ALBERT

Description: Key Points A 20-gene gene expression-based assay accurately and robustly assigns COO subtypes of DLBCL using formalin-fixed paraffin-embedded tissue.

Description: The expression of Cyclin D1 is dysregulated in approximately half of cases of plasma cell myeloma due to translocations, aneusomy, or other abnormalities. Recent studies using quantitative mRNA analysis have suggested that increased Cyclin D1 mRNA expression is associated with a favorable prognosis. Previous attempts to examine the significance of cyclin D1 protein expression by immunohistochemistry have been hampered by the use of antibodies with weak staining and high background. In this study, we employ a newly available, commercial antibody that gives superior staining in B5 fixed tissues. We performed immunohistochemistry for Cyclin D1 on bone marrow core biopsies from a series of 44 newly diagnosed plasma cell myeloma patients who were uniformly treated on a Phase II study of rituxan, melphalan and prednisone. 22 patients (50%) were positive for Cyclin D1, defined as any plasma cells with positive nuclear staining. Cyclin D1 positive and negative cases displayed no significant differences in the initial levels of β2m (3.6±0.5 mg/L vs. 3.5±0.5 mg/L, p=0.860), number of bone marrow plasma cells (63±5.5% vs. 47±6.2%, p=0.063), or proportion of cases classified as SWOG stage 3-4 (2 of 22 (9%) vs. 5 of 22 (23%), p=0.412). The cyclin D1 positive cases displayed a superior overall survival with an estimated 3-year survival of 95% for Cyclin D1 positive cases versus 56% for Cyclin D1 negative cases (p=0.032). The cyclin D1 positive cases also displayed a trend towards better progression-free survival (median progression free survival of 15.7 months for Cyclin D1 positive versus 12.8 months for Cyclin D1 negative, p=0.13). In a Cox proportional hazards regression model, used to compare the effect of Cyclin D1 protein expression on overall survival time while adjusting for stage, the Cyclin D1 positive patients continued to show a strong trend to better overall survival (p=0.062). This study demonstrates that cyclin D1 immunohistochemistry, which could be readily performed in most pathology laboratories, is capable of identifying a subset of plasma cell myeloma with a favorable survival. Additional studies are ongoing to determine if these results can be generalized to other forms of therapy. If confirmed, routine cyclin D1 immunohistochemistry at the time of diagnosis may offer important prognostic information that could identify lower risk patients for whom less intensive therapies might be appropriate.

Description: Cytogenetic aberrations identified by conventional metaphase cytogenetics (MC) have an important diagnostic and prognostic role in evaluating patients with myelodysplastic syndromes (MDS), and results can affect the choice of therapy. Fluorescence in situ hybridization (FISH) can complement MC by providing information derived from both interphase and metaphase nuclei. However, clinically practical FISH strategies are limited to detection of the most common lesions in MDS, including −5/del(5q), −7/del(7q), del(20q), and trisomy 8. The ability to obtain informative results from interphase nuclei and the relative ease of scoring greater numbers of cells are advantages of FISH as compared to MC. Still, the clinical relevance of small numbers of abnormal cells, apart from detection of residual disease, remains unclear. Single nucleotide polymorphism array (SNP-A)-based karyotyping can reveal genetically unbalanced defects with superior resolution compared to MC and FISH, as well as identify segmental uniparental disomy (UPD) that cannot be detected by either method. We sought to determine whether the overall diagnostic yield for detecting common recurring genetic defects associated with MDS could be improved using a strategy incorporating MC, FISH and SNP-A. Using a standardized approach, we focused our investigation on detection of −5/del(5q), −7/del(7q), trisomy 8, and del(20q). We studied 62 patients, including 42 MDS, 5 MDS/MPD, and 15 secondary AML, with standard MC, FISH probes for chromosomes 5, 7, 8, and 20, and SNP-A karyotyping using Affymetrix 250K and/or 6.0 