Primary Mediastinal Diffuse Large B-cell Lymphoma Research Articles

Prognostic factors and clinical survival outcome in patients with primary mediastinal diffuse large B-cell lymphoma in rituximab era: A population-based study.

The goal of this study was to investigate the clinical characteristics, prognostic variables, and survival of patients with primary mediastinal diffuse large B cell lymphoma (PMBCL) in the rituximab era. The Surveillance, Epidemiology, and End Results (SEER) database was used to identify PMBCL patients diagnosed between 2000 and 2019. The Kaplan-Meier (K-M) technique and log-rank test were used to assess overall survival (OS) and disease-specific survival (DSS). The independent prognostic variables for OS and DSS were identified using univariate and multivariate Cox regression analysis. Nomograms were created to predict survival prospects according to identified prognostic indicators. Totally, 841 patients were enrolled with PMBCL. One-year, 5-year, and 10-year OS rates were 93.99%, 85.04%, and 81.76%, and the corresponding DSS rates were 95.27%, 87.37%, and 85.98%. The results of multivariate Cox regression analysis demonstrated that age, years of diagnosis, Ann arbor staging, and chemotherapy were independent prognostic factors for survival. Nomograms designed exclusively for PMBCL were created to forecast the likelihood of 1-year, 5-year, and 10-year OS and DSS, respectively. The Harrell concordance index (C-index) for the nomograms predictions of OS and DSS were 0.704 and 0.733, respectively, which showed the established model harboring powerful and accurate performance. The present study revealed that incidence of PMBCL has been consistently rising over the last 20 years. Simultaneously, survival rates have improved tremendously. Rituximab based immunochemotherapy has emerged as an effective treatment option, leading to enhanced OS and DSS outcomes. Furthermore, the nomograms specifically developed for PMBCL have demonstrated robustness and accuracy in forecasting OS and DSS rates at 1, 5, and 10 years. These predictive tools can be valuable for clinicians in accurately estimating prognosis and establishing personalized treatment plans and follow-up protocols.

THE ADDITION AT DAY 9 OF HD‐MTX TO THE (DA)‐EPOCH SCHEME WITH OR WITHOUT RITUXIMAB IS AN EFFECTIVE REGIMEN IN UNTREATED ADVANCED STAGE HIGH RISK LYMPHOMA: A FEASIBILITY STUDY

DA-EPOCH is an infusional regimen designed to improve the response rate in highly proliferative tumors by prolonging cell exposure to low concentrations of chemotherapeutic agents. It was demonstrated as effective regimen in both T and B cell high grade lymphomas with an elevated proliferative index. Moreover, the addition of Rituximab is currently the standard of care in any B cell lymphoma treatment strategy. Previous studies have shown that high dose methotrexate (HD-MTX) therapy is better than intrathecal MTX administration to prevent CNS relapse, but so far few data are available that explore the feasibility of combination therapy including HD-MTX and DA-EPOCH with or without Rituximab. Our pilot study reported the result of the above combination therapy in a series of high risk advanced stage lymphoma patients (pts). Five patients were enrolled in this feasibility study: 3 pts were affected by Diffuse Large B Cell Lymphoma (DLBCL) no GC type, 1 pt had a diagnosis of Primary Mediastinal Diffuse Large B Cell Lymphoma (PMDLBCL) and 1 pt had an ALK+ Anaplastic Large Cell Lymphoma (ALCL). All pts showed a stage IV disease with ³ 2 extranodal sites, high LDH level, a very high proliferation index evaluated by Ki67 (median 90%, range 60-100%) and intermediate/high IPI score (3). High risk of CNS relapse was present in all pts because of type of extranodal sites (gut, bone, liver, heart, mediastinum, pancreas) and for high proliferation rate. The combination therapy included classical DA-EPOCH-R scheme with exception of Rituximab in ALCL with the addition of high dose (3.5 g/m2) Methotrexate at day 9 after urine alkalinization and hydration. All patients were scheduled to receive a total of 6 courses of therapy including 4 courses of the classic DA-EPOCH scheme and 2 combined therapy cycles. G-CSF prophylaxis was administered to all patients starting on day +9 and day +12 in the case of DA-EPOCH or combination therapy, respectively. The aim of the study was to evaluate the impact of adding HD-MTX to DA-EPOCH on the time between DA-EPOCH- (R) cycles. Secondary endpoints were response rate, PFS, toxicity, and CNS relapse rate. After a total of 9 courses administered of combination therapy, no delay in DA-EPOCH-(R) schedule of 21 days was observed. All patients showed a very favorable toxicity profile with only G3 neutropenia without infectious complications and G2 hepatotoxicity with elevations in transaminases. Three out of 5 pts completed the treatment strategy obtaining a CR and are now in follow-up, while the others are still on treatment. No CNS relapse were observed. Our preliminary results showed the feasibility of the combination therapy DA-EPOCH-R/HD-MTX with satisfactory results on controlling very aggressive disease. However, only prospective trials can define the optimum scheduling of this regimen and the possibility to use as standard therapy in very aggressive lymphomas with high risk of CNS relapse. Keywords: DA-R-EPOCH; high-dose methotrexate; non-Hodgkin lymphoma (NHL).

Utility of Bone Marrow Biopsy and Aspirate for Staging of Diffuse Large B Cell Lymphoma in the Era of Positron Emission Tomography With 2-Deoxy-2-[Fluorine-18]fluoro-deoxyglucose Integrated With Computed Tomography.

