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Multiple myeloma (MM) is a heterogeneous hematologic malignancy associated with several risk factors including genetic aberrations which impact disease response and survival. Thorough risk classification is essential to select the best clinical strategy to optimize outcomes. The SKY92 molecular signature classifies patients as standard- or high-risk for progression. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) measures impact of SKY92 on risk classification and treatment plan. Newly diagnosed MM patients had bone marrow aspirates analyzed for SKY92. Physicians completed a questionnaire for each patient capturing risk classification, hypothetical treatment plan, and physician confidence in the treatment plan, before and after unblinding SKY92. One hundred forty seven MM patients were enrolled. Before unblinding SKY92, physicians regarded 74 (50%) patients as clinical standard-risk. After unblinding SKY92, 16 patients were re-assigned as high-risk by the physician, and for 15 of them treatment strategy was impacted, resulting in an escalated treatment plan. For the 73 (50%) clinical high-risk patients, SKY92 indicated 46 patients to be standard-risk; for 31 of these patients the treatment strategy was impacted consistent with a de-escalation of risk. Overall, SKY92 impacted treatment decisions in 37% of patients (

Purpose: Most bladder cancers are early-stage tumors known as papillary non–muscle-invasive bladder cancer (NMIBC). After resection, up to 70% of NMIBCs recur locally, and up to 20% of these recurrences progress to muscle invasion. There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. We previously identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence in a pilot cohort that STAG2-mutant tumors recurred less frequently than STAG2 wild-type tumors. Here, we report a STAG2 biomarker validation study using two independent cohorts of clinically annotated papillary NMIBC tumors from the United States and Europe. Experimental Design: The value of STAG2 immunostaining for prediction of recurrence was initially evaluated in a cohort of 82 patients with papillary NMIBC (“Georgetown cohort”). Next, the value of STAG2 immunostaining for prediction of progression to muscle invasion was evaluated in a progressor-enriched cohort of 253 patients with papillary NMIBC (“Aarhus cohort”). Results: In the Georgetown cohort, 52% of NMIBC tumors with intact STAG2 expression recurred, whereas 25% of STAG2-deficient tumors recurred (P = 0.02). Multivariable analysis identified intact STAG2 expression as an independent predictor of recurrence (HR = 2.4; P = 0.05). In the progressor-enriched Aarhus cohort, 38% of tumors with intact STAG2 expression progressed within 5 years, versus 16% of STAG2-deficient tumors (P < 0.01). Multivariable analysis identified intact STAG2 expression as an independent predictor of progression (HR = 1.86; P = 0.05). Conclusions: STAG2 IHC is a simple, binary, new assay for risk stratification in papillary NMIBC. Clin Cancer Res; 24(17); 4145–53. ©2018 AACR.

Introduction/Objective Concurrent diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Hodgkin lymphoma (HL) is rare. CLL/SLL can rarely advance into Hodgkin-variant of Richter transformation, or there can be a simultaneous presence of separate CLL/SLL and HL from different clonal origins. Due to its rarity, the epidemiological features and outcome of concurrent CLL and HL are not well-known. Here we have used the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database to identify concurrent CLL/SLL and HL cases and analyzed overall and disease-specific survival across various epidemiological factors. Methods/Case Report We identified all patients diagnosed with CLL/SLL and HL between the period of 1975 to 2017. Next, we identified the patients with a simultaneous CLL/SLL and HL diagnosis by matching the patient identification number. Overall survival and disease-specific survival were calculated using Kaplan-Meier curves and Cox proportional hazards models. Results (if a Case Study enter NA) We identified 166 cases with a concurrent diagnosis of CLL, and HL. 4 cases were excluded from analysis as the diagnosis of CLL and HL were not simultaneous. The age distribution of the patient showed a unimodal distribution, with most patients being diagnosed between the age of 50 and 79. 67% of patients were male, and 92% of patients were Caucasian. The majority of the CLL was diagnosed in bone marrow or lymph nodes, while almost all HL were diagnosed in lymph nodes. Both disease-specific and overall survival were worse for patients with the advanced age of diagnosis. Race or sex did not significantly affect patients’ survival. Conclusion Our comprehensive review of clinical and epidemiological features of concurrent CLL and HL cases shows that the age of diagnosis is the most significant factor in determining the survival of these patients.

Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

Objectives: Five proteins from the soluble N -ethylmaleimide–sensitive factor activating protein receptor (SNARE) complex family were studied in normal hematopoietic cells in bone marrow; normal lymphocytes at different stages of maturation and differentiation in bone marrow, thymus, tonsil, and lymph node; malignant lymphomas; and leukemias. Methods: Sixty-eight reactive and 380 hematopoietic and lymphoid neoplasms were immunohistochemically stained for syntaxin 7 (STX7), vesicle-associated membrane proteins (VAMP2, VAMP7, VAMP8), and synaptosomal-associated protein 23 (SNAP23). Results: STX7 has potential for being a useful marker for distinguishing between normal B precursors (hematogones) vs B lymphoblasts, as well as between the “popcorn” cells of nodular lymphocyte-predominant Hodgkin lymphoma vs the Reed-Sternberg cells of classic Hodgkin lymphoma or the B cells of T-cell, histiocyte-rich B-cell lymphoma. VAMP2 is uniquely expressed by both reactive and malignant plasma cells, in contrast to B-cell non-Hodgkin lymphoma. There is differential expression of SNARE proteins in normal and neoplastic lymphoid tissue depending on lymphocyte maturation stage. Conclusions: Differential SNARE protein expression in the lymphoid system may have potential use in diagnosis and may offer clues to lymphoma biology. VAMP2 is a promising new plasma cell marker.

Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced-dose FCR (FCR-Lite) plus lenalidomide (FCR(2) ) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR(2) . Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR(2) . Twenty patients were evaluable. After four cycles of FCR(2) , response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR(2) . After 17.4 months of median follow-up, one progression and one death occurred. Our findings suggest that FCR(2) combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes.

Lymphocytic neoplasm involving the heart is not common and usually presents with pericardial effusion or focal myocardial infiltration. Myocardial infarctions due to leukemic infiltration of the coronary arteries are rarely reported. We present the case of a 52-year-old Guatemalan man with a one-year history of untreated T-cell prolymphocytic leukemia. He was admitted to our hospital for chemotherapy and evaluation of a pulmonary cavitary lesion by wedge resection. During sedation, the patient experienced acute respiratory failure and hypovolemic shock, from which he could not be resuscitated. Autopsy revealed that leukemic cells extensively infiltrated the aorta, myocardium, and coronary arteries. The lumina of the 3 major coronary artery branches showed 70% to 95% stenosis, with multifocal remote myocardial infarctions. Tumor cells were also detected in the lungs and other organs. The acute cardiorespiratory insufficiency secondary to leukemia—particularly the extensive infiltration of the coronary arteries and myocardium, and the multiple myocardial infarctions—eventually resulted in cardiac death.

Spectrins are large, rod-like, multifunctional molecules that participate in maintaining cell structure, signal transmission, and DNA repair. Because little is known about the role of spectrins in normal hematopoiesis and leukemogenesis, we immunohistochemically stained bone marrow biopsy specimens from 81 patients for αI, αII, βI, and βII spectrin isoforms in normal reactive marrow (NRM), myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia (AML) with well-characterized cytogenetic abnormalities, acute erythroid leukemia (EryL), and acute megakaryoblastic leukemia (MegL). In NRM, spectrin isoforms were differentially expressed according to cell lineage: αI and βI in erythroid precursors; αII and βII in granulocytes; and βI and βII in megakaryocytes. In contrast, 18 (44%) of 41 AMLs lacked αII spectrin and/or aberrantly expressed βI spectrin (P = .0398; Fisher exact test) and 5 (100%) of 5 EryLs expressed βII spectrin but lacked βI spectrin. The frequent loss and/or gain of spectrin isoforms in AMLs suggests a possible role for spectrin in leukemogenesis.