SNP array platform. The detection rate for del(5q) was 35%, 35%, and 37% by MC, FISH, and SNP-A, respectively. No single method detected all of the defects, and detection rates improved when results of all methods were combined. For example, the rate for detection of del(5q) increased incrementally to 39% (MC+FISH), 44% (MC+SNP-A), 42% (FISH+SNP-A), and 44% when all 3 methods were applied. Similar findings were observed for −7/del(7q), trisomy 8, and −20/del(20q): after combining all methods the detection rates improved from 8% to 17%, from 10% to 17%, and from 8% to 10%, respectively, as compared with MC alone. Discrepant results among these methods were related to poor growth (N=2) and low percentage of positive metaphases (small clonal size; N=2). In addition, small somatic deletions (N=6) and UPD (N=2) were not detected by MC or FISH. Larger defects that were detected by SNP-A (e.g., from 5q14.2 to 5q23.1) did not overlap with either loci 5p15.2 (D5S630) or 5q31 (EGR1) used in the FISH probes. We conclude that metaphase cytogenetics, interphase FISH, and SNP-A are complementary techniques that, when applied and interpreted together, can improve the diagnostic yield for identifying genetic lesions in MDS. SNP-A allows for identification of topographically smaller defects and copy-neutral loss of heterozygosity without a requirement for successful cytogenetic analysis. While FISH affords the ability to quantitate the number of affected cells, it is only useful to screen for specific, known defects of a certain size. Whether novel defects as identified by FISH or SNP-A karyotyping will have prognostic impact or affect the results of therapy is the subject of ongoing investigation.

Description: Abstract 1948 Poster Board I-971 Survival after treatment of diffuse large B-cell lymphoma (DLBCL) is influenced by differences in the tumor microenvironment. Gene expression profiling (GEP) studies have shown that the angiogenesis-related signature (stromal-2 signature) is prognostically unfavorable. However, the clinical and biological significance of angiogenesis quantified in tumor tissue sections of DLBCL from patients treated with rituximab plus chemotherapy (R-CT) is not yet fully explored. CD31, the platelet adhesion molecule PECAM1, is one of the genes included in the “stromal-2 signature” reported in the GEP studies. The objective of this study was to determine whether the microvessel density (MVD) and microvessel number (MVN) in DLBCL patients treated with R-CT were associated with the clinicopathological features of the tumors and related to the outcome of the patients. The MVD and MVN were assessed in a series of 160 patients with DLBCL from the Leukemia Lymphoma Molecular Profiling Project consortium (LLMPP) 86M /74F; median age 64 yrs. The GEP was investigated in 116 of these including 50 germinal center B (GCB), 55 activated B-cell (ABC) and 11 unclassifiable cases. An independent series of 129 patients from the Catalan Lymphoma-Study Group (GELCAB) (67M/62F; median age 64 yrs) was used to validate the results. Front-line treatment was R-CT in all cases of both series. Tissue Microarrays (TMA) were constructed from pretreatment biopsy specimens of de novo DLBCL. High grade B cell lymphoma otherwise unclassifiable, primary mediastinal B cell lymphoma, T-cell-rich B cell lymphoma, and tumors associated with immunodeficiency were excluded. All cases were stained in an automated immunostainer with an antibody against CD31 (DAKO). The MVD and MVN were quantified using digitalized images of the tumor using Olympus Cell B Basic Imaging Software. Microvessel areas were defined as vascular areas delineated by CD31+ staining. The MVD was calculated as the sum of all microvessel areas divided by the total area analyzed. The MVN was the sum of all identified individual vessels, divided by the total area analyzed. TMAs were independently scored by two observers and discrepancies were resolved over a double-headed microscope. To determine whether the angiogenic values scored using the TMA were representative of the tumor sample, whole tissue sections and TMA cores from the same tumor were evaluated in 40 cases and compared by a linear regression analysis. MVD and MVN were grouped in quartiles when necessary and considered high or low when above or below the 50th percentile, respectively. Linear correlation analysis between the CD31 (+) MVD results on TMA cores and on the corresponding whole tissue sections in 40 cases showed a good correlation (R2=0.81). In the LLMPP cohort, DLBCL with an ABC profile showed higher MVD than those with GCB profile (p=0.05). In addition, higher MVD was observed in patients with advanced stage (p