About one-third of patients with diffuse large B cell lymphoma (DLBCL) have lymphomatous bone marrow involvement (BMI) at the time of diagnosis, and bone marrow aspirate/biopsy (BMAB) is considered the gold standard to detect such involvement. [18F] fluorodeoxyglucose positron emission tomography combined with computed tomography (PET-CT), has become standard pretreatment imaging in DLBCL and may be a noninvasive alternative to BMAB to ascertain BMI. Prior studies have suggested that PET-CT scan may obviate the need for BMAB as a component for staging patients with newly diagnosed DLBCL, but this is not yet a standard of practice. The aim of this retrospective study was to determine the accuracy of PET-CT in detecting BMI in DLBCL and to define 2-year and 5-year overall survival based on BMI by BMAB versus PET-CT. We reviewed institutional records of all patients with newly diagnosed DLBCL between January 2004 and December 2013 who underwent pretreatment PET-CT and BMAB. PET-CT images were visually assessed for BMI, including the posterior iliac crest. Patients with primary mediastinal DLBCL, previous history or coexistence of another lymphoma subtype, and those with a nondiagnostic BMAB, and in whom the PET-CT did not show marrow signal abnormality, were excluded from the analysis. Ann Arbor stage was determined using PET-CT with and without the contribution of BMAB, and the proportion of stage IV cases by each method was measured. Among 99 eligible patients, the median age was 62 years (range, 24-88 years), 62 (63%) were male, 53 (53%) had elevated serum lactate dehydrogenase, and 17 (16%) had an Eastern Community Oncology Group performance status of > 2. Thirteen (12%) patients had more than 1 extra-nodal site of lymphoma involvement. Revised International Prognostic Index score was 1 in 39 (37%) patients, 2 in 42 (40%) patients, 3 in 20 (19%) patients, and 4 in 4 (4%) patients. A total of 38 (36%) patients had BMI established by either PET-CT (n= 24; 24%), BMAB (n= 14; 14%), or by both modalities (n= 12; 12%). Twelve (50%) of the 24 patients with positive PET-CT had BMI by DLBCL, whereas only 2 (3%) of the 75 patients with negative PET-CT showed BMI. BMAB upstaged 1 (2%) of the 53 stage I/II patients to stage IV. The sensitivity and specificity of PET-CT scan to detect BMI by DLBCL was 86% (95% confidence interval, 51.9%-95.7%) and 87% (95% confidence interval, 76%-92%), respectively. Eighty-five (86%) patients had concordant results between lymphomatous BMAB and PET-CT (12 patients were positive for both; 73 patients were negative for both), and 14 (14%) patients had a discordant interpretation (2 patients were positive by BMAB and negative by PET-CT, and 12 patients were negative by BMAB and positive by PET-CT). The positive predictive value of PET-CT was only 50%, whereas the negative predictive value was 98%. The accuracy of PET-CT was 86%. Although patients with positive BMAB had inferior 5-year overall survival estimates compared with those with negative BMAB (66% vs. 85%; P= .08), no such difference was demonstrated between PET-CT-positive and PET-CT-negative patients (79% vs. 83%; P= .30). In patients with newly diagnosed DLBCL, PET-CT is accurate in detecting BMI by DLBCL. Although PET-CT has a very high negative predictive value for BMI, it overestimates the number of cases with marrow involvement by DLBCL. In clinical practice, routine BMAB may no longer be necessary for all patients with DLBCL who are staged by PET-CT, unless the results would change both staging and therapy. The prognostic implication of BMI identified by PET-CT compared with BMAB remains unknown. Whether a PET-CT precludes the need for a BMAB in patients with DLBCL remains to be evaluated in a prospective study.

18f]PET-CT Scan Is Highly Accurate in Identifying Marrow Involvement of Diffuse Large B-Cell Lymphoma

BACKGROUNDRecent advances in imaging and the use of prognostic indices and molecular profiling have improved our ability to characterize disease and predict outcomes in diffuse large B cell lymphoma (DLBCL). About 1/3rd of patients with DLBCL have bone marrow involvement (BMI) at the time of diagnosis, and bone marrow aspirate/biopsy (BMAB) is considered the gold standard to detect such involvement. [18F] fluorodeoxyglucose (FDG) positron emission tomography combined with computed tomography (PET-CT), has become a standard pre-treatment imaging in DLBCL and may be a noninvasive alternative to BMAB to ascertain BMI. Prior studies have suggested that PET-CT scan may obviate the need for BMAB as a component for staging patients with newly diagnosed DLBCL, but owing to a variety of reasons this is not yet a standard of practice. The aim of this retrospective study which included 99 patients with newly diagnosed de-novo DLBCL, who had undergone both BMAB and PET-CT, was to determine the accuracy of PET-CT in detecting BMI in DLBCL and define overall survival (OS) in these patients based on BMI by BMAB vs. PET-CT. METHODSThis study is a single institution retrospective review of patients' medical records. All patients with newly diagnosed DLBCL at Virginia Mason Medical Center between January 2004 to December 2013 who underwent pretreatment PET-CT and BMAB were included. PET-CT images were visually assessed for BMI including the posterior iliac crest. Patients with primary mediastinal DLBCL, previous history or co-existence of another lymphoma subtype and those with a non-diagnostic BMAB, and in whom the PET-CT did not show marrow signal abnormality were excluded from the analysis. Ann Arbor stage was determined using PET-CT with and without the contribution of BMAB, and the proportion of stage IV cases by each method was measured. RESULTS99 eligible patients were identified. The median age was 62 years (range, 24-88), 62 (59%) were male, 53 (50%) had elevated LDH and 17 (16%) had an ECOG performance status of >2. Thirteen (12%) patients had > 1 extra-nodal site of lymphoma involvement. R-IPI score was 1 in 39 (37%), 2 in 42 (40%), 3 in 20 (19%), and 4 in 4 (4%) patients. A total of 38 (36%) patients had BMI established by either PET-CT (n=24, 19%), BMAB (n=14, 13%), or both (n=12, 11%). 12 of the 24 patients (50%) with positive PET-CT had BMI by DLBCL, while only 2 of the 81 patients (2%) with negative PET-CT showed BMI. BMAB upstaged 1 of the 53 (2%) stage I/II patients to stage IV. The sensitivity of PET-CT scan to detect BMI by DLBCL was 86% while the specificity was 87%. 84 patients (85%) had concordant results between lymphomatous BMAB and PET-CT (12 patients were positive for both, and 72 patients were negative for both), but 15 patients (15%) had a discordant interpretation (3 patients were positive by BMAB and negative by PET-CT, and 12 patients were negative by BMAB and positive by PET-CT). PET-CT was highly accurate for detecting BMI at diagnosis in de-novo DLBCL. Although patients with positive BMAB patients had inferior 5 year OS estimates compared to negative BMAB (66% vs. 85%), no difference was demonstrated between PET-CT positive vs. PET- CT negative patients. (79% vs. 83%) (Table 1) CONCLUSIONSIn patients with newly diagnosed DLBCL, PET-CT is highly accurate in detecting BMI by lymphoma. In clinical practice, routine BMAB may no longer be necessary for all patients with DLBCL, who are staged by PET-CT, unless the results would change both staging and therapy. The prognostic implication of BMI identified by PET-CT compared to BMAB remains unknown. Whether a PET-CT precludes the need for a BMAB in patients with DLBCL remains to be evaluated in a prospective study. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No Association of EBV or Immunosuppression Status with Outcomes in US Patients with Diffuse Large B-Cell Lymphoma Treated in the Immunochemotherapy Era

