 and HMGA1 as best candidate MRs for therapeutic targeting of FL transformation. We show that targeting these MRs by small interfering RNA can reverse transformed signature. Furthermore, to infer novel small molecules to target transformed DLBCL cells study we used gene expression profiles from DLBCL cell lines treated with a library of FDA-approved and late-stage experimental 92 compounds and computed the similarity of these profiles with the profile obtained by silencing MR genes in DLBCL cell lines. Based on the gene signature similarity with gene profiles from DLBCL cell lines after MR silencing we predicted several compounds which in experimental settings recapitulated synergistic mechanism of MRs and induced cell death in transformed DLBCL cell lines but not in FL or control normal B-cells. In conclusion, our studies demonstrate that integration of computational predictions and experimental validations provide novel Master Regulators genes of FL transformation to DLBCL and small molecule inhibitors with anti-tumorigenic potential for DLBCL therapy.

Adenoid cystic carcinoma of female breast-an interesting pathological diagnosis

Adenoid cystic carcinoma (ACC) of the breast is a very rare and indolent subtype of malignant breast tumors, accounting for less than 0.1% of all primary breast cancers, occurring in approximately 1 out of 1 million women each year. To date, there have been about 933 cases reported as per English literature. A 50year old female presented with a right breast mass. Sono mammograhy revealed a large, well defined, solid appearing, lobulated mass. On fine needle aspiration, a differential diagnosis of metaplastic carcinoma, phylloide’s tumor, papillary neoplasm and primary chondrosarcoma of the breast was made and biopsy was advised. Partial mastectomy was done and a histopathological diagnosis of Adenoid Cystic Carcinoma of the breast was made. ACC is of special interest because of its favourable prognosis and distinctive histological appearance. Specifically, they are negative for ER, PR, and HER2-neu, yet on microarray genomic analysis, ACC is distinct from triple negative breast cancer. This tumor occurs predominantly in women in their sixth decade and usually presents as a tender breast mass, often in the subareolar area. The optimal treatment of ACC of the breast has not been defined, although the mainstay of treatment is surgery. Both partial mastectomy and modified radical mastectomy have been used, and the role of adjuvant radiation therapy is not clear.

Primary Cutaneous B-Cell Lymphoma: Management and Patterns of Recurrence at the Multimodality Cutaneous Lymphoma Clinic of The Ohio State University.

The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear. We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality. We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or ≥T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the risk of recurrence. We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria for PCBCL and were classified as having systemic B-cell lymphoma with cutaneous involvement. The remaining 55 patients included 25 with PCMZL, 24 with PCFCL, 2 with primary cutaneous large B-cell lymphoma leg type, and 4 with unclassifiable disease. According to the International Society of Cutaneous Lymphoma-European Organization for Research and Treatment of Cancer staging, 30 cases were T1 (55%), 14 T2 (25%), and 11 T3 (20%). Comparing the time to first recurrence (TFR) by indolent PCBCL subtypes, we found no difference in the recurrence risk for either stage (T1, p = .51 vs. T2/T3, p = .30). Comparing TFR by treatment modality, we found no difference in TFR within T1 patients (p = .34) or T2/T3 patients (p = .44). Our limited analysis highlights the importance of complete staging at diagnosis and suggests that the treatment modality does not affect the risk of recurrence in T1 indolent PCBCL.

Clinical characteristics and prognostic analysis of 90 patients with primary gastro-intestinal marginal zone lymphoma

目的了解原发胃肠道黏膜相关淋巴组织结外边缘区B细胞淋巴瘤（MALT淋巴瘤）患者临床特征及预后情况。方法回顾性分析90例原发胃肠道MALT淋巴瘤患者资料，对患者临床特征和相关预后因素进行分析。结果90例患者中胃内起病者78例，非胃内起病者12例。国际预后指数（IPI）评分0~2分者80例，3~5分者10例。与胃内起病者比较，非胃内起病者多为IPI 3~5分的高危患者（7.7%对33.3%，P=0.025）、幽门螺旋杆菌（Hp）感染率显著降低（50.0%对87.2%，P<0.01）。IPI评分0~2分的低危患者可选择抗Hp治疗、手术、放疗及化疗等治疗，其中化疗可提高患者无进展生存（PFS）率。接受化疗的高危患者3年总生存（OS）率达100.0%。单因素分析结果显示，ECOG评分（P=0.006）、Musshoff分期（P=0.008）、IPI评分（P=0.000）、LDH水平（P=0.019）和是否接受化疗（P=0.026）是影响患者PFS率的相关因素。多因素分析结果显示IPI评分（3~5分）（OR=8.325，95%CI 3.171~21.853，P= 0.000）和是否接受化疗（OR=0.319，95% CI 0.121~0.838，P=0.020）是影响患者PFS率的独立预后因素，ECOG评分（≥2分）是影响患者OS率的独立预后因素（OR=5.092，95% CI1.005~25.788，P=0.049）。结论原发胃肠道MALT淋巴瘤是一种低度恶性的淋巴瘤，以低危患者多见，多数患者可获得长期生存。低危患者可选择放疗或抗Hp治疗作为起始治疗方案，高危患者应选择化疗。