α-Synuclein is a key component of the Lewy body, a large globular protein complex that forms in the nervous system of patients with Parkinson disease and other dementias [1-3]. Since α-synuclein also occurs in megakaryocytic and erythroid lineages [4-7], we wondered what role synucleins had in the hematopoietic system. Therefore, we studied the expression of α-, β-, and γ-synucleins in a comprehensive panel of patient bone marrows and leukemic cell lines. We observed under expression of α-synuclein in the megakaryocytes of myeloproliferative neoplasm (MPN), but not normal reactive marrow (NRM) or myelodysplastic syndrome (MDS). Conversely, we observed over expression of β-synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that α- and β-synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs.

Purpose: Bladder cancer is the sixth most common human cancer. Most cases are early-stage tumors known as papillary non-muscle invasive bladder cancer (NMIBC). After resection, 60-70% of NMIBCs recur locally, and ~15% progress to muscle invasion and metastasis. There is an unmet need for a biomarker to stratify tumors on their likelihood of recurrence. Such a biomarker could make it possible to identify those patients most likely to benefit from adjuvant intravesical therapy such as BCG. Furthermore, lower-risk patients could become eligible for less frequent post-resection surveillance by cystoscopy than the extremely intensive current standard of care. We recently identified STAG2 as among the most commonly mutated genes in NMIBC and provided initial evidence that STAG2 mutant tumors may recur less frequently than STAG2 wild-type tumors. Here we report a STAG2 biomarker study using an independent cohort of clinically annotated papillary NMIBC tumors. Experimental Design: We identified all cases of papillary NMIBC treated at the Lombardi Comprehensive Cancer Center prior to 2013. STAG2 immunohistochemistry was performed and correlated with time to recurrence. This assay is particularly robust because (i) it utilizes a monoclonal antibody whose epitope is in the extreme carboxyl-terminus of STAG2, and ~85% of tumor-derived mutations of STAG2 are truncating; (ii) STAG2 is on the X-chromosome, so only a single mutation is required for complete gene inactivation; and (iii) STAG2 is among the most abundant proteins in the human proteome. Results: 52% of NMIBC tumors with STAG2 expression recurred, whereas only 25% of NMIBC tumors with loss of STAG2 expression recurred (p=0.017). Multivariate analysis identified STAG2 as the only significant independent predictor of recurrence (p=0.050). The relative risk of recurrence for patients with STAG2-expressing tumors was 2.408 times the risk for patients with STAG2-negative tumors. Conclusions: Here we demonstrate that a simple, robust assay for identifying STAG2-mutant tumors stratifies patients into two groups: (i) patients with retention of STAG2 expression (wild-type), ~52% of whom will recur; and (ii) patients with loss of STAG2 expression, of whom only ~25% will recur. Of note, STAG2 expression status, unlike pathologic grade–the current standard–was a significant predictor of recurrence. This information could help physicians make more informed decisions about the need for adjuvant immunotherapy/chemotherapy and also help inform the frequency of post-resection surveillance needed for individual patients. In conclusion, STAG2 is a simple, powerful, and potentially useful biomarker for prediction of recurrence in papillary NMIBC. Citation Format: Alana Lelo, Brent T. Harris, Deborah L. Berry, Krysta Chaldekas, Anagha Kumar, David Solomon, Jeffry Simko, Pritish Bhattacharyya, Ciaran Mannion, Jung-Sik Kim, George Philips, Todd Waldman. STAG2 as a biomarker for prediction of recurrence in papillary non-muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1558.

Background: Kaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus type 8 (HHV8), is consistently identified in 2 human immunodeficiency virus (HIV)-associated lymphoproliferative disorders: primary effusion lymphoma (PEL) and multicentric Castleman disease. Rarely, KSHV/HHV8-positive extracavitary solid tissue lymphomas occur, often at extranodal sites, which are not associated with an effusion. These solid variants of PEL are similar morphologically, immunophenotypically, clinically and genetically to classic PEL. Case Report: Here we report a case of a 46-year-old HIV-positive patient with lymphadenopathy and Kaposi sarcoma of the skin. The lymph node biopsy shows a KSHV/HHV8-positive high-grade B-cell lymphoma with co-infection with Epstein-Barr virus, which supports the diagnosis of a solid variant of PEL. The same lymph node is also multifocally involved in Kaposi sarcoma. Conclusion: Analysis of viral infection is of primary importance to define this solid variant of PEL. The exact oncogenic mechanisms of HHV8 are not clearly defined. It is believed that it is related to a few latent viral gene products including ORF73, ORF72, and ORF71 which increase proliferation and impair apoptosis through variant regulatory processes. To the best of our knowledge, this is the first reported case of solid tissue PEL along with Kaposi sarcoma involving the same anatomic site.

Fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard of care for fit chronic lymphocytic leukemia (CLL) patients requiring first therapy. However, side effects can be significant, and patients with poor risk features have inferior outcomes. The purpose of this study was to evaluate reduced-dose FCR (FCR-Lite) plus lenalidomide (FCR(2) ) followed by lenalidomide maintenance as a strategy to shorten immunochemotherapy in untreated CLL. Patients received four to six cycles of FCR(2) . Patients who were minimal residual disease (MRD) negative in peripheral blood (PB) and bone marrow (BM) initiated 12 months of lenalidomide maintenance after either four or six cycles (based on MRD status). The primary study endpoint was the complete response (CR) rate after four cycles of FCR(2) . Twenty patients were evaluable. After four cycles of FCR(2) , response rates were: CR, 45.0%; CR with incomplete blood count recovery (CRi), 5.0%; partial response (PR), 45.0%; and stable disease (SD), 5.0%. BM and PB samples from 27.8% and 52.9% of patients, respectively, were MRD negative. After six cycles, response rates were: CR, 58.3%; CRi, 16.7%; and PR, 25.0%. BM and PB samples from 50.0% and 72.7% of patients, respectively, were MRD negative. Overall, 75% of evaluable patients achieved a CR or CRi following FCR(2) . After 17.4 months of median follow-up, one progression and one death occurred. Our findings suggest that FCR(2) combines encouraging clinical activity with acceptable toxicity in previously untreated CLL. Lenalidomide can be safely added to FCR and may reduce chemotherapy exposure without compromising outcomes.

Based on gene expression profiling, diffuse large B-cell lymphomas arising in immunocompetent patients can be divided into germinal center and activated B-cell types. Since little is known about acquired immunodeficiency syndrome associated diffuse large B-cell lymphomas, we tested whether the protein expression of germinal center and activated B-cell markers differed between acquired immunodeficiency syndrome (AIDS) vs non-AIDS diffuse large B-cell lymphomas. We immunohistochemically stained tissue microarrays of 39 de novo diffuse large B-cell lymphomas: 12 AIDS associated and 27 non-AIDS, with germinal center (BCL6, CD10, CyclinH) and activated B-cell markers (MUM1, CD138, PAK1, CD44, BCL2). We scored each case for percent positive cells (0–19% ¼ 0; 20–49% ¼ 1; 50–100% ¼ 2). The activated B-cell and germinal center summation scores of each case were used as (x, y) coordinate data points to construct two-dimensional contour-frequency plots. The contour plot of non-AIDS diffuse large B-cell lymphomas showed two distinct clusters: a cluster with a high germinal center phenotype (cluster 1) and a cluster with a high activated B-cell phenotype (cluster 3). In contrast, the AIDS-related diffuse large B-cell lymphomas formed a single aggregate (cluster 2) (P ¼ 0.02, Fisher exact test). When the contour plots of the AIDS-related and the non-AIDS cases were superimposed, cluster 2 of the AIDS cases expressed an intermediate germinal center/activated B-cell phenotype compared to clusters 1 and 3 of the non-AIDS diffuse large B-cell lymphomas. Our results confirm that non-AIDS diffuse large B-cell lymphomas segregate into two groups with either germinal center or activated B-cell phenotype. We report the new finding that the AIDS status of the patient predicts the immunophenotype of the diffuse large B-cell lymphomas. Modern Pathology (2006) 19, 438–446. doi:10.1038/modpathol.3800493; published online 27 January 2006

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap. No single phenotypic marker or molecular abnormality is pathognomonic. We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL. We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization). After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells. Hierarchical clustering yielded 2 major clusters significantly associated with morphologic diagnosis (P < .001). For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points. This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P < .001). Protein expression of multiple GC and ABC markers can separate BL and DLBCL.