Description: Background: We recently clarified the use of consolidative autologous stem cell transplantation (ASCT) as first remission consolidation therapy for high grade diffuse aggressive T and B non-Hodgkin's lymphoma (NHL)in patients with high-intermediate (HI) or High (H) age adjusted IPI disease (Stiff et al, NEJM 369:1681). After receiving CHOP or R-CHOP for 5 cycles responding patients were randomized to either 3 more induction cycles or 1 cycle followed by an ASCT using either a BCNU or TBI based preparative regimen. We found a PFS but not OS advantage for those randomized to transplant and no differential treatment effect for those with T-NHL patients as compared to B-NHL in the initial analysis of this study. In light of Phase II data suggesting a value of early ASCT for T-NHL, a lack of randomized ASCT trials for T-NHL and the inferior prognosis for T-NHL as compared to B cell disease, we further evaluated this sub group, since a post hoc analysis of the entire trial did find a survival advantage for those with H IPI disease. This then provided a unique opportunity to evaluate the role of ASCT consolidation for T-cell NHL in the setting of a prospective randomized trial. Method: Among the 370 eligible B-NHL and T-NHL patients with HI/H IPI disease treated on this trial, 40 had a T-NHL phenotype and were the subject of this analysis. Individual patient files were re-reviewed and those randomized after the first 5 cycles of CHOP were further analyzed for stage, IPI group, histology (centrally reviewed), and response to induction and consolidation and updated survival outcome. Results: Of the 40 T-NHL patients enrolled on study, 28 (70%) were randomized after induction therapy, a similar ratio to the entire trial (68%). Twelve were not randomized; 1 was ineligible for study, and of the eligible 11, 9 were HI IPI and 8 had peripheral T cell (PTCL-NOS). These 11 were not randomized due to patient choice in 2, and all of the remaining 9 pts progressed early: 2 after C1; 3 after C3, 1 after C4, and 3 after C5. For the 28 randomized, their median age was 50 and 19 were males. Of the group, 21/28 had B symptoms at diagnosis, 14 had stage IV disease, and 18 and 10 were in the HI and H IPI groups respectively. Histologies included 11 with PTCL-NOS, 7 angioimmunoblastic and 10 anaplastic large cell NHL. At randomization 13 were to continue CHOP and 15, ASCT. Of the 15 assigned to ASCT, 3 did not undergo transplant (2-refusals, 1- unable to mobilize); 7 received the BCNU-etoposide-cyclophosphamide and 5 the TBI-etoposide-cyclophosphamide preparative regimen. The 5 year estimates of PFS and OS for the randomized ASCT vs CHOP only groups (intent to treat) were 40% vs 38% (p=0.56) and 40% vs 45% (p=0.98) respectively. We found no difference in outcome based on IPI group, histology or stage of disease. Interestingly, only 1/7 patients who received BCV as the ASCT preparative regimen are long term survivors vs 4/5 receiving the TBI-based regimen. Conclusions: We did not observe a PFS/OS advantage for those with high-risk T-NHL in first remission randomized to ASCT following CHOP induction vs CHOP alone in this retrospective analysis. In addition, the 30% early drop out rate before randomization due primarily to early progression strongly suggests that more optimal induction regimens need to be developed for this disease. While the numbers are small the finding that TBI based preparative regimens might be associated with a higher PFS is of interest and deserves further study. Support: NIH/NCI grants CA180888 and CA180819; Bristol-Myers Squibb. Contributions of Dr. Raymond R Tubbs, deceased, are gratefully acknowledged. Figure 1 Figure 1. Disclosures Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.