Background:EBV+ DLBCL not otherwise specified (EBV+ DLBCL NOS) is defined by the 2016 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues as EBV+ DLBCL in patients without a history of known immunosuppression. Among Asian patients, adverse outcomes have been associated with EBV+ vs EBV- DLBCL, and circulating EBV has been found in the majority of patients. Outcome studies of unselected North American patients are few and non-confirmatory. No formal assessment of immunosuppression status has been incorporated into these analyses, leading to the variable inclusion of patients with a history of immunocompromised states. We sought to determine the prevalence, presenting clinical and pathology characteristics, and outcomes of DLBCL by EBV and immunosuppression status in an unselected prospective cohort study of North American patients.Methods:From 2002-2012, we enrolled consecutive, newly diagnosed patients with lymphoma who were ≥ 18 years and HIV negative into the Molecular Epidemiology Resource (MER). Clinical, laboratory, and treatment data were abstracted from medical records. All DLBCL patients with available tissue microarrays (TMAs), excluding primary mediastinal DLBCL and post-transplant lymphoproliferative disorders, were included. Medical records were reviewed using a standard protocol to classify patients as immunocompromised based on a documented history of primary immunodeficiency or iatrogenic immunosuppression. DLBCL cell of origin was classified as germinal center (GCB) vs non-GCB using the Hans algorithm. CD30 was determined using immunohistochemistry; positivity cutoff was 20% of neoplastic cells. EBV testing was performed by in-situ hybridization for EBV encoded small RNAs (EBERs), and scored by an expert hematopathologist. Event free survival (EFS) was defined as time from diagnosis until recurrence, retreatment, or death due to any cause. Associations with EFS and Overall Survival (OS) were obtained using the methods of Kaplan-Meier (KM). Hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox regression models.Results:1,100 patients with DLBCL were enrolled into the MER; 362 had TMAs available for this analysis. Median age was 63 years (range 20-89) and 59% were male. 89.5% of patients were treated with immunochemotherapy. 16 cases (4.4%) were EBV+, and 39 cases (10.8%) were considered immunocompromised. EBV positivity was more common in immunocompromised vs immunocompetent patients, with a trend towards significance (10.3% vs 3.7%; P = 0.08). The non-GCB subtype was more frequent in EBV+ vs EBV- DLBCL (62.5% vs 34.1%; P < 0.01), but similar between immunocompromised vs immunocompetent patients (48.7% vs 33.7%; P = 0.10). CD30 positivity was also more frequent in EBV+ vs. EBV- DLBCL (25.0% vs 8.1%; P < 0.01), but similar between immunocompromised vs immunocompetent patients (12.8% vs 8.4%, respectively; P = 0.45). With a median follow-up of 59 months (range 0.7-155.2) there were 151 events and 119 deaths. KM curves by EBV and immunosuppression status are shown in the figure. There was no association of EBV positivity with EFS (HR = 0.76; 95% CI 0.34-1.72) or OS (HR = 0.99; 95% CI 0.43-2.25). A history of immunosuppression was not associated with EFS (HR = 1.17; 95% CI 0.72-1.89) or OS (HR = 1.02; 95% CI 0.58-1.78). In the subset of immunocompetent patients, there was no association of EBV positivity with EFS (HR = 0.54; 95% CI 0.17-1.70) or OS (HR = 0.71; 95% CI 0.23-2.25). Similar results were obtained after adjustment for the International Prognostic Index. Circulating viral DNA was detected in 2/5 EBV+ and 4/49 EBV- DLBCL patients.Conclusions:The prevalence of EBV+ DLBCL NOS is <5% among patients in a large North American cohort, similar to other western populations. There was no evidence of an association of EBV or immunosuppression status with EFS or OS, with low power for detecting associations with EBV. Circulating viral DNA was infrequent among either EBV+ or EBV- DLBCL patients. While immunosuppression has been previously shown to be a risk factor for DLBCL, it was not found to be associated with EFS or OS. Overall, these results suggest divergent outcomes among EBV+ DLBCL patients between western and non-western populations, underscoring differences in host factors or circulating viral strains. [Display omitted] DisclosuresAnsell:BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

How I manage patients with grey zone lymphoma.

Since grey zone lymphoma (GZL) was originally included in the 2008 World Health Organization classification as a B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL), new biological and clinical knowledge have been learned. It is important to highlight that diagnosis of this entity is complex and involvement by haematopathologists with expertise in this disease is recommended. It is recognized now that patients with GZL may present clinically with primary mediastinal localization or systemic disease without mediastinal involvement. Regardless of clinical presentation, patients with GZL have relatively high relapse rates, especially compared with primary mediastinal DLBCL or cHL. Interestingly, relapsed/refractory GZL patients appear to be salvaged fairly successfully, especially with haematopoietic stem cell transplantation (HSCT). Off of a clinical trial, we recommend R-CHOP (rituximab, cyclophosphamide, doxorubicin, oncovin, prednisolone) or dose-adjusted EPOCH-R (etoposide, prednisolone, oncovin, cyclophosphamide, doxorubicin, rituximab) for frontline treatment of GZL. Additionally, we advocate use of consolidative radiotherapy for localized and/or bulky disease. For patients with relapsed/refractory GZL, salvage chemotherapy followed by consolidative autologous HSCT should be considered. Finally, continued biological and pathologic examination of this unique disease entity is warranted as well as exploration towards the integration of targeted therapeutic agents (e.g., brentuximab vedotin, programmed cell death 1inhibitors, B-cell receptor inhibitors, proteasome inhibitors, etc.) into the treatment paradigm of GZL.

Using the pathology report in initial treatment decisions for diffuse large B-cell lymphoma: time for a precision medicine approach.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non Hodgkin lymphoma in the Western world, and is potentially curable with standard R-CHOP chemoimmunotherapy. Historically, clinical risk assessments provided prognostic information, but did not define treatment approach. We are now in an era where the heterogeneity of DLBCL is defined genetically and molecularly, and rational subset-specific therapeutic targets are guiding clinical trials. Primary mediastinal DLBCL is a unique clinicopathologic entity, and alternatives to R-CHOP may confer superior outcome. Rearrangement of the myc oncogene occurs in ~10% of patients with DLBCL, and confers a very poor prognosis with standard R-CHOP, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as "double-hit" DLBCL. A larger subset of DLBCL demonstrates overexpression of both myc and bcl-2 by immunohistochemistry. Cell of origin, determined by gene expression analysis, immunohistochemistry algorithms, or a novel Lymph2Cx platform, provides prognostic information, and guides therapeutic decisions in both relapsed and de novo disease. This article will define specific subsets of DLBCL and provide subtype-specific treatment options, including novel approaches under investigation. Understanding these key features of the pathology report, and limitations of these assays defining subsets of DLBCL, allows for an evolving precision medicine approach to this disease.