Background. Multiple articles discuss the rare incidence and potential causes of second hematologic disorders arising after treatment of Chronic Myelogenous Leukemia (CML), leading to the theory of imatinib, the current treatment regimen for CML, as a possible trigger for the development of secondary neoplasms. Our case eliminates the possibility of imatinib as the sole cause since our patient received a diagnosis of simultaneous plasma cell myeloma, CML, and a Jak2 mutation positive myeloproliferative disorder (MPD) arising de novo, prior to any treatment. We will further investigate into alternative theories as potential causes for multiple hematopathologic disorders.Case Report. There are currently no reported cases with the diagnosis of simultaneous plasma cell myeloma, chronic myelogenous leukemia, and Jak2 positive myeloproliferative disorder. We present a case of a 77-year-old male who was discovered to have these three concurring hematopathologic diagnoses. Our review of the literature includes a look at potential associations linking the three coexisting hematologic entities.Conclusion. The mechanism resulting in simultaneous malignancies is most likely multifactorial and potentially includes factors specific to the host, continuous stimulation of the immune system, previous chemotherapy or radiation, a potential common pluripotent stem cell, or, lastly, preexisting myeloma which may increase the susceptibility of additional malignancies.

Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis. Outcomes are particularly poor following immunochemotherapy failure or relapse within 12 months of induction. We conducted a Phase I/II trial of lenalidomide plus RICE (rituximab, ifosfamide, carboplatin, and etoposide) (RICER) as a salvage regimen for first-relapse or primary refractory DLBCL. Dose-escalated lenalidomide was combined with RICE every 14 d. After three cycles of RICER, patients with chemosensitive disease underwent stem cell collection and consolidation with BEAM [BCNU (carmustine), etoposide, cytarabine, melphalan] followed by autologous stem cell transplantation (autoSCT). Patients who recovered from autoSCT toxicities within 90 d initiated maintenance treatment with lenalidomide 25 mg daily for 21 d every 28 d for 12 months. No dose-limiting or unexpected toxicities occurred with lenalidomide 25 mg plus RICE. Grade 3/4 haematological toxicities resolved appropriately, and planned dose density and dose intensity of RICER were preserved. No lenalidomide or RICE dose reductions were required in any of the three cycles. After two cycles of RICER, nine of 15 patients (60%) achieved a complete response, and two achieved a partial response (13%). Combining lenalidomide with RICE is feasible, and results in promising response rates (particularly complete response rates) in high-risk DLBCL patients.

Introduction: Cure rate of Mature T/NK cell lymphoma (TCL) is rather low and multiple trials are being conducted to improve frontline therapy outcomes. Consolidation with autologous stem cell transplant is becoming widely used as a mean of improving survival (SCT). Based on data from several retrospective trials, pts who achieve CR may not benefit from consolidative SCT. There is no data available on the role of PET-CR as defined by using Deauville criteria (which became standard in response assessment of NHL (The Lugano Classification 2014)). We performed retrospective analysis of 59 pts with TCL examining the correlation between PFS/OS and iPET and eotPET. Methods: 59 pts newly diagnosed pts with TCL treated between 2008-2016 for whom interim and eotPET scan were available. It was our routine practice to obtain baseline, interim (after 3 cycles of chemotherapy) and eotPET. Pathology slides of outside cases were centrally evaluated by a hematopathologist to confirm diagnosis. Baseline, interim and eotPET were centrally reviewed by a nuclear medicine radiologist blinded to clinical outcomes who assigned Deauville score (DS) to every PET. Responses were recorded according to the Lugano classification 2014. Descriptive statistics and Kaplan Meier method was used to calculate the Progression-free survival (PFS) and Overall survival (OS), two-sided Log-rank test was used to compare OS and PFS between PET groups. Results: Detailed demographic is presented in Table1. Median age at diagnosis is 59, sixty two percent males, 37% female; ALCL 34%, PTCLnos 22%, AITL 19%, and ATLL 10%; most of pts were advanced stage. Most common chemotherapy regimens used were CHOP/CHOEP, HCVAD, and CODOX, SMILE. Median follow up time for the entire cohort was 22.7mo. Forty nine percent of pts progressed and 29% of pts died during follow up. Cause of death for majority of pts was disease progression. Following Deauville scores were assigned on iPET and eotPET respectively: DS1 in 37% and 39%, DS2 in 30% and 35%, DS3 in 15% and 6%, DS4 in 9% and 4%, DS5 in 9% and 16%. We analyzed mPFS and mOS for PET-CR using DS1-2 or DS1-3 to define it. Sixty seven percent and 82% were considered in PET-CR on iPET based on DS 1-2 and DS 1-3 respectively. PET-CR went up to 77% and 83% respectively on eotPET. For final analysis, DS1-2 was used to define PET-CR as no statistically significant difference in mPFS and mOS was noted between DS1-2 and DS1-3. With median follow up of 22.7mo, two-year mPFS and mOS for the cohort were 50% and 74% respectively. Two- year mPFS for iPET-CR and eotPET-CR were 62%. Two-year mOS for iPET-CR and eotPET-CR were 86%% and 83%. Two-year mPFS for iPET-PR and eotPET-PR were 37% and 67%. Two-year mOS for iPET-PR and eotPET-PR were 70% and 100 % (not statistically significant difference with PET-CR mPFS and mOS). None of the pts with PD on iPET were alive at two year. Two-year mOS for eotPET-SD and eotPET-PD are 40%. Negative predictive value of iPET and eotPET is 61%, positive predictive value is 65% and 72% respectively. Conclusion: While PET-SD and PD is quite predictive of poor survivorship, significant number of PET-CR pts will relapse. Even though PET-CR rate to frontline therapy is high, it does not translate into durable responses for significant number of pts with TCL. Thus, PET-CR is not a sensitive enough measure to be considered as a predictor of long-term remission in TCL. It is important to develop response assessment tools which will correlate better with long term survivorship of TCL patients. Figure 1 Overall survival stratified on PET response Figure 1. Overall survival stratified on PET response Figure 2 Progression free survival stratified on PET response Figure 2. Progression free survival stratified on PET response Disclosures Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Leslie:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau. Skarbnik:Pharmacyclics: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Mato:Theradex: Research Funding; TG Therapeutics: Research Funding; ProNAi: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma: Research Funding; Abbvie: Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Abbvie: Consultancy. Chow:Seattle Genetics: Speakers Bureau. Protomastro:COTA: Employment. Leslie:Celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Subtypes of diffuse large B-cell lymphoma (DLBCL) that have inferior outcomes after front-line therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) have been identified. While it is agreed that R-CHOP is probably not adequate in these patients, there is no standard treatment approach for patients with DLBCL with high-risk features. We present results of a retrospective cohort study of high-risk DLBCL (defined as having at least one unfavorable risk factor: non-germinal center [GC] subtype by immunohistochemistry [IHC], Ki-67 ≥ 80%, high International Prognostic Index [IPI], c-MYC rearrangement) treated with R-HCVAD/R-MTX-AraC (rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine; R-HCVAD) as front-line therapy. With a median follow-up of 25.3 months, the 3-year PFS and OS estimates are 79% (95% confidence interval [CI], 65-88%) and 76% (95% CI, 61-86%), respectively, which are higher than those for historical comparisons with R-CHOP data for high-risk patients. These data are in accord with other recent reports of dose-intense front-line therapy of high-risk DLBCL. This analysis represents the largest reported cohort of patients with DLBCL treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in patients with DLBCL treated with dose-intensive regimens.