Description: In 2000, gene expression profiling (GEP) studies discovered two distinct, predominant genetic profiles associated with either a germinal center B-cell (GCB) or activated B-cell (ABC) cell-of-origin (COO) contributing to the morphologically and clinically heterogeneous nature of diffuse large B-cell lymphoma (DLBCL) (Alizadeh et al NEJM 2000). Follow-up GEP and sequencing studies confirmed the validity of the COO subgroup classification. Recently, we established the Lymph2Cx assay, which uses 20 gene probes, Nanostring technology (Seattle, WA), and formalin-fixed paraffin-embedded tissues (FFPET) to classify DLBCL into reproducible COO subgroups (Scott et al Blood 2014). Expression of the anti-apoptotic BCL2 and proliferative MYC oncogenes are also highly associated with prognosis, such that double protein positive cases have a significantly worse outcome (Johnson et al J Clin Oncol 2012). However, in at least one study BCL2/MYC was reported to over-ride the prognostic significance of COO (Hu S et al Blood 2013). We further investigated the relationship between COO, as determined by Lymph2Cx, with BCL2 and MYC protein status. Fifty-six DLBCL FFPET the from Scott et al, Blood 2014 series were constructed on a tissue microarray (TMA) including 20 ABC, 27 GCB, and 9 unclassifiable. For BCL2 staining, we used the standard BCL2 clone (124, Ventana Medical Systems, Tucson, AZ) and rabbit monoclonal antibody (SP66, Spring Biosciences), which reportedly is more sensitive for IHC (Kendrick et al Hum Pathol 2014 in press). The EP121 clone (Epitomics) was used for MYC. All cases were successfully stained with both BCL2 antibodies and MYC on the BenchMark¨ XT instrument. The stained TMAs were independently scored in increments of 10% by two hematopathologists (K.T. and L.M.R) and positivity for BCL2 and MYC were assessed at cut-offs of ³50% and ³40%, respectively, as previously described (Johnson et al J Clin Oncol 2012). All patients received R-CHOP therapy and overall survival (OS) and progression free survival (PFS) were estimated with the Kaplan-Meier method using date of lymphoma diagnosis. Significant differences were determined using the log-rank test and a P-value of less than 0.05. The University of Arizona Institutional Review Board in accordance with the Declaration of Helsinki approved the use of human tissues and clinical data for this study. The ABC-DLBCL displayed worse OS and PFS compared to GCB-DLBCL using the Lymph2Cx assigned COO with PFS reaching significance (P=0.007). These correlations were slightly more pronounced compared to analysis with COO determined from the gold standard (Lenz et al NEJM 2008), which achieved a PFS difference with a P=0.03. BCL2 expression was detected in a higher frequency of ABC cases either alone (70% vs 56%) or concurrently (50% vs 30%) with MYC using SP66, and to a lesser extent with 124. More importantly, BCL2 when co-expressed with high levels of MYC portends a poor clinical outcome (Figure 1). When BCL2+/MYC+ cases were examined according to subtype, ABC-DLBCL displayed a worse OS and PFS, although there were not enough cases to reach statistical significance (Figure 2). The SP66 antibody was superior for BCL2 detection and demonstrating the prognostic significance of BCL2+/MYC+ cases in the total cohort. The Lymph2Cx COO designations also reflected the predominant correlation of BCL2 t(14;18) translocations with GCB-DLBCL (38%, 9/24 cases vs 0% 0/18 ABC cases, P = 0.005) within the cohort displaying the typical overall frequency (19%, 9/47 cases). The Lymph2Cx assay provides a reliable, robust and straightforward assessment of DLBCL COO that overcomes limitations of large scale GEP and is consistent with the well known BCL2 and MYC subtype associations. The COO remains relevant even in the context of BCL2 and MYC status indicating that both of these factors are important for prognosis; however, at this time there are not enough cases for a multivariate comparison. With the advent of targeted therapies and precision medicine, the ability to distinguish DLBCL COO will have strongly impact clinical trials and patient management at time of diagnosis. Figure 1. Overall and progression free survival of DLBCL subtypes as assigned by Lymph2Cx according to BCL2 and MYC protein status. Figure 1. Overall and progression free survival of DLBCL subtypes as assigned by Lymph2Cx according to BCL2 and MYC protein status. Figure 2. Overall and progression free survival of concurrent BCL2 and MYC protein positive cases according to DLBCL subtypes as assigned by the Lymph2Cx. Figure 2. Overall and progression free survival of concurrent BCL2 and MYC protein positive cases according to DLBCL subtypes as assigned by the Lymph2Cx. Disclosures Scott: NIH: Patents & Royalties. Wright:NIH: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Jaffe:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Rosenwald:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Campo:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Chan:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Connors:NIH: Patents & Royalties. Braziel:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Ott:Nanostring: The author is a potential inventor on a patent applicaiton using Nanostring technology for a different assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Delabie:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Cook:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Weisenburger:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Greiner:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Fu:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Staudt:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties. Gascoyne:NIH: Patents & Royalties; Celgene: Consultancy. Rimsza:Nanostring: The author is a potential inventor on a patent application using Nanostring technology for the Lymph2Cx assay, which has been licensed from the NIH by Nanostring Patents & Royalties.