Sequencing-Based Detection of Circulating Tumor DNA in the Autologous Stem Cell Grafts of Patients with Diffuse Large B-Cell Lymphoma Undergoing Hematopoietic Stem Cell Transplantation

▪Introduction: High dose chemotherapy followed by autologous stem cell transplantation (ASCT) cures a subset of patients with chemosensitive relapsed or refractory (rel/ref) diffuse large B-cell lymphoma (DLBCL). Several factors associated with post-ASCT outcome have been identified, including pre-ASCT PET status, but better biomarkers are needed in order to optimally select candidates for the procedure. In other lymphoma subtypes with defining chromosomal translocations, PCR detection of pre- and post-ASCT minimal residual disease (MRD) in peripheral blood and of tumor contamination in the stem cell product is associated with inferior outcome. Until recently, MRD detection in DLBCL was limited by the rarity of detectable circulating disease using conventional techniques. The immunosequencing platform (Adaptive Biotechnologies, Corp.) is a next-generation-sequencing (NGS)-based MRD assay that detects small amounts of circulating tumor DNA (CTD) in patients with lymphoid malignancies. The assay detects CTD at diagnosis in most DLBCL patients and CTD levels track with response to induction therapy (Armand, 2013). Persistence of CTD or recurrence of CTD after completion of therapy is highly associated with DLBCL relapse (Kurtz, 2015; Roschewski, 2015). We evaluated whether CTD in autologous stem cell grafts was predictive of outcome in patients with rel/ref DLBCL undergoing ASCT.Methods: We retrospectively studied patients with rel/ref DLBCL, including transformed indolent lymphoma (TIL), who had paired archival tumor and autologous stem cell specimens and underwent ASCT at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2003-2013. Genomic tumor DNA was extracted from archival formalin-fixed paraffin-embedded (FFPE) tissue and analyzed using the NGS-based MRD assay. PCR amplification of IGH-VDJ, IGH-DJ,and IGK regions using universal consensus primers was performed followed by NGS to determine the tumor clonotype(s), defined as having a frequency > 5% in the tumor specimen. DNA from all available autologous peripheral blood or bone marrow stem cell specimens from each patient was amplified using universal consensus primers and sequenced to determine the level of CTD, defined as the number of lymphoma molecules per diploid genome.Results: We identified 98 eligible patients with rel/ref DLBCL/TIL. The median age was 60 (range 22-77) years; 63% were male; 65% had DLBCL, 29% had TIL, and 5% had primary mediastinal DLBCL; the median number of prior lines of therapy was 2 (range 2-5); all had received prior rituximab; 38% had primary refractory disease; 60% were in complete remission at ASCT; 96% received CBV conditioning. Median follow-up was 56 (range 19-123) months. The 4y progression-free survival (PFS) and overall survival (OS) in the entire cohort were 46% and 64%, respectively.Among 83 patients (85%) with sufficient DNA for clonotype determination, a clonotype was identified in 59 (71%). CTD data was complete in 53 patients (52 received peripheral blood stem cells (PBSC) and 1 received bone marrow). Eight patients (15%) had detectable CTD (CTD+) in the stem cell autografts (all PBSC) and 6/8 relapsed after ASCT. One CTD+ patient had early non-relapse mortality less than 1 month after ASCT and was never restaged. Seven of 8 CTD+ patients had TIL histology, 5 of whom relapsed (4 with aggressive lymphoma). The 4y PFS and OS in CTD+ v CTD- patients were 13% v 48% (P =0.01), and 38% v 67% (P =0.013), respectively [Figure 1]. In multivariable models including CTD status and pre-ASCT characteristics, CTD+ was the only factor associated with OS (HR 3.1, p=0.018), but was not significantly associated with PFS.Discussion: In patients with rel/ref DLBCL undergoing ASCT, the presence of CTD in the autologous stem cell graft is associated with inferior survival. CTD detection in the autograft may be more common in patients with TIL. In studies evaluating CTD detection in DLBCL, the plasma compartment has been more sensitive for detecting CTD than mononuclear cells. The use of concentrated cell specimens in this study may have decreased the sensitivity of the assay. Nevertheless, if the present findings are confirmed in a larger population, CTD detection may permit the identification of a subgroup of patients with a particularly poor outcome after ASCT, for whom alternative approaches could be considered. [Display omitted] [Display omitted] DisclosuresHerrera:Sequenta, Inc.: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Kong:Adaptive Biotechnologies, Corp.: Employment, Other: Stockholder. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Rodig:Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding. Faham:Adaptive Biotechnologies Corp.: Employment, Other: Stockholder. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Sequenta, Inc.: Research Funding.

Utility of Bone Marrow Biopsy in the Staging of Diffuse Large B-Cell Lymphoma in the Era of PET-CT

BACKGROUNDDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Recent advances in imaging, use of prognostic indices and molecular profiling has improved our ability to characterize disease and predict outcomes in DLBCL. About one-third of patients with DLBCL have bone marrow involvement at the time of diagnosis, and bone marrow aspirate/biopsy (BMAB) is considered gold standard to detect such involvement. 18 F-fluro-2-deoxy-D-glucose positron emission tomography combined with computed tomography (PET-CT), has become standard pre-treatment imaging in DLBCL and may be a non-invasive alternative to BMAB. Prior studies have suggested that PET-CT scan may obviate the need for BMAB as a component for staging patients with newly-diagnosed DLBCL, but owing to a variety of reasons this is not yet a standard of practice. We investigated whether FDG uptake-based bone marrow assessment can replace BMAB in newly-diagnosed DLBCL.METHODSThis study is a single institution retrospective medical records' review. All patients with newly-diagnosed DLBCL at Virginia Mason Medical Center between January 2003 to December 2013 who underwent pre-treatment PET-CT and BMAB were included. FDG-PET/CT images were visually assessed for bone marrow involvement in posterior iliac crest. Patients with primary mediastinal DLBCL, previous history or coexistence of another lymphoma subtype and those with a non-diagnostic BMAB, and in whom the PET-CT did not show marrow signal abnormality were excluded from the analysis. Ann Arbor stage was determined using PET-CT with and without the contribution of BMAB, and the proportion of stage IV cases by each method was measured.RESULTS105 eligible patients were identified. The median age was 62 years (range, 24-88), 62 (59%) were male, 53 (50%) had elevated LDH and 17 (16%) had an ECOG performance status of >2. Thirteen (12%) patients had > 1 extra-nodal site of lymphoma involvement. R-IPI score was 0-1 in 39 (37%), 2 in 42 (40%), 3 in 20 (19%), and 4 in 4 (4%) patients. A total of 38 (36%) patients had bone marrow involvement established by either PET-CT (n=24, 19%), BMAB (n=14, 13%), or both (n=12, 11%). 12 of the 24 patients (50%) with positive PET-CT had marrow involvement by DLBCL, while only 2 of the 81 patients (2%) with negative PET/CT showed marrow involvement. BMAB upstaged 1 of the 53 (2%) stage I/II patients to stage IV. The sensitivity of PET-CT scan to detect marrow involvement by DLBCL was 86% while the specificity was 87%. The positive predictive value of PET-CT was only 50% while the negative predictive value was 98%.CONCLUSIONSIn patients with newly diagnosed DLBCL, PET-CT is complementary to BMAB in detecting marrow involvement by lymphoma. Although PET-CT has a high negative predictive value for bone marrow involvement, it overestimates the number of cases with marrow involvement by lymphoma. In clinical practice, routine BMAB may no longer be necessary for all patients with DLBCL, who are staged by PET-CT, unless the results would change both staging and therapy. The prognostic implication of marrow involvement identified by PET-CT compared to BMAB remains unknown. DisclosuresNo relevant conflicts of interest to declare.