Synucleins are small soluble proteins found in normal brain that facilitate rapid release of neurotransmitters. α-synuclein is a major component of the Lewy body of neurodegenerative diseases and γ-synuclein is a marker of aggressive carcinomas. As the role of γ-synuclein has not yet been investigated in the lymphoid system, we immunohistochemically stained normal lymphoid organs, lymph nodes with reactive lymphoid hyperplasia, and malignant lymphomas. The anti-γ-synuclein antibody strongly stained the follicular dendritic cell (FDC) meshworks and vascular and lymphatic endothelial cells in reactive lymphoid tissues, in B-cell lymphomas with a nodular pattern, and in angioimmunoblastic T-cell lymphomas. There were no γ-synuclein-positive FDC meshworks in B-cell or T-cell lymphomas with a diffuse pattern. This is in contrast to CD21, which only stained the arms of the FDCs; γ-synuclein highlighted both the long slender cellular processes and the cell body, thereby clearly demonstrating the number of individual FDCs. In addition, γ-synuclein was strongly expressed by the neoplastic counterpart of reactive FDCs (FDC sarcoma) and by the neoplastic counterparts of normal lymphatic and vascular endothelial cells (Kaposi sarcoma, hemangioma, and angiosarcoma). Only a few spindle cell neoplasms (SSNs) derived from smooth muscle, peripheral nerve, or gastrointestinal stroma expressed γ-synuclein; however, γ-synuclein was not expressed by 11 other types of SSNs tested. These results suggest that γ-synuclein is a promising new adjunct marker for identifying reactive FDCs and for diagnosing FDC sarcoma and benign and malignant vascular tumors.

Transplantation of hematopoietic progenitor cells from red cell-incompatible donors occurs in 30-50% of patients. Immediate and delayed hemolytic transfusion reactions are expected complications of red cell-disparate transplantation and both ABO and other red cell systems such as Kidd and rhesus can be involved. The immunohematological consequences of red cell-incompatible transplantation include delayed red blood cell recovery, pure red cell aplasia and delayed hemolysis from viable lymphocytes carried in the graft ('passenger lymphocytes'). The risks of these reactions, which may be abrupt in onset and fatal, are ameliorated by graft processing and proper blood component support. Red blood cell antigens are expressed on endothelial and epithelial tissues in the body and could serve to increase the risk of GvHD. Mouse models indicate that blood cell antigens may function as minor histocompatibility antigens affecting engraftment. Similar observations have been found in early studies of human transplantation for transfused recipients, although current conditioning and immunosuppressive regimens appear to overcome this affect. No deleterious effects from the use of red cell-incompatible hematopoietic grafts on transplant outcomes, such as granulocyte and platelet engraftments, the incidences of acute or chronic GvHD, relapse risk or OS, have been consistently demonstrated. Most studies, however, include limited number of patients, varying diagnoses and differing treatment regimens, complicating the detection of an effect of ABO-incompatible transplantation. Classification of patients by ABO phenotype ignoring the allelic differences of these antigens also may obscure the effect of red cell-incompatible transplantation on transplant outcomes.

Spectrins are large, rod-like, multifunctional molecules that participate in maintaining cell structure, signal transmission, and DNA repair. Because little is known about the role of spectrins in normal hematopoiesis and leukemogenesis, we immunohistochemically stained bone marrow biopsy specimens from 81 patients for αI, αII, βI, and βII spectrin isoforms in normal reactive marrow (NRM), myelodysplastic syndrome, myeloproliferative neoplasm, acute myeloid leukemia (AML) with well-characterized cytogenetic abnormalities, acute erythroid leukemia (EryL), and acute megakaryoblastic leukemia (MegL). In NRM, spectrin isoforms were differentially expressed according to cell lineage: αI and βI in erythroid precursors; αII and βII in granulocytes; and βI and βII in megakaryocytes. In contrast, 18 (44%) of 41 AMLs lacked αII spectrin and/or aberrantly expressed βI spectrin (P = .0398; Fisher exact test) and 5 (100%) of 5 EryLs expressed βII spectrin but lacked βI spectrin. The frequent loss and/or gain of spectrin isoforms in AMLs suggests a possible role for spectrin in leukemogenesis.

Relapsing polychondritis is characterized by recurrent inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and the tracheobronchial tree. The eye is also a frequent target organ in relapsing polychondritis, and proptosis is a well-recognized manifestation of eye involvement. Similar to other rheumatologic diseases, an association of relapsing polychondritis with malignancy has been reported. We describe a patient with relapsing polychondritis who presented with exophthalmos. When treatment directed toward control of her underlying disease was only partially effective, further investigation revealed that she had an orbital mucosa-associated lymphoid tissue (MALT)-type B cell lymphoma. We hypothesize that the lymphoma resulted from malignant transformation of the relapsing polychondritis-induced inflammatory pseudotumor and emphasize that neoplastic disease should be considered in the differential diagnosis in patients with relapsing polychondritis presenting with exophthalmos.

A 58-year-old man with 10 year history of chronic lymphocytic leukaemia (CLL) presented with a bulging mass (3.2×1.6×1.5 cm) in the right anterior abdominal wall. On microscopic examination the mass was found to be an epithelial neoplasm in the background of lymphoid proliferation. The epithelial cells were of moderate size, with scant cytoplasm and round nuclei, forming glandular, alveolar or sheet-like structures. These cells were immunoreactive for cytokeratin 20, chromogranin and synaptophysin. The above findings supported a diagnosis of Merkel cell carcinoma (MCC). The background small lymphocytes expressed phenotypic markers of B cells (CD20) and CD5, consistent with his known diagnosis of CLL. The incidence of a patient with a known history of CLL who develops a secondary MCC is rare. This is believed to be the second case report of a single lesion containing CLL and MCC.

Background: Rituximab has increased the CR rate, improved both PFS and OS and changed the pattern of relapse of DLBCL pts treated with R-CHOP (leading to a > 50% cure). In contrast to the pre rituximab era, the majority of failures occur early (80% of failures occur in the 1st 18 months). The observation made that few relapses (7-8%) occur after 24 months of pts enrolled in clinical trials needs validation in the community setting. We report here a large cohort of pts treated at our institution over a period of 7 years with rituximab-containing chemotherapy regimens. Methods:We performed a retrospective cohort analysis to describe the survival experiences of adult patients with de novo DLBCL treated at our institution between 2007 and 2013. Patients were identified using Hematopathology and John Theurer Cancer Center outcomes databases. Patients who didn’t receive rituximab as part of their initial combination chemotherapy were excluded, as well as transformed DLBCL, primary CNS DLBCL, HIV-related DLBCL pts, those lacking follow up data. Results: A total of 245 patients with DLBCL treated at our institution were identified. Baseline characteristics were as follows: median age was 63 (20-92), 53% males, 75% stage III-IV and 24% stage I-II; IPI score was high in 25% of pts, high-int in 22%, low-int in 45% and low in 7%. Most patients received R-CHOP (66%), while 34% were treated with dose intense regimens based on high risk features such as high IPI, Ki-67 over 80% (R-HyperCVAD, DA-R-EPOCH, R-Magrath), only two patients had frontline planned stem cell transplant. 91% of the patients achieved a CR, 7% were primary refractory (progressed during therapy), 2% PR/SD ). With a median follow up time of 32.5 months, the median OS and PFS have not been reached (75% of patients are alive at 55.9 months). In contrast, the median OS of relapsed patients was only 14.4 months No gender-specific differences in survival were observed. No differences in PFS and OS were observed based on frontline chemotherapy regimen. Achieving CR significantly determines survival (p. Conclusion: Our series confirm outside clinical trial setting that in contrast to the pre-rituximab era, late relapses are rarely observed in patients treated with rituximab–containing induction therapy. The majority of relapses occur within the first two years of the initial therapy. Our findings validate the data from the Mayo clinic experience (Maurer et al, JCO 2014). This observation not only provides reassurance to patients but also support the current imaging guidelines with no longer a need for routine imaging surveillance for relapse in DLBCL beyond 2 years after frontline therapy. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