Description: Background: Next generation sequencing (NGS) of bone marrow or peripheral blood is increasingly being used in the upfront evaluation of patients with a new diagnosis of myeloid neoplasm (MN). This testing identifies salient mutations that are relevant in the biology of MN. Information obtained from NGS can inform patients and their family members about potential predisposition to current and future cancer diagnosis. Informing patients of the utility of NGS testing with regard to detection of GL risk as well as its current use in detection of somatic mutations is important. Additional relevant family history data can be combined in the clinical context of patient's personal oncologic history with the presence of a variant allele frequency (VAF) 〉30%-50% to enhance the prediction of GL predisposition. However, there is not a current consensus/guideline for further evaluation for possible GL predisposition for MN patients in the era of NGS results. Methods: At our institution, we identified 401 patients with the diagnosis of MN who were sequenced by NGS from 2012-2017. We performed a retrospective review of this panel of patients to identify specific characteristics that may warrant further GL testing. Among these, we focused our study on MN patients that harbored a TP53 mutation (N=66), although future work will include patients with other mutations including but not limited to genes such as RUNX1, GATA2, and ETV6 which are also known to be associated with GL predisposition to MN. We collected demographic information, specific diagnosis, personal history of cancer and corresponding treatment, family history of cancer in first and second degree relatives as well as cytogenetic abnormalities. The location, variant allele frequency (VAF), mutation type, and significance for each TP53 mutation was annotated. Additional mutations in any of the 36 other disease-relevant genes such as ASXL1, BCOR, JAK2 were also fully annotated. Results: In our cohort of 66 patients, 27 were females and 39 were males. AML/ALL was the most common diagnosis (32/66; 48.5%) followed by 31.8% (21/66) with MDS, 13.6% (9/66) with MPN, and 6% (4/66) with MPN/MDS. Clinically, of the 19 (30%) patients with prior history of cancer, 13 had treatment with chemotherapy and/or radiation. Forty-four (67%) patients had family history of cancer, with 41 including a first degree relative and 9 including a second degree relative. Breast cancer was the most common diagnosis among those with family history of cancer (12/44). We further examined the characteristics of the TP53 mutations in our cohort. We identified that 48/66 (72.7%) cases had a single TP53 mutation of which 43 had a VAF 〉30% and 41 had a variant of known significance. Among the 18/66 (27.3%) cases with two TP53 mutations, 7 had a VAF 〉30% and all 18 had a variant of known significance. Only 1 case had a third TP53 mutation, which was a variant of known significance and had a VAF 〉30%. Additionally, at least one other co-mutation in a relevant gene was seen in 44% patients (29/66). Of these, the most common were DNMT3A (n=9), JAK2 (n=5), TET2 (n=5), with 3 each of BCORL1, IDH2 and NOTCH1. In terms of cytogenetics, samples were available for 60 patients of which only 4 (6.7%) had normal cytogenetics. Of those with abnormal cytogenetics, 49/56 (87.5%) had complex cytogenetics, 38/56 (67.9%) had deletion of chromosome 5q (del (5q)) and 21/56 (37.5%) had deletion of chromosome 17p (del (17p13.1)), all conferring adverse risk according to the 2017 European LeukemiaNet recommendations. Conclusion: Despite the widespread use and availability of NGS, patients may not have clarity on the possible implications of these test results. Our cohort demonstrates that there is a significant number of MN cases that warrant further annotation to determine GL versus somatic contributions. Further identification and follow up of the GL patients will offer clarity on how these genetic risks predict future outcomes. This cohort represents work that is a stepping stone for design and justification of a future prospective study that will propose and validate criteria for GL evaluation in patients with hematological neoplasms. Disclosures Nazha: MEI: Consultancy. Gerds:Apexx Oncology: Consultancy; Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Carraway:Novartis: Speakers Bureau; Balaxa: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; FibroGen: Consultancy; Agios: Consultancy, Speakers Bureau.

Description: Background: Patients with Hodgkin’s Lymphoma with relapse or refractory disease after salvage therapy and transplant face a paucity of active agents. New modalities of treatment are necessary. Vorinostat (SAHA) is an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases. After initial phase I data (Kelley WK, et al 2005) showed prolonged stable disease in patients with Hodgkin’s, a Phase II study of this agent was launched in patients with relapsed or refractory Hodgkin’s lymphoma. Methods: Eligible patients had relapsed or refractory Hodgkin’s lymphoma, bidimensionally measurable disease, and performance status 0-2. Patients may have received up to five prior chemotherapy regimens; previous autologous transplant is allowed. Vorinostat was dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning was performed after every three cycles, as was marrow biopsy for those with marrow involvement at time of entry into study. This was a 2-stage design with a maximum planned accrual of 35 eligible patients. Objective response was the primary endpoint. Results: Of 27 patients accrued to the first stage of this study, 25 are eligible (14 males, 11 females). Median age is 41 (19–71) years. Toxicities attributable to drug of grade 3 or higher include fatigue, anorexia, anemia, and thrombocytopenia. One partial response was observed, for a response probability of 4% (95% CI: 0%, 20%). Although there were not adequate responses to open the second stage of accrual, four patients had stable disease lasting at least one year. Of these four, one opted for radiation at 12 months, another progressed at 14 months, whereas two continue on treatment, one with bulky disease who is stable at 12 months, one with symptomatic lung involvement and bulky disease who remains stable at 16 months. One additional patient remains on treatment with stable disease at 9 months. Conclusions: Although the low response rate led to closure of this trial after the first stage of accrual, we observed that treatment with the oral histone deacetylase inhibitor Vorinostat can lead to protracted stable disease in patients with relapsed/refractory Hodgkin’s Lymphoma. Studies in combination with other molecular agents or chemotherapy may be warranted.

Description: Background: Waldenström Macroglobulinemia (WM) or Lymphoplasmacytic Lymphoma (LPL) is an indolent B-cell neoplasm accounting for only 1-2% of all hematological malignancies. More than 90% of patients with WM carry a point mutation L265P in the MYD88 gene which promotes tumor survival and is shown to be significant for diagnostic and risk stratification. Criteria for diagnosis requires presence of serum monoclonal IgM protein and 〉 10% bone marrow lymphocytes with plasmacytoid differentiation. We aimed to present the patients characteristics and survival outcomes of WM/LPL patients treated at our center, according to their MYD88 gene status. Methods: We reviewed medical records of all patients diagnosed with WM/LPL between May 2002 and May 2018 for whom MYD88 status was known. Baseline demographic characteristics, ECOG PS, pertinent laboratory values including IgM level at diagnosis, initial therapy, mutation status and cytogenetics was obtained. Kaplan-Meier survival estimation curves were used to illustrate the probability of survival over time stratified by MYD88 status and compared by the log rank test. Results: A total of 99 patients diagnosed with WM/LPL were included, 91 Caucasians (92%), 54 (55%) male, median age 67 years (range, 43-89) and with 63 (64%) patients having ECOG PS 0 or 1. IgM level at diagnosis was available for 88 patients, with a median of 2055 mg/dL (range, 10-11,700) and serum free light chain ratio was estimated at a median of 2.13 (range, 0.01- 37331). Other pertinent laboratory data were: median hemoglobin 11.4 g/dL (range, 6.2- 16.4), median serum viscosity 2.4 CP (range, 1.5- 6.7), median serum M protein 1.4 g/L (range, 0- 5.84), median 24 hour urine protein 11mg (range, 4- 1344) and median serum LDH 173 U/L (range, 71-476). The median international prognostic score (ISSWM) for our cohort was 3. A mutant MYD88 was positive in 85 (86%) patients, while 14 (14%) patients had wild- type MYD88. Complex karyotype was present in 24 (25%) patients. Rituximab monotherapy was the initial treatment in 48 (49%) patients. Twenty-two [22%] patients each received bortezomib-based and bendamustine-rituximab regimen as initial therapy and 7 (7%) patients received frontline rituximab- chemotherapy. Median follow-up of the cohort was 2.8 years (0.08-15.5). At last follow-up, 25 (25%) patients had died. Median OS from diagnosis for the entire cohort was 7.9 years (95% CI, 6.6 to N.R.). OS rate at 5 years was 0.73 (95% CI, 0.61 to 0.87). Patients with mutant MYD88 had significantly longer median OS as compared to those with wild-type MYD88 - 16.3 years (95% CI, 6.7 to N.R.) vs 6.6 years (95% CI, 1.9 to N.R.) [P=0.01] (Figure 1). Conclusion: Within the limitations of a retrospective study with a heterogeneously treated cohort, these data add to the body of literature supporting that outcomes of patients wild-type for MYD88 are worse than those with the L265P mutation when treated with rituximab alone, a proteasome inhibitor or conventional rituximab- chemotherapy. Also, despite an expansion on the therapeutic landscape, the treatment of choice in Waldenström Macroglobulinemia is still lead by rituximab monotherapy in newly diagnosed patients. Further studies should investigate the prognostic impact of MYD88 mutation in the context of BTK inhibitors. Disclosures Hill: Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria.

Description: Abstract 543 Background: Non-Hodgkin lymphomas (NHL) that show some but not all of the morphologic, phenotypic or cytogenetic features that define Burkitt lymphoma (BL) have been controversial throughout the history of lymphoma classification systems. In particular, MYC translocations are found in essentially all cases of BL, but are also found in some diffuse large B-cell lymphoma (DLBCL). The 2008 WHO classification introduced a category for “B-cell lymphoma, unclassified, with features intermediate between DLBCL and BL” (BCLU), but the clinical utility of this diagnostic category is limited because the category is known to be heterogeneous, the diagnostic criteria remain vaguely defined, and the most appropriate management of such cases is unclear. A recently available monoclonal antibody has allowed for detection of MYC protein by immunohistochemistry (IHC).The spectrum of clinicopathologic features associated with MYC dysregulation in non-Burkitt, diffuse aggressive NHL is not yet clear. We therefore examined the clinical significance of high grade (i.e., “Burkitt-like”) morphology and MYC protein expression in a series of DLBCL and BCLU. Design: 370 eligible patients were enrolled on SWOG S9704, a phase III randomized study of diffuse aggressive NHL treated by CHOP±R for 5 cycles and randomized to either 3 additional cycles of CHOP±R or autotransplant. Exclusion of T-cell neoplasms, BL, follicular lymphoma, lymphoblastic lymphoma and mantle cell lymphoma by 2008 WHO criteria resulted in 260 cases of diffuse aggressive B-cell NHL. Each case was reviewed for morphologic features including blastoid cytology, intermediate cell size, and/or starry sky background. MYC protein and phenotypic profile (GC vs. non-GC per Hans algorithm) were evaluated by IHC. Where sufficient tissue was available, FISH studies for MYC and/or BCL2 translocations were performed. Results: 31/260 cases (12%) showed high grade morphology, consistent with BCLU. Cases with high grade morphology did not show distinct clinical features at presentation and were phenotypically heterogeneous [13/27 (48%) GC, 14/27 (52%) non-GC]. In multivariate analysis including IPI and use of rituximab, high grade morphology did not correlate with outcome. MYC IHC was positive in 27/198 (14%) cases. MYC positivity was associated with CD10 [10/17 (59%) vs 25/80 (31%), p=0.032], BCL2 [21/26 (81%) vs 42/79 (53%), p=0.013], and MYC translocations by FISH [7/14 (50%) vs 6/54 (11%), p