A Phase II Study of MLN8237 (Alisertib) Alone and in Combination with Rituximab in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas (NHL)

Introduction: Aurora A kinase is a serine-threonine kinase important in the cell cycle. Overexpression of Aurora A kinase has been associated with the development of NHL with Aurora A kinase activity amplified in aggressive NHL. Alisertib is an orally bioavailable Aurora A kinase inhibitor that targets a key molecule in the cell cycle of dividing cells that leads to mitotic spindle defects and apoptosis. Due to demonstrated pre-clinical and early clinical efficacy of Alisertib in the treatment of B-cell NHL, we conducted a phase 2 trial with Alisertib alone and in combination with rituximab in patients with relapsed aggressive and indolent NHL.Methods: Patients ≥ 18 years with relapsed or refractory B-cell NHL including follicular lymphoma (FL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL) and Burkitt’s lymphoma (BL) who had received one prior therapy and transformed NHL (tNHL) at any time after diagnosis of transformation were eligible. Additional eligibility included ECOG Performance Status 0-2, adequate renal and liver function, absolute neutrophil count (ANC) ≥ 1000/µL and platelets ≥ 75,000/µL. Patients with indolent NHL (FL, MZL or LPL/WM) were accrued to Cohort A and all other patients (MCL, DLBCL, BL and tNHL) were accrued to Cohort B. Patients treated on Cohort A received Alisertib at a dose of 50 mg twice daily (BID) for days 1-7 of 21 day cycles with rituximab (375 mg/m2) added on day 1 of cycles 5-12 in patients who failed to achieve a complete response (CR) after cycle 4. Patients treated on Cohort B received Alisertib at a dose of 50 mg BID for days 1-7 of 21 day cycles with rituximab added on day 1 of cycles 3-10 in patients who failed to achieve a partial response (PR) or CR after cycle 2 and on day 1 of cycles 5-12 in any patient remaining on monotherapy who had not achieved a CR after cycle 4. Response was assessed according to the International Harmonization Project criteria (Cheson, JCO 2007) and patients were evaluated by imaging after cycle 2, 4, 6 and after every 3 cycles thereafter. Toxicity was assessed per NCI CTCAE v4.0.Results: Eleven patients were enrolled in this trial, 1 patient in Arm A with FL and 10 patients in Arm B with DLBCL (n=6), primary mediastinal DLBCL (n=1), and tNHL (n=3). The median age was 58 years (range 35-77); 10 patients had Stage III-IV disease; the median number of prior therapies was 4 (range 2-6); and 5 patients had prior autologous stem cell transplant. Patients received a median of 2 treatment cycles (range 1-5). Two patients in Cohort B received rituximab added on day 1 of cycle 3 for SD. Grade 3/4 adverse events included grade 3 neutropenia (36%), grade 3 fatigue and dehydration (18%), grade 3 mucositits (9%), grade 3 cystitis (9%), grade 3 pancreatitis (9%), grade 3 pneumonitis (9%) and grade 3 thromboembolic disease (9%). One patient required dose reduction for mucositis, 1 patient went off study for pneumonitis, 1 patient went off study due to patient preference and 8 patients came off study for PD. The overall response rate was 9%, with 1 patient achieving a partial response (PR). This patient had Stage IV CD5+ DLBCL with 2 prior therapies. The patient had SD after 2 cycles and rituximab was added, with response improving to a PR after 5 cycles. The patient went off study after 5 cycles to proceed with allogeneic stem cell transplantation and remains in remission 262 days post-transplant.Conclusions: In this heavily pre-treated, high-risk population of patients with relapsed/refractory NHL, the oral agent Alisertib was overall well tolerated with one responding patient with refractory CD5+ DLBCL able to proceed to allogeneic transplant who remains in continuous remission. Enrollment continues to both cohorts A and B in this trial to the defined interim analysis point of 16 patients in each arm, with a requirement of 5 responses in each arm to continue the study. DisclosuresMaddocks:Pharmacyclics, Seattle Genetics, MorphoSys: Advisory Board Other, Research Funding. Cohen:Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; BMS: Research Funding; Janssen: Research Funding. Christian:Immunomedics: Research Funding.

I. Pathological and clinical diversity in diffuse large B‐cell lymphoma

I. Pathological and clinical diversity in diffuse large B‐cell lymphoma

Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma (DLBCL).

8552 Background: DLBCL is potentially curable with combination chemotherapy such as CHOP-R. Although it is generally regarded appropriate to start chemotherapy promptly after diagnosis, the impact of the time from diagnosis to treatment initiation on treatment outcome is unknown. Methods: Patients diagnosed with DLBCL and treated with at least one cycle of CHOP-R with curative intent during 2003 – 2008 in British Columbia were identified in the Lymphoid Cancer Database. Additional demographic data were obtained from the BC Cancer Registry. The BC Cancer Agency provincial pharmacy database was used to obtain dates of chemotherapy administration. The impact of the time interval from the date of pathologic diagnosis to treatment on overall survival (OS) and progression-free survival (PFS) was evaluated. Results: A total of 793 patients were identified: 199 (25%) received CHOP-R &lt;2 weeks after diagnosis, 244 (31%) at 2-4 weeks, 293 (37%) at 5-8 weeks, and 57 (7%) at &gt;8 weeks. High international prognostic index, primary mediastinal DLBCL, and hospitalization at the time of CHOP-R start were associated with earlier initiation of chemotherapy (p&lt;0.001 for all factors). Distance to chemotherapy from home (p=0.237), rural vs. urban location (p=0.952), geographic region (p=0.458), and median household income (p=0.127) were not associated to treatment start. Five-year PFS and OS respectively were 54% (SD 4%) and 61% (SD 4%) for treatment &lt;2 weeks, 63% (SD 3%) and 66% (SD 3%) for 2-4 weeks, 70% (SD 3%) and 74% (SD 3%) for 5-8 weeks, and 60% (SD 7%) and for 61% (SD 8%) &gt;8 weeks, p=0.006 (PFS) and p=0.024 (OS). A multivariate analysis demonstrated no significant difference between the groups. Conclusions: In a publicly funded healthcare system, earlier initiation of chemotherapy was strongly associated with poor prognostic factors, as well as inferior PFS and OS. The timing of chemotherapy initiation appears to be related to clinical factors instead of system or socioeconomic barriers. Notwithstanding the lack of detrimental outcomes in those commencing CHOP-R after 8 weeks, clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.

Programmed Death-1 Ligand Is Uniformly Expressed On Primary Mediastinal Diffuse Large B-Cell Lymphoma Cells with No Influence On Patient Survival.