Introduction: Fludarabine, cyclophosphamide, rituximab (FCR) remains the standard of care for the treatment of newly diagnosed, fit CLL pts requiring therapy. However, the FCR side effects profile is non-trivial and CLL pts with poor risk features have inferior outcomes. Strategies aimed at minimizing toxicity without compromising efficacy have been reported including modifications of the optimal dosing and duration of FCR using a dose-reduced approach (Foon et al, “FCR lite”) or reduction in number of FCR cycles based on MRD status (Strati et al). In the era of biological agents, both preclinical and clinical data have shown the efficacy of lenalidomide (Len) in CLL likely through its role as an immunomodulator and interference with interactions between CLL and its microenvironment. In CLL, Len presents a clinical opportunity both in combination with chemotherapy and as maintenance strategy. This was the rationale for our trial using Len in combination with FCR and as maintenance to improve outcomes and shorten therapy. Methods: We conducted a phase 2 cohort study examining the combination of dose-reduced FCR and Len (“FCR2”) followed by Len maintenance for treatment naïve, CLL pts requiring therapy (NCIWG criteria). Eligible pts (age ≥18 yr, ECOG 0-2, CrCl ≥30 ml/min, absence of AIHA) were treated with 4-6 cycles of FCR2 (D1-3 fludarabine 20 mg/m2, D1-3 cyclophosphamide 150 mg/m2, D1&15 rituximab 500 mg/m2 every 28 days). Len was administered on D 8-28 of each cycle (starting dose of 5 mg increasing to 10 mg and 15 mg in cycle ≥ 2 based on toxicity algorithm). Pts who were MRD (-) in PB and BM (multicolor flow cytometry) initiated Len maintenance after cycle 4 FCR2 (otherwise proceeded to 6 cycles). Supportive care included asa 81 mg, pegfilgrastim, and antimicrobial prophylaxis (ciprofloxacin, bactrim, fluconazole, acyclovir). Daily Len maintenance started two months after FCR2 completion in responding pts for a total of 12 months (5-15 mg based on toxicity algorithm). The primary study endpoint was the proportion of CR pts after cycle 4 of FCR2 with ≥ 8/19 (≥ 40%) CR+CRi considered a positive result and worthy of further study (α 0.05, β 90%). Secondary endpoints included MRD status, ORR, OS, PFS and toxicity (CTCAE V. 4.0). We report the primary endpoint and preliminary data on non-survival secondary endpoints. Results: 25 pts met inclusion criteria for enrollment of which 22 pts enrolled and 19 were evaluable (consent was withdrawn on 3 pts after ≤ 4 FCR2 cycles due to pt preference n=1, physician preference n=2, one additional pt withdrew consent after cycle 5 to proceed with Allo SCT.) Baseline characteristics expressed as median (range) were as follows: age 62.5 yr (42-75 yr), ECOG PS 1 (0-2), WBC 115.4 x 109/L (8.7-301.7), Hb 12.2 g/dL (7.8-15.3), Plt 131 x 109/L (60-178), IgG 602 mg/dL (294-1018), β2mg 2.8 μg/mL (1.74-6.69), LDH u/L 471 (132-1022), BM % lymphs 75 (25-100%), baseline SPD 23.4 (2.9-63.5). In addition 30% pts had Rai stage III-IV, 53% unmutated-CLL, 5% del17p and 30% del11q. After 4 cycles of FCR2 (n=19) response rates were as follows CR 47%, CRi 5%, PR 42%, SD 5% (pts were MRD neg in 29% BM and 56% PB samples, 3 pts (16%) were MRD neg in both PB and BM). After 6 cycles of FCR2 (n=16), response rates improved and were as follows: 63% CR, 13% CRi, 19% PR, 5% PD (pts were MRD neg in 50% BM and 72% PB samples). Table 1 shows MRD status following 4 and 6 cycles of FCR2. During induction, 12 pts required a treatment interruption or dose reduction of Len per protocol (median dose of len was 10 mg). The most common grade 3-4 toxicities were as follows (% events): neutropenia (51%), leukopenia (20%), hyperglycemia (5%), NTP fever (5%). Grade 3-4 TLS and tumor flare were not noted. The med follow up for the entire cohort is 13.1 months (7.3-22.5 months). One progression has occurred in a pt who withdrew from study after 2 cycle of FCR2. One death has occurred in a pt with del17p who died on D+255 following allogeneic SCT in CR from the complications of cGVHD. 10 pts have gone on to initiate Len maintenance. Conclusions: FCR-lite in combination with Len is feasible and demonstrates encouraging clinical activity in a high-risk, CLL pt population with an acceptable toxicity profile. A significant proportion of pts are MRD neg in PB and/or BM following FCR2. Addition of Len to FCR may minimize chemotherapy exposure without compromising outcome. Table 1:MRD StatusFollowing Cycle 4 FCR2Following Cycle 6 FCR2Bone Marrow29%50%Peripheral Blood56%72% Disclosures Mato: Celgene : Honoraria, Research Funding, Speakers Bureau.

Background: The survival of mantle cell lymphoma (MCL) has improved (median OS now >5 years) due to the use of dose-intensive strategies in younger patients (pts) achieving a deeper and earlier response (including molecular CR) and the application of novel therapies in the relapsed/refractory setting, where patients are typically chemoresistant. However, given the median age at onset in the mid to late 60's, and the remaining variability in outcomes, additional strategies are needed. A number of prognostic factors have been reported in MCL including MIPI, Ki67 and blastoid variants among others, the latter being frequently associated with del 17p or p53 mutations and a particularly poor outcome. Recent studies have begun to describe the genomic landscape of MCL by whole-genome, whole-exome and targeted sequencing. However, comprehensive evaluation of genomic alterations relevant for MCL pathogenesis and that could be potentially informative for patient's prognosis and patient's stratification remains to be elucidated. Methods: We studied 33 FFPE or cryopreserved blood MCL specimens by performing integrated DNA and RNA sequencing (N=18) or DNA sequencing alone (N=15). All samples were obtained at diagnosis before patients received Rituximab-HyperCVAD as frontline therapy. In this MCL cohort, treated at our institution, the median age was 59 y (range 35-75), all were stage IV, median Ki-67 was 30 % (range 5-80%), MIPI was low risk (27%), intermediate risk (30%), high risk (42%), and there were 4 blastoid variants (2 with del 17p by FISH or cytogenetics). Genomic DNA and total RNA were extracted and captured using custom bait-sets targeting all exons of 405 cancer-related genes by DNA-Seq, and 265 frequently rearranged genes by RNA-Seq (FoundationOne Heme). Captured libraries were sequenced to high depth in a CLIA-certified, CAP-accredited, NYS-approved clinical laboratory, with an average depth of 400X for DNA and >8M unique pairs for RNA. Results: In total, we identified 125 genomic alterations with an average of 3.8 per sample, including 45 base substitutions/indels, 33 truncations, 1 gene amplification, 6 gene deletions, and 40 rearrangements (Figure 1). IGH/CCND1 t(11,14) translocation was detected in 32/33 samples, and CCND1 over-expression was found in all translocation positive cases by RNA-seq, when available. Consistent with published reports, ATM and TP53 were among the most frequently altered genes, found in 45% and 18% of the samples, respectively. Mutations of TP53 and ATM were correlated with the short overall survival (OS) in our cohort. The median OS was not reached in TP53wt pts compared with 5.3 months in TP53mut pts, and not reached in pts with wild-type TP53 and ATM versus 10.4 months in either TP53mut or ATMmut pts (Fisher's exact test p-value=0.01, Figure 2). Gene alterations of chromatin remodeling pathway were identified in 18 out of 33 samples, including SMARCB1 (4), SMARCA4 (2), ARID1A (3), ARID2 (1), PBRM1 (1), CHD2 (1), WHSC1 (5), MLL2 (2), SETD2 (1), EZH2 (1), and ASXL1 (1). Alterations in SMARCB1 (also known as SNF5 and INI1) and ARID1A, members of the SWI/SNF chromatin-remodeling complex, have not been reported in MCL previously. Other frequently altered genes included NOTCH1/2 (12%), and the cell cycle genes CDKN2A/B (9%). GAs associated with approved agents or clinical trials of targeted therapies were identified in 67% of the samples. The most common genes with potential therapeutic implications were ATM (PARP inhibitors), CDKN2A and CCND1 (CDK4/6 inhibitors) and NOTCH1 (Notch1 inhibitors). Summary: 1. We identified relevant genomic alterations in MCL patients from baseline peripheral blood and/or tissue (with no significant difference in source of materials) in all samples tested. 2. We discovered novel recurrent mutations in chromatin remodeling genes SMARCB1 and ARID1A in MCL, and demonstrated that 55% of tumors carried alterations in epigenetic regulation overall. 3. In our frontline cohort of MCL patients treated with R-HyperCVAD, we identified the prognostic value of DNA damage response genes ATM and TP53 on outcome. These findings highlight the possibilities for improved prognosis and novel therapeutic strategies based on comprehensive genomic analysis of these pathways Figure 1. Frequency of genomic alterations in the 33 MCL samples. Figure 1. Frequency of genomic alterations in the 33 MCL samples. Figure 2. Kaplan–Meier overall survival curves according to ATM and TP53 status. Figure 2. Kaplan–Meier overall survival curves according to ATM and TP53 status. Disclosures Wang: Foundation Medicine, Inc.: Employment, Equity Ownership. Nahas:Foundation Medicine, Inc.: Employment, Equity Ownership. Yelensky:Foundation Medicine, Inc.: Employment, Equity Ownership. Otto:Foundation Medicine, Inc.: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc.: Employment, Equity Ownership. He:Foundation Medicine, Inc.: Employment, Equity Ownership. Ross:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine, Inc.: Employment, Research Funding. Miller:Foundation Medicine, Inc.: Employment, Equity Ownership.

Morphologic features of Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) overlap. No single phenotypic marker or molecular abnormality is pathognomonic. We tested a panel of 8 germinal center (GC) and activated B-cell (ABC) markers for their ability to separate BL and DLBCL. We diagnosed 16 BL and 39 DLBCL cases from 21 patients with AIDS and 34 without AIDS based on traditional morphologic criteria, Ki-67 proliferative index, and c-myc rearrangement (fluorescence in situ hybridization). After immunohistochemically staining tissue microarrays of BL and DLBCL for markers of GC (bcl-6, CD10, cyclin H) and ABC (MUM1, CD138, PAK1, CD44, bcl-2), we scored each case for the percentage of positive cells. Hierarchical clustering yielded 2 major clusters significantly associated with morphologic diagnosis (P.001). For comparison, we plotted the sum of the GC scores and ABC scores for each case as x and y data points. This revealed a high-GC/low-ABC group and a low-GC/high-ABC group that were associated significantly with morphologic diagnosis (P.001). Protein expression of multiple GC and ABC markers can separate BL and DLBCL.

Background: Coexistence of Chronic lymphocytic lymphoma (CLL) to Acute lymphoblastic leukemia is extremely rare with only a few reported cases [1-5]. Chronic lymphocytic leukemia is a neoplasm of small monomorphic round to irregularly shaped lymphocytes of B-cell lineage. Adverse prognostic factors in CLL include flow cytometric expression of ZAP-70 and CD38 which are surrogate markers for the mutational status of IVIg. T-cell acute lymphoblastic leukemia (T-ALL) is a neoplasm of lymphoblasts that are of T-cell lineage and are small to medium-sized cells. Case Report: We present a case of a 62-year-old man, diagnosed with B-Chronic Lymphocytic Leukemia who was treated successfully twice. A year following an allogeneic stem cell transplantation (SCT), the CLL returned for a third time along with a secondary diagnosis of T-cell acute lymphoblastic leukemia. Our review of literature explores the potential pathophysiologic mechanisms of the coexistence of these two diagnoses. Conclusion: Chronic lymphocytic leukemia has been known to evolve into various lymphoid transformations, including diffuse large b-cell lymphoma, and prolymphocytic leukemia, however the coexistence and transformation of CLL to T-cell acute lymphoblastic lymphoma is extremely rare. Potential mechanisms of this phenomemon may include a common genetic predisposition, a malignant transformation of a common progenitor cell, immune deregulation, chronic stimulation of T-cells by the B-CLL cells, adverse effects of chemotherapy exposure, increased T-cell resistance to apoptosis, or to the slight occurrence of pure chance. Numerous hypotheses exist, however the precise relation of the two entities coexisting is unknown due to limited research and only a few known cases.

8557 Background: MIPI score (age, LDH, WBC, ECOG PS) defines 3 distinct risk groups in MCL pts. Though MIPI has been validated in series with dose intensive (DI) strategies and rituximab, a number ...

Plasmacytoma presents as primary or secondary tumours. Primary lesions arise in the bone marrow and other extrmedullary sites in the absence of systemic disease. Secondary lesions are the result of systemic disease, usually myeloma, but rarely are the product of direct extension from bony lesions. Primary plasmacytomas can be single or multiple. Cases with multiple lesions have a poorer prognosis.1–3 A 60-year-old male presented with multiple violaceous lesions on his right forearm and left posterior shoulder. He was otherwise in good health. Punch biopsies of two lesions were taken and submitted for routine processing. Peripheral blood was submitted for flow cytometry. …

Background The implementation of chemoimmunotherapy (R-CHOP) has dramatically improved the outcome of B-cell NHL particularly DLBCL (> 50% OS at 5 years with very few late relapses). Most failures to R-CHOP occur early (80% in the 1st 18 months), are not easily salvageable even with high dose therapy-ASCT and are not reliably predicted with current available prognostic models. There is a growing awareness of the molecular heterogeneity of DLBCL beyond well-established germinal center (GC) and non-GC subtypes. Additional genomic alterations include structural alterations (such as in the “double-hit” lymphoma (DHL) (harboring rearrangements or additional copies of MYC and BCL2 or less commonly BCL6); predominantly deregulated or activated driving pathways (ex NF-κB particularly associated with mutations in genes such as CARD11, CD79B or MYD88 in ABC subtype). The recent use of high-resolution technologies has revealed a much higher complexity of the mutational landscape in NHL. Methods Here, we studied 35 DLBCL primary tumors from very poor outcome DLBCL patients with a median OS of 8.4 months (range .3-44.5 months). Targeted DNA and RNA sequencing using a NGS based genomic profiling assay was performed in a CLIA certified laboratory (Foundation Medicine) and genomic alterations were compared to those previously published for DLBCL: Genomic DNA and total RNA was isolated from 40µm of tissue from archived clinical formalin fixed and paraffin-embedded (FFPE) blocks. Illumina adaptor-ligated sequencing libraries were created and captured by solution hybridization using two custom DNA oligonucleotide baitsets targeting all coding exons of 374 cancer-related genes and 24 genes frequently rearranged for DNA-seq, and 272 genes frequently rearranged for RNA-seq. All captured libraries were sequenced to high depth (Illumina HiSeq), averaging >810X unique coverage for DNA and >20,000,000 total pairs for RNA, to enable accurate detection of genomic alterations. Results We identified 214 genomic alterations, an average of 6.1 per sample, in 71 genes: 87 substitutions/indels, 85 nonsense or frameshifting mutations resulting in truncation of known tumor suppressor genes, 4 gene amplifications, 15 homozygous gene deletions, and 25 translocations. In the 35 samples, 12 harbored immunoglobulin (Ig) translocations with MYC, BCL2 or BCL6 (2 MYC/IgH, 7 BCL2/IgH, and 6 BCL6/IgH or IgL) and RNA-seq allowed detection of 4 non-Ig partner BCL6 fusions, including RHOH-BCL6, ST6GAL1-BCL6, and GAPDH-BCL6. Alterations aggregated in pathways previously implicated in DLBCL pathogenesis, including chromatin modification (18%) and NF-κB signaling (16%). More than 50% of ABC-DLBCL and 27% of GCB-DLBCL carry somatic mutations in multiple genes, regulators of NF-κB signaling. Intriguingly, alterations in TP53 and MLL2 occurred at approximately double the frequency previously reported for DLBCL overall (32% vs. 17% and 47% vs 24%, respectively, Pasqualucci et al, Nature Genetics, 2011), reflecting likely the poor outcome population of our cohort. Conclusions We demonstrate technical feasibility of comprehensive genomic profiling of DLBCL from clinical FFPE specimens, with a low overall failure rate (1/36 samples for DNA, 2/36 for RNA), deep unique coverage and simultaneous detection of multiple rearrangements (BCL2, BCL6, Myc) using a combination of DNA and RNA sequencing. We additionally observe a potentially interesting enrichment of alterations in P53 and MLL2 in aggressive disease, with cohort expansion and more detailed genotype/phenotype correlative analysis ongoing. Disclosures: Wang: Foundation Medicine: Employment. Nahas:Foundation Medicine: Employment. Donahue:Foundation Medicine: Employment. He:Foundation Medicine: Employment. Otto:Foundation Medicine, Inc: Employment. Lipson:Foundation Medincine, Inc: Employment. Yelensky:Foundation Medicine, Inc: Employment. Ross:Foundation Medicine: Employment. Stephens:Foundation Medicine, Inc: Employment. Miller:Foundation Medicine: Employment.