AbstractAbstract 2671 Introduction:Primary mediastinal diffuse large B-cell lymphoma (PMBCL) is an uncommon disease with an aggressive clinical course and potential curability. Growing evidence suggests that host antitumor immunity suppression may play a role in resistant cases. The most studied candidate molecules are ligands PD-L1 (CD 274) and PD-L2 (CD 273) expressed by lymphoma cells, which effectively suppress host T cells. The PD ligand genes are located on chromosome 9p24.1 close to Janus kinase 2 (JAK2) gene. The clinical impact of PD-L1/PD-L2 protein expression has not been described in PMBCL. Methods:Tumor samples of 27 previously untreated patients were analyzed. Clinical characteristics were as follows: median age at diagnosis 35 years (20–74), female-to-male ratio 1.7:1, most patients (70%) had limited mediastinal disease and a mean tumor diameter of 10.7 cm. The IPI and aaIPI scores were low in 67% and 37%, intermediate-low in 26% and 41% and intermediate-high in 7% and 22%, respectively. No patients were assigned to a high risk group. All patients were treated with anthracycline-based chemotherapy 15% with CHOP and 85% with third-generation intensive regimen. Therapy was intensified in 70% of the cases with high-dose therapy and autologous stem cell transplantation. Most of the patients (70%) received rituximab and 15% were also treated with IF radiotherapy. Formalin-fixed and paraffin-embedded tissues were processed in routine tissue sections (approx. 5 micrometers) and placed on plus slides. After antigen retrieval with the use of the enzymatic or microwave oven processes, indirect immunohistochemistry with commercially available primary antibodies in optimized dilution was performed: CD20 clone L27, CD23 clone 1B12, CD30 clone Ber-H2, CD10 clone G27-P, Bcl-2 clone 100, Bcl-6 clone PGB6p, MUM1/IRF4 clone MUM1p, CD274 polyclonal, CD273 polyclonal, and HLADR clone TAL.1B5. For visualization, a secondary antibody with the standard avidin-biotin (ABC) method was applied. Results were expressed as a percentage of positive tumor cells and H-score (product of percentage of positive cells and staining intensity). Cytogenetic analysis with a locus-specific FISH probe (9p24) and arrayCGH was carried out in 15 (56%) of the patients. Results:Final treatment response was assessed in 26 (96%) patients (1 patient did not passed restaging procedures yet), CR was achieved in 22 (85%), PR in three and one patient progressed. After a median follow-up of 73 months (6.1 yrs), 22/26 (84%) patients are alive in the 1st CR, and only three patients died. Five-year PFS was 82.6% (95% CI 0.67–0.98) and five-year overall survival was 90.9% (95% CI 0.79–1.00). All samples expressed PD-L2 in (a median of) 80% of tumor cells with a median H-score of 90. PD-L2 protein expression was very low - six cases were negative and in positive cases, median expression was only 5% (H-score 5). HLA-DR expression was detected in all cases with a median positivity of 70% (H-score 140). Cytogenetic analysis detected amplification of 9p24.1 in 8/15 (53%) of the cases. When analyzing clinical characteristics, only correlation of high HLA-DR expression with limited clinical stage (p=0.04) and low IPI (p<0.01) was found. There was no correlation between treatment response quality and HLA-DR or PD-L2 expression, but high PD-L1 expression (above the median) correlated with non-CR status after treatment (p=0.07). Due to a low number of relapses, there was no relationship between protein expression and survival. No difference was found between cases with or without JAK-2 copy gain in terms of PD-1L expression (71% vs. 73%, p=0.92) or PD-L1 H-score (80 vs. 73, p=0.55); expression of PD-2L was higher (4% vs. 9%, p=0.19) in cases with JAK-2 amplification. Conclusion:Frontline intensive therapy is very effective in PMBCL patients. This is why no clear prognostic impact of protein expression of PD ligands or HLA expression was observed. There was constant high PD-L1 protein expression in PMBCL, low PD-2L expression and a high proportion of cases with JAK-2 gene amplification. Preliminary data show relationship between tumor immunogenicity (HLA-DR expression) and lymphoma aggressiveness. High PD-1L protein expression may probably influence treatment response quality. Further analyses are needed to clarify correlation between 9p24.1 amplification and PD-L protein expression. Supported by grants: MZ ÈR IGA NT 11103, LF-2012-007 and MSM 6198959205. Disclosures:Prochazka:Roche: Travel grants Other.

EBV(+) Diffuse Large B Cell Lymphoma Is Infrequent in Upper Central United States and Lacks Unique Clinical Characteristics or Adverse Prognosis Compared to EBV (−) Counterparts: Results From University of Iowa/Mayo Clinic SPORE

AbstractAbstract 1604 BackgroundEBV (+) DLBCL of the elderly is a lymphoproliferative disorder recently included as a provisional entity in the 2008 WHO classification of lymphoid tumors. Defined as EBV (+) DLBCL in patients over the age of 50 years without known immunosuppression, information is evolving in this entity. To date, the true incidence of EBV (+) DLBCL in adults remains imprecisely determined and may vary regionally. This study sought to determine the incidence, presenting clinical characteristics, and outcome of EBV (+) in an unselected cohort of DLBCL patients enrolled in a prospective observational study. MethodsThe University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) is a prospective, longitudinal observational study designed to collect information on patterns of care and outcomes for patients with newly diagnosed lymphoma. Patients seen at the Mayo Clinic, Rochester MN and the University of Iowa within 9 months of their initial diagnosis of lymphoma are offered enrollment. HIV (+) patients are excluded. Baseline patient reported data, clinical data and initial management are collected using a standard protocol and a central pathology review is performed. After enrollment, patients are actively followed for events (disease progression, retreatment, and death) and disease related comorbidities. Tissue Micro Arrays (TMA) are constructed on available primary biopsy specimens. Epstein Barr Encoded RNA (EBER) EBV testing was performed by in-situ hybridization, and scored by an expert hematopathologist. EBER reactivity in more than 30% of malignant cells were required for EBV(+) designation. All DLBCL patients from the MER with available TMA excluding primary mediastinal DLBCL and post transplant lymphoproliferative disorders (PTLD) are included in the current analysis. Event free survival (EFS) was defined as time from diagnosis until recurrence, retreatment, or death due to any cause. Results184 newly diagnosed DLBCL patients with available TMAs were enrolled in the MER from 2002–2009. The median age at enrollment was 62 (range 18–89) and 57% were male. 89.7% were treated with immunochemotherapy. At a median follow-up of 66 months (range 1–116), 80 patients (43%) had an event which included 59(32%) deaths. TMA testing was positive for EBV in 13 (7 %) samples with an even distribution among age groups. There was a trend toward higher percentage of stage III/IV disease (85 vs 57%, p = 0.052), and BM involvement (46 vs 16%). EBV (+) was not associated with other extranodal disease or further identifiable differences in presenting clinical characteristics. Controlling for IPI, the hazard ratio for EFS among EBV+ in DLBCL pts over 50 was 0.41 (95% CI = 0.13–1.32) p = 0.14. EFS and OS curves for pts over 50 are shown below. There were no events or deaths in the 4 EBV+ pts under age 50. ConclusionsEBV+ DLBCL represents a small proportion of DLBCL patients presenting for care to our academic medical centers, consistent with reports from other regions. Substantial unique clinical characteristics at presentation for those pts with EBV+ disease were not identified, and outcomes were no worse than EBV (−) counterparts. Given the apparent regional differences in reports of EBV(+) DLBCL of the elderly, future clinical series will need to establish a more precise definition or determine more distinctive features to justify adoption of EBV(+) DLBCL of the elderly as a full entity in the WHO classification. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Positive Maternal-Fetal Outcomes with Treatment of Lymphoma During Pregnancy: UT MD Anderson Cancer Center Prospective Experience

Positive Maternal-Fetal Outcomes with Treatment of Lymphoma During Pregnancy: UT MD Anderson Cancer Center Prospective Experience

Temporary Mechanical Circulatory Support for Takotsubo Cardiomyopathy Secondary to Primary Mediastinal B-Cell Lymphoma

Left heart mechanical circulatory support (MCS) through the left chest via the pulmonary vein and descending thoracic aorta is a good option for patients with an inaccessible anterior mediastinum and/or poor peripheral access. We report the case of a 19-year-old small female with a newly discovered bulky primary mediastinal diffuse large B-cell lymphoma (PMBL) who developed refractory inverted Takotsubo cardiomyopathy (TC) with cardiogenic shock. Temporary MCS was implemented in order to stabilize the patient and proceed with a chemotherapy treatment. Given the patient's oncologic "frozen" mediastinum and the presence of poor peripheral arterial access, the left heart temporary MCS was successfully implanted through a left mini-thoracotomy via the left inferior pulmonary vein and descending thoracic aorta. This is the first report of temporary MCS to treat inverted TC and diffuse PMBL.

Cell of Origin Determination in Diffuse Large B-Cell Lymphoma: Performance of Immunohistochemical (IHC) Algorithms and Ability to Predict Outcome

Abstract 950 INTRODUCTION:Diffuse large B-cell lymphoma (DLBCL) can be categorized by its cell of origin (CoO) as either being derived from a germinal center B-cell (GCB) or activated B-cell (ABC). Primary mediastinal DLBCL represents a third, distinct entity. This classification was initially defined by gene expression profiling (GEP), which remains the gold standard for such determination. Determination of CoO will likely become the basis for patient selection for clinical trials of targeted therapies. Several algorithms and methods have been developed that use immunohistochemistry (IHC) to differentiate GCB-DLBCL from non-GCB DLBCL. These include the Hans algorithm (utilizes staining for CD10, Bcl-6 and Mum1), the Choi algorithm (utilizes additional staining for GCET1 and FoxP1) as well as the Tally method (does not use Bcl-6 and utilizes LMO2 as a tie-breaker stain for otherwise equivocal cases). Recently, it has been recognized that IHC approaches to assign CoO may not be reproducible even at highly experienced laboratories. We sought to determine the performance of these IHC assays in our laboratory as a necessary step in developing trials based on CoO stratification. METHODS:We reviewed 108 adult (age ≥18) cases of de novo DLBCL, the majority of which were treated with chemoimmunotherapy (R-CHOP or R-CVP) at the Cleveland Clinic from 2000–2010. Diagnostic biopsies were available for all cases. IHC staining was performed on tissue microarrays (TMAs), and published algorithms (Hans, Choi and Tally) were applied to categorize cases as GCB or non-GCB. In addition, gene expression profiling was completed in a subset of these cases, for which frozen tissue was available. A linear predictor score for gene expression profiling (GEP) was used to assign cases in 31 of 33 cases with 2 technical failures at the array stage (overall success rate 84.8%). Clinical details including age, sex, International Prognostic Index (IPI) stage at diagnosis, treatment, progression free survival (PFS) and overall survival (OS) were captured for 69 of the 108 patients. Actuarial survival analysis was performed according to the Kaplan and Meier method, and the curves compared by the log-rank test. RESULTS:For the 69 patients with adequate clinical follow-up, the median age was 64 years old (range 18–88). There were 49% males and 51% females. The distribution of patients with stage I, II, III, and IV disease at the time of diagnosis was 20%, 14%, 20%, and 32% (14% had unknown stage). The 5-year overall survival of patients was 88%. Results of the Hans algorithm, Choi algorithm and Tally method were interpretable in 98 (90.7%), 95 (87.9%) and 88 (81.5%) of 108 cases, respectively. Inability to assign subtypes was due to suboptimal staining of the TMA (tissue loss or poor staining of an individual core). Using GEP to assign CoO, 42% of cases were classified as GCB, 42% as ABC and 14% were unclassifiable. The sensitivities of the Hans, Choi and Tally approaches to identify the CoO predicted by GEP were 0.83, 0.83, and 0.58 for correctly identifying GCB cases, respectively, and were 0.70, 0.70 and 0.80 for identifying non-GCB cases, respectively. The positive predictive values of the Hans, Choi and Tally approaches were 0.83, 0.83, and 1.0 for GCB and 0.78, 0.78, and 0.89 for non-GCB. As shown in the figure, 5-year overall survival was significantly superior for GCB relative to ABC cases using GEP (100% vs. 58.9%, P < 0.001) and for GCB vs. non-GCB cases for the algorithms of Hans (100% vs. 82.3%, P = 0.0197) and Choi (95.6% vs. 78.0%, P = 0.0482). The Tally method was not predictive of outcome, possibly due to insufficient power (5-year OS 94.4% for GCB vs. 80.7% for non-GCB, P = 0.1725). Similar findings were observed for progression-free survival. [Display omitted] CONCLUSIONS: The Hans and Choi algorithms are reasonable methods for identifying PFS and OS differences based on CoO for de novo DLBCL treated with chemoimmunotherapy. The positive predictive value is universally high for all algorithms tested, but the sensitivity of IHC for identifying CoO was fair, particularly for the Tally method. IHC represents a valid biomarker to identify non-GCB cases. Clinical trials of DLBCL that stratify patients by IHC are feasible provided the performance characteristics of the algorithms are taken into consideration during study design. Disclosures:No relevant conflicts of interest to declare.

Limited PET-CT May Be Adequate for Interim and End of Therapy Response Assessment in Patients with Early Stage Hodgkin and Aggressive Non-Hodgkin Lymphoma - A Retrospective Single Center Study

Abstract 1562 Background:PET-CT is of central importance in the staging of patients with Hodgkin (HL) and non-Hodgkin aggressive lymphoma and in the assessment of their response to therapy. Repeated imaging of patients is associated with cumulative exposure to substantial doses of radiation that have been linked to an increased life attributed risk of cancer. Reduction of the PET CT imaging region will decrease significantly the cumulative radiation dose. Objectives:This study aims to evaluate whether a limited PET-CT focused to the initially involved field of view (FOV) at diagnosis, above or below the diaphragm, is sufficient for effective follow up and decision making in patients with early stage curable lymphoma. Methods:We retrospectively reviewed all patients treated in our center for HD and non-Hodgkin aggressive lymphoma that were diagnosed with stage I or II disease according to the Ann-Arbor staging system during September 2006 to December 2010. Included were patients that had a PET-CT preformed as part of their initial staging and that were followed by interim PET-CT and/or a PET CT at the completion of therapy. Clinical and epidemiologic data were extracted from the patients' medical charts. All PET-CT were reviewed by a nuclear medicine specialist. We then analyzed whether limiting the PET-CT imaging to the initially involved FOV at diagnosis, above or below the diaphragm, would miss findings obtained by standard PET CT. Results:Out of 668 patients 44 were eligible for full analysis. Patient median age at diagnosis was 37.5 years (range 19–84) and 59% of patients were females. Twenty seven patients had HD and 17 had diffuse large B cell lymphoma (DLBCL). Two cases of primary mediastinal DLBCL were included in the DLBCL group. Forty two patients had stage II disease while 2 patients were diagnosed at stage I. Thirty five patients (79%) had their lymphoma located above the diaphragm while 9 patients (21%) had disease involvement below the diaphragm.One hundred twenty seven PET-CT examinations were analyzed. Of these, 44 were preformed at diagnosis. Of the 43 interim exams preformed 32 were compatible with complete response (CR) and 11 were compatible with partial response (PR). Of the 40 PET-CT preformed at the end of treatment 34 were compatible with CR, 4 were compatible with PR and 2 showed a stable or progressive disease. There was no single case in which disease progressed outside the initially involved FOV. Thus, elements of response to therapy were contained and available for analysis within the preliminary filed of involvement in all cases. Conclusion:Our findings suggest that limiting PET-CT analysis of the initially involved FOV, above or below the diaphragm, in patients with early stage curable lymphoma may be satisfactory for response assessment and the associated clinical decision making. The use of limited PET-CT will significantly reduce patient exposure to cumulative radiation. The time required to complete limited PET-CT is reduced by 50% and the cost by more than 15%. To our best of knowledge this is the first analysis demonstrating the potential utility of reduction of PET CT FOV in curable lymphoma in adults. Disclosures:No relevant conflicts of interest to declare.

Relapsed and Refractory Primary Mediastinal Diffuse Large B-Cell Lymphoma: Outcome with ICE-Based Treatment.

Introduction: Primary mediastinal diffuse large B-cell lymphoma (PMLBL) is a distinct subtype of diffuse large B-cell lymphoma (DLBCL) with specific clinical, molecular and genetic features. The clinical presentation is similar to that of Hodgkin's lymphoma (HL); this similarity extends to the molecular level based on gene expression profiling revealing PMLBL is more similar to HL than to DLBCL subtypes. At MSKCC, initial therapy for PMLBL pts treated on protocol has employed dose-dense chemotherapy without radiation (RT) with excellent results [Hamlin, et. Al, BJH, 130(5), 2005]. In patients (pts) with relapsed (rel) and primary refractory (ref) disease, outcome with HDT/ASCT is largely undefined. We report MSKCC's experience with rel and ref PMLBL pts enrolled on sequential protocols with uniform second-line therapy (SLT) followed by HDT/ASCT, analyzed by intent-to-treat from initiation of SLT.Methods: Forty-two PMLBL pts were retrospectively identified across intent-to-transplant second-line chemotherapy protocols active at MSKCC from 1989 to 2004. Clinical characteristics at the time of rel or ref disease, including KPS, LDH, stage, and extranodal sites were recorded. Second-line age-adjusted IPI (aaIPI) and IPI values were calculated at rel/ref diagnosis. Event-free and overall survivals were assessed.Results: Patient demographics (n=42) revealed: rel disease 52.4% (n=22), ref 48% (n=20), 95% were <60 yrs. Advanced stage: 43%, LDH > ULN: 60%, KPS < 80%: 26%; aaIPI 0/1/2/3: 29%/21%/31%/14% (n= 40; 2 missing data); IPI 0&1/2/3/4&5: 45%/19%/14%/17%. Median time from initial diagnosis (dx) to dx of rel/ref disease was 7.2 months (range 2.4 to 37 months); 86% of relapses had occurred by 1 year. Initial therapy was CHOP (50%), NHL-15 (41%) [Portlock CS., et. al, Ann. Oncol., 15(10), 2004], or other (9%). 81% of pts (n=34) received a single second-line program prior to HDT/ASCT: ICE 47.5%, RICE 52.5%. Rituximab was included as part of treatment (at anytime) in 62% of cases. Most patients (81%) did not receive RT with their initial therapy, thus allowing RT to be utilized prior to HDT/ASCT (76% of pts). Ultimately, 81% of pts underwent ASCT. EFS and OS for all pts were 60% and 58% respectively, at a median follow-up for surviving pts of 5.9 years (range, 1.4 to 17 yrs) from diagnosis of rel/ref disease. EFS for rel pts compared with ref pts is 68% vs. 50% (p=0.17). EFS of transplant vs. no transplant pts was 71% vs. 12.5% (p=<0.0001). EFS for ICE vs. RICE was 62.5% vs. 64%; Of stage, LDH, and KPS, only stage was prognostic by log rank for EFS. EFS by aaIPI 0/1/2/3 was 83%/56%/54%/17% (p=0.008); EFS by IPI 0&1/2/3/4&5 was 68%/63%/67%/14% (p=0.001).Conclusions: This represents the largest intent-to-treat assessment of rel and ref PMLBL reporting SLT with HDT/ASCT. It reveals HDT/ASCT for chemosensitive pts with rel or ref PMLBL results in excellent EFS and OS, more similar to rel/ref HL than DLBCL; a rituximab effect on EFS was not evident in this series. The integration of RT as part of SLT prior to HDT/ASCT might have contributed to these favorable results. In the second-line setting, the aaIPI may divide PMLBL into good (0), intermediate (1–2) and poor (3) risk groups.

BCL2 Expression Is a Prognostic Marker for the Activated B-Cell–Like Type of Diffuse Large B-Cell Lymphoma

The role of BCL2 as a predictor of survival in diffuse large B-cell lymphoma (DLBCL) is controversial. DLBCL is heterogeneous, and the expression of BCL2 is variable within the two major subgroups of DLBCL, germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, as well as primary mediastinal DLBCL. In this study, we investigated the correlation of BCL2 expression with survival in the two major subgroups of DLBCL, as well as the mechanisms of BCL2 expression. There was no significant correlation between BCL2 protein expression and overall survival within the GCB subgroup, but BCL2 expression had a significant adverse effect on overall survival within the ABC subgroup (P = .008). This correlation was also observed at the mRNA level (P < .04). The difference remained significant when the analyses were performed at different cutoff values. The t(14;18) was frequently observed in the GCB subgroup and was highly associated with BCL2 expression. Patients with ABC DLBCL did not exhibit t(14;18) but had a markedly higher frequency of chromosome 18q21 amplification, on which BCL2 resides. Thus, alternative mechanisms such as 18q21 amplification or activation of the nuclear factor-kappa B pathway, as reported previously, seem to be mainly responsible for the upregulation of BCL2 expression in the ABC subgroup. Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.