Abstract 3638 Although the vast majority of patients with Hodgkin Lymphoma (HL) do well with standard frontline therapy, about 20% will continue to relapse and have poor clinical outcome, even with high dose therapy and autologous stem cell transplant. Recent progress in the understanding of HL has led to an increasing awareness of the importance of the microenvironment and the cross-talk with cytokines and chemokines (JCO, Steidl et.al. 2011). However, given a low number of HL tumor cells present in lymph node biopsies, it is difficult to develop predictive biomarkers criteria for clinical outcome solely based on the characteristics of Reed Sternberg cells. To identify potential HL biomarkers, a bioinformatics approach was used to derive 151 genes that are potentially related to lymphomagenesis and outcome. These genes were screened against a library of non-tissue (mostly effusions) derived 9 HL cell lines that originated from refractory/relapsing HL patients. Two genes, Fibroblast Growth Factor-2 (FGF2/bFGF) and Syndecan-1 (SDC1/CD138), were found consistently overexpressed across all HL cell lines when compared to normal purified B-cells from PBL. We then tested a panel of lymphoma tissues including Hodgkin and non-Hodgkin subtypes by immunohistochemistry. FGF2 and SDC1 again were found overexpressed only in HL against 148 other lymphoma tissue samples (p Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau.

Abstract 3658 Background: While current front-line treatment options for the management of MCL are still debated, a growing consensus in the lymphoma community suggest that MCL pts show superior outcomes with either consolidative ASCT or dose-intensive treatment approaches over CHOP-like regimens and that cytarabine containing regimens achieve earlier and deeper (hence more durable) responses. On the other hand, such dose-intensive strategies can be difficult to administer to the elderly (a relevant issue with a median age at diagnosis of mid 60's) or in pts with comorbidities. Few studies have looked at the comparative effectiveness of initial therapies in MCL in the community setting. Methods: Utilizing KM and Cox regression analyses, we performed a single-center, retrospective cohort analysis to describe the survival experience of 139 MCL pts (med follow up 50 months) treated in the front-line setting with R-CHOP (n=35), R-HCVAD (n=63) or induction-chemotherapy followed by HDT-ASCT (n=41). The primary endpoints of this retrospective cohort analysis were overall (OS) and progression free survival (PFS). The proportional hazards assumption was met for this analysis. Results: The JTCC MCL outcomes database contains 214 total patient entries (newly dx + relapsed MCL) from 1993–2012 of which 139 pts met inclusion/exclusion criteria with complete outcomes data available. The R-CHOP, R-HCVAD and HDT-ASCT groups were comparable in terms of known prognostic factors including age (median 60), ECOG PS (median 1), MIPI score (median score 4, 30% int risk, 29% high risk) and Ki-67 (median 30% and range 5–95%). The median PFS was superior for pts treated with either R-HCVAD (53 months) or ASCT (63 months) (p== 65 (n=25) treated with either R-HCVAD (med PFS 46 months) or HDT-ASCT (med PFS 54 months). Median OS favored pts treated with R-HCVAD or HDT-ASCT (103 months and 108 months respectively) over R-CHOP (67 months) but did not meet statistical significance (p=.16, LR test). Conclusions: These data represent the largest published single center experience of MCL patients treated in the front-line setting. Our results confirm a recent NCCN report showing benefit of dose-intensive/high dose strategies in MCL over conventional therapy with more than doubling median PFS over R-CHOP. Of notice when compared to recently updated STiL trial (Rummel ASCO 2012, abst #3) our results are c/w with a median PFS of 22 months after R-CHOP but appear superior to med PFS (35 months) seen with bendamustine-rituximab in MCL even in a subset of elderly pts >= age 65. Our results support the use of dose-intensive strategies in a fit geriatric patient population. Finally the excellent PFS seen in that setting represents a promising platform for integrating novel agents in combination and/or maintenance in future strategies to prevent recurrence and continue to improve MLC pts outcome. Disclosures: Mato: Genentech: Speakers Bureau; Seattle Genetics: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Abstract 1579 Background: There is a growing awareness of the biological heterogeneity of MCL, which likely translates into differences in outcomes. Cytokines play an important role in the pathogenesis of lymphoma. Recent reports suggest that cytokine profiles can identify DLBCL (ASH 2010: Abstract 991) and HL pt (ASH 2011: Abstract 429) subsets with inferior outcomes. A distinct cytokine profile for MCL has not yet been defined. We therefore examined serum cytokines levels in MCL pts to gain insight into which may have biological relevance and their association with clinical outcomes. Methods: Serum samples from MCL pts (57% newly diagnosed, 43% relapsed) were prospectively collected and linked to relevant clinical data from our MCL outcomes database. Cytokine levels were determined quantitatively utilizing a commercially available protein array system. We first used Wilcoxan tests to identify relevant cytokines by comparing the distribution of 507 serum cytokines levels in MCL cases (n=97) to serum cytokines levels from normal controls (n=20). For cytokines that showed significant differences, we report the ratio of median values (cases vs. controls). To maintain a type I error rate of.05 we adjusted for multiple comparisons (Hochberg's method). Using Cox regression model and adjusting for multiplicity, we next examined the association between serum cytokines levels and outcome (PFS) in a MCL cohort uniformly treated with R-HyperCVAD (R-HCVAD). Results: 214 pts with MCL were identified of which 97 pts had available serum samples. Clinical characteristics were as follows: med age 62 yr, med MIPI score of 4, med Ki67 25% (range 5–95%) and median follow up of 35 months. Our analysis identified 22 cytokines with statistically significantly distinct levels in MCL pts (vs. normal serum controls) including (p Conclusions: Our results are the first to demonstrate a serum cytokines signature associated with MCL and additionally suggest an association between serum cytokines levels and outcome in MCL patients treated with R-HCVAD. These results may provide new insight into the biology of MCL and add to the known heterogeneity of MCL biology. An elevated pretreatment baseline serum cytokines subset, (mostly related to tumor and inflammatory processes) was found to be associated with an increased likelihood of disease relapse and an inferior outcome in patients with MCL treated with R-HCVAD and may predict pts at higher risk of relapse in that setting. Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Feldman:Merck: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Allos: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

8051 Background: The use of dose-intensive strategies (R-HyCVAD) and/or high dose therapy with autologous stem cell transplant (HDT/ASCT) in the1st-line setting in MCL has shown improvement in PFS ...

8050 Background: Prognostic models in MCL are still debated particularly in dose-intensive treatment approaches (R-HyCVAD or HDT/ASCT) since they include both age (med age dx, mid 60s) and performa...

Abstract 1782 Background: Chemo immunotherapy (R-CHOP) has improved outcomes of both GC (germinal center) and ABC (activated B-cell) subtypes of DLBCL. However outcomes in DLBCL patients treated with R-CHOP with ABC subtype (vs. GC) and/or with poor-risk features (High IPI, high Ki-67) remain inferior. These patients might benefit from more dose-intensive or high-dose therapy approaches. In our practice at The John Theurer Cancer Center, we have employed a risk-adaptive strategy with R-HCVAD to treat patients with DLBCL with aggressive features. Methods: Utilizing Kaplan Meier (KM) survival and Cox regression analyses, we conducted a retrospective cohort study to describe the outcome of patients treated with R-HCVAD in the 1st-line setting with the following high-risk features: high Ki-67 (MIB-1), high IPI, multiple extra-nodal (EN) sites, bulky disease or immunohistochemistry (IHC) staining patterns (GC vs. non GC by Hans’ model). The primary study endpoints were PFS and OS. The proportional hazards assumption was met for this analysis. Results: 45 patients (median age 57, range 34–71 yrs) with newly diagnosed DLBCL treated with R-HCVAD (median 6 cycles, range 1–8) were available for this analysis, representing 1010 total months of follow up at-risk. Baseline characteristics included: stage III-IV (90%), IPI ≥ 3 (52%), median Ki-67 (80%, range 10–100%), median EN sites (2), non-GC subtype (34%), bone marrow (BM) involvement (38%), EBER positive (14%), HIV negative (100%). With 17 months (range 9–64 months) median follow up, median OS and PFS (graph) are not yet reached. 2-yr PFS and OS were 80% (95% CI 61–91%) and 78% (95% CI 61–88%) respectively. In Cox regression analysis, survival outcomes were not adversely affected by: patient age > 60 (HR .8, p=.18), LDH > ULN (HR 2.3, p=.3), non-GC IHC pattern (HR .5, p=.5), BM involvement (HR 1.9, p=.4), Ki-67 ≥ 80% (HR 1.7, p=.6) or EN sites ≥ 2 (HR 4.7, p=.15). Conclusions: This analysis represents the largest reported cohort of DLBCL patients treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor-risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in DLBCL patients treated with dose-intensive regimens. A randomized trial comparing R-HCVAD to R-CHOP in selected high-risk patients is warranted. Disclosures: No relevant conflicts of interest to declare.

8092 Background: TheMIPI was developed to risk stratify MCL pts for OS based on 455 pts for whom 33% received a rituximab-containing regimen, 18% underwent ASCT and none were treated with HCVAD. MI...

Abstract 4305 Post-transplant lymphoproliferative disorder (PTLD) is one of the major complications of organ transplantation. Most PTLDs are associated with Epstein-Barr virus (EBV) infection of B-lineage lymphocytes. Central nervous system (CNS) involvement is rare. Although most PTLDs following solid organ transplants is of recipient origin, PTLDs following bone marrow or stem cell transplant are mostly of donor cell origin. Origin of the tumor cells are of crucial importance in deciding treatment and predicting prognosis. Here we report a case of PTLD of diffuse large B cell Lymphoma of donor tissue origin determined by chimerism analysis. The patient was a 52-year-old woman with myelofibrosis (Myeloproliferative disorder) who received unrelated donor peripheral blood stem cell transplantation. The donor was an ABO compatible, HLA matched unrelated donor. Post transplant immunosuppression therapy was administered. The post transplant history was complicated by multiple viral infections, including BK, CMV and EB virus. Four months after transplantation, the patient developed fever and mental status changes, MRI of brain showed multiple enhancing lesions. Brain biopsy revealed brain tissue with dense infiltration of large atypical lymphoid cells predominantly perivascular in location. Immunohistochemical stains reveal that the large atypical lymphoid cells are of B-cell origin and these cells are 100% positive for Ebstein Barr virus by EBV encoded RNA by in-situ hybridization. The flowcytometry study revealed a monoclonal population of B cells with Kappa light chain restriction. These findings support the diagnosis of post transplant lymphoproliferative disorder (PTLD) of diffuse large B-cell lymphoma type. To determine the origin of tumor cells, chimerism analysis of the host DNA (buccal) and tumor DNA were performed. Short tandem repeat (STR) multiplex PCR assay were performed using the AmpFlSTR Identifiler PCR amplification kit (Applied Biosystems, Foster City, CA). After amplification, samples were analyzed on an ABI 310 DNA Sequencer (Applied Biosystems). The allele distribution was significantly different between the recipient DNA (from buccal swab) compared to tumor DNA indicating donor origin of the tumor (PTLD). The patient was then placed on high dose methotrexate and dexamethasome, however her condition deteriorated dramatically and the patient expired shortly following the diagnosis. It is known that the major pathogenetic defect of PTLD is the insufficient EBV-specific cytotoxic T-cell control of EBV-driven B-cell proliferations. Despite this understanding, determining the right therapy for any given patient with PTLD remains a major clinical issue. It is important to identify patients who will benefit from reduction of immunosuppression, who will benefit from Rituximab. It is also important to develop more effective, less toxic chemotherapies for resistant or aggressive disease. The chimerism analysis performed on our patient to identify tumor cell origin is an unique and reliable method to help directing clinical management of PTLD. Disclosures: No relevant conflicts of interest to declare.

As research laboratories and clinics collaborate to achieve precision medicine, both communities are required to understand mandated electronic health/medical record (EHR/EMR) initiatives that will be fully implemented in all clinics in the United States by 2015. Stakeholders will need to evaluate current record keeping practices and optimize and standardize methodologies to capture nearly all information in digital format. Collaborative efforts from academic and industry sectors are crucial to achieving higher efficacy in patient care while minimizing costs. Currently existing digitized data and information are present in multiple formats and are largely unstructured. In the absence of a universally accepted management system, departments and institutions continue to generate silos of information. As a result, invaluable and newly discovered knowledge is difficult to access. To accelerate biomedical research and reduce healthcare costs, clinical and bioinformatics systems must employ common data elements to create structured annotation forms enabling laboratories and clinics to capture sharable data in real time. Conversion of these datasets to knowable information should be a routine institutionalized process. New scientific knowledge and clinical discoveries can be shared via integrated knowledge environments defined by flexible data models and extensive use of standards, ontologies, vocabularies, and thesauri. In the clinical setting, aggregated knowledge must be displayed in user-friendly formats so that physicians, non-technical laboratory personnel, nurses, data/research coordinators, and end-users can enter data, access information, and understand the output. The effort to connect astronomical numbers of data points, including ‘-omics’-based molecular data, individual genome sequences, experimental data, patient clinical phenotypes, and follow-up data is a monumental task. Roadblocks to this vision of integration and interoperability include ethical, legal, and logistical concerns. Ensuring data security and protection of patient rights while simultaneously facilitating standardization is paramount to maintaining public support. The capabilities of supercomputing need to be applied strategically. A standardized, methodological implementation must be applied to developed artificial intelligence systems with the ability to integrate data and information into clinically relevant knowledge. Ultimately, the integration of bioinformatics and clinical data in a clinical decision support system promises precision medicine and cost effective and personalized patient care.

Background High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment. Methods and materials Bioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses. Results To identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFβ1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients. Conclusion The results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing).