ALBERT

Description: Introduction: Multiple myeloma (MM) is more common in men than women but the mechanism(s) driving this are not understood. In our previous study (Myeloma IX) we found sex disparities in the cytogenetic lesions present in myeloma cells at the time of diagnosis and that female sex was associated with reduced overall survival in the context of treatment with traditional chemotherapy (CVAMP/MP) and thalidomide combinations. Here, we evaluate sex differences in almost 4000 patients recruited to the UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated. Methods: Myeloma XI recruited newly diagnosed patients of all ages, with pathways for transplant eligible (TE) and ineligible (TNE) patients. An induction randomisation compared the triplet combination of cyclophosphamide, lenalidomide and dexamethasone to a similar combination with thalidomide (CRD vs CTD). Eligible patients underwent autologous stem cell transplant (ASCT) and in both pathways a maintenance randomisation compared lenalidomide (+/-vorinostat) until disease progression versus observation. We compared baseline characteristics of males and females using Fisher's Exact test for categorical characteristics and the Wilcoxon-Mann-Whitney test for continuous characteristics with p1 lesion present. Results: Of 3894 patients enrolled in the trial 2268 (58%) were male and 1626 (42%) were female, in keeping with the known sex disparity in MM. There was no difference in the median age, WHO performance status, ethnicity and most laboratory values of the two groups. Females were more likely to have the molecular risk lesions t(14;16) and del(17p) and had proportionately more HiR and UHiR disease, Table 1. Despite these differences, PFS and OS from induction randomisation did not significantly differ (PFS: Males 25 months, [95% CI 24, 26], Females 24 months, [95% CI 22, 25] and OS: Males 67 months, [95% CI 62, 70], Females 70 months, [95% CI 64, 74]). Molecular lesions that have been associated with outcome remained prognostic in both sexes, with a stepwise reduction in PFS and OS with cumulative risk lesions. PFS: Males SR 29 months, HiR 23 months, UHiR 16 months (p 〈 0.0001), Females SR 27 months, HiR 18 months, UHiR 17 months (p = 0.0007); OS: Males SR 77 months, HiR 59 months, UHiR 34 months (p 〈 0.0001), Females SR 82 months, HiR 54 months, UHiR 41 months (p 〈 0.0001). There was, however, no significant difference in PFS or OS when we compared males and females with a given cytogenetic lesion or cytogenetic risk. There was a significant difference in the proportion of patients of either sex who continued through the trial and underwent ASCT in the TE pathway (Males 72%, Females 67%; p = 0.031), but no significant difference in those that entered the maintenance randomisation (TE: Males 56%, Females 50%, p = 0.107; TNE Males 45%, Females 42%, p = 0.249). There was no significant PFS or OS difference by sex when analysed within each treatment pathway (TE, TNE), induction regimen (CTD, CRD) and maintenance approach (lenalidomide maintenance, observation). Conclusions: Females had a higher proportion of the adverse molecular risk lesions del(17p) and t(14;16) and were more likely to have HiR and UHiR disease. In the context of Myeloma XI trial treatment this did not correspond to a difference in PFS or OS, either overall or within the induction or maintenance randomisation treatment options (even though males were more likely to undergo ASCT). This suggests that in women the treatment delivered may have been able to overcome some of the adverse effect of the risk lesions present or that other factors affecting outcome were more important. on behalf of the NCRI Haematological Oncology Clinical Studies Group. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Davies:Janssen, Celgene: Other: Research Grant, Research Funding; Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Honoraria, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Gregory:Abbvie, Janssen: Honoraria; Amgen, Merck: Research Funding; Celgene: Consultancy, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Russell:DSI: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. OffLabel Disclosure: CTD/CRD induction therapy for myeloma, Lenalidomide maintenance 10mg 21/28 days

Description: Background Transplant non-eligible (TNE) myeloma patients are a very heterogeneous group that is not well-defined on the basis of age alone, but rather by the interplay of age, physical function, cognitive function and comorbidity better defined as 'frailty'. The International Myeloma Working Group (IMWG) has published a scoring system for myeloma patient frailty that predicts survival, adverse events and treatment tolerability using age, the Katz Activity of Daily Living (ADL), the Lawton Instrumental Activity of Daily Living (IADL), and the Charlson Comorbidity Index (CCI). It has been proposed to be useful in determining the feasibility of treatment regimens and appropriate dose reductions but has not been validated prospectively. We hypothesize that by defining subgroups of patients based on the IMWG frailty score, and guiding up-front dose adjustments we can personalize therapy to improve treatment tolerability and therefore short-term outcomes, along with quality of life. In addition we plan to compare the use of single agent immunomodulatory (IMiD) based maintenance therapy with an IMiD and proteasome inhibitor maintenance doublet to try and improve long-term outcomes for patients. Study Design and Methods Myeloma XIV (NCT03720041) is a phase III, multi-center, randomized controlled trial to compare standard (reactive) and frailty-adjusted (adaptive) induction therapy delivery with the novel triplet ixazomib, lenalidomide and dexamethasone (IRd), and to compare maintenance lenalidomide (R) to lenalidomide plus ixazomib (IR) in patients with newly diagnosed multiple myeloma not suitable for a stem cell transplant. The trial outline is shown in Figure 1. All participants receive induction treatment with ixazomib, lenalidomide and dexamethasone and are randomized (R1) on a 1:1 basis at trial entry to the use of frailty score-adjusted up-front dose reductions vs. standard up-front dosing followed by toxicity dependent reactive dose modifications during therapy. Following 12 cycles of induction treatment participants alive and progression-free undergo a second randomization (R2) on a 1:1 basis to maintenance treatment with lenalidomide plus placebo versus lenalidomide plus ixazomib. Participants and their treating physicians are blinded to maintenance allocation. The primary objectives of the study are to determine: Early treatment cessation (within 60 days of randomization) for standard versus frailty-adjusted up-front dosingProgression-free survival (PFS, from maintenance randomization) for lenalidomide + placebo (R) versus lenalidomide + ixazomib (IR) The secondary objectives of the study include determining: progression-free survival (PFS) for standard versus frailty-adjusted up-front dosing reductions, overall survival (OS), overall response rate (ORR), treatment compliance and total amount of therapy delivered, toxicity & safety including the incidence of Second Primary Malignancies (SPMs), Quality of Life (QoL), cost-effectiveness of standard versus frailty-adjusted up-front dosing of IRd and cost-effectiveness of IR versus R. Exploratory analyses include the association of molecular subgroups with response, PFS and OS. Seven hundred and forty participants will be enrolled into the trial at R1 to give 80% power to demonstrate a difference in early cessation and ensure that at least 478 participants remain and are randomized at R2 (based on attrition rates in our previous study Myeloma XI). At R2 478 patients will give us 80% power to detect an eight month difference in PFS between R and IR. Disclosures Cairns: Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria. Royle:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Best:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Bowcock:Takeda: Honoraria, Research Funding. Boyd:Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Drayson:Abingdon Health: Consultancy, Equity Ownership. Henderson:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jones:Celgene: Honoraria, Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Consultancy; Celgene, Janssen: Honoraria; Celgene: Research Funding. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Frailty adjusted dosing. Ixazomib and lenalidomide combination as maintenance.

Description: Background: NGS of myeloid mutations is an integral part of AML clinical decision-making. There is currently no information regarding concordance between NGS panels in AML using samples from the same patient across various platforms in different diagnostic laboratories. To study this important question, we analyzed NGS of myeloid mutations in diagnostic samples from The Beat AML Master Trial (BAMT) for newly diagnosed older AML patients, and compared variant calls made between institutional laboratories enrolling the study subject with those made by Foundation Medicine (FM), the central laboratory used for treatment assignment in this precision medicine trial. Methods: We identified newly diagnosed AML patient samples (peripheral blood (PB) and/or bone marrow (BM)) from 2 lead institutions in the BAMT(Ohio State, OSU and Oregon Health and Sciences University, OHSU) that were analyzed by both the institutional and by FM from Nov 15, 2016 to Apr 15, 2019. Samples sent to both laboratories 〉3 days apart were excluded. Samples were analyzed at the institutional laboratories using their respective NGS mutational panels and by FM using the FoundationOne®Heme(FMH) NGS panel which utilizes capture based sequencing. The OSU NGS assay utilizes sequencing on Illumina MiSeq. The OHSU NGS assay employs semiconductor-based sequencing (Ion Torrent PGM platform). The variant allele frequency (VAF) sensitivity for detection for all 3 laboratories range from 1-2%. We evaluated the ability to identify mutations in 8 genes : FLT3, IDH1/ 2, NPM1, TET2, DNMT3A, WT1 and TP53 used in treatment assignment in theBAMT. A detection cutoff of 2% was used to define the presence or absence of a mutation. Overall, agreement was defined as the number of times the local and central laboratories made the same call divided by the total number of patients. Sensitivity was defined as the number of present calls made locally divided by the number of present calls made centrally, and specificity as the number of absent calls made locally divided by the number of absent calls made centrally. The overall kappa statistic, controlling for institution, provided another measure of agreement between local and central calls, where a value of 1 indicates perfect agreement. Results: 194 patient samples were identified using methods above and analyzed locally at the screening institution (125 at OSU, 69 at OHSU) and centrally at FM. Type of tissue analyzed for variants between local site and FM were 59 PB, 129 BM, and 6 with BM/PB mismatch. Overall agreement in presence/absence calls between local and central results for each of the 8 genes was over 95% (Table 1). There was perfect agreement for NPM1. The sensitivity was above 94% for all genes except TP53 (88.6%) and WT1 (63.6%). Failure to detect a mutation locally was primarily due to reporting of all TP53 variants, including variants of unknown significance (VUS) (5) by FM as agreed upon in the study protocol, detection at low levels below local site sensitivity cutoff (1), detection of variants in a portion of gene not covered at the local site(1)and possible artifact (1). For the WT1 gene, discordance in 5 samples included VUS (3) reported by FM ,a variant detected in a portion of the gene not covered at the local site(1).and difference in leukemic tissue analyzed with mutation not detected by the central laboratory on a PB sample, and present at the institutional lab on a BM sample; affecting the overall agreement and specificity but not sensitivity. Specificity was at least 98% for each of the 8 genes. Finally, most discrepancies in reported mutations in FLT3 (n=2), IDH1 (n=1), IDH2 (n=2), DNMT3A (n=4) and TET2 (n=5) were due to reporting of VUS in one laboratory and not by another. Conclusion: Detection of pathogenic myeloid mutations using orthogonal assays showed a high degree of concordance for genes used in therapeutic assignment on the BAMT.The small number of discordant results, in TP53 and WT1, were attributed to the reporting of VUS. This study illustrates the importance of quality control and standardization as NGS continues to be widely utilized in AML for clinical decision making, with a variety of platforms across multiple laboratories. Our next steps involve evaluating the differences in VAFs reported between local and central laboratories when a given mutation is identified, as well as the potential reasons for observed differences and clinical implications of known pathogenic mutations vs putative VUS. Disclosures Borate: Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy. Vergilio:Foundation Medicine: Employment; Roche Holding AG: Equity Ownership. Stein:Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Baer:Astellas: Research Funding; Abbvie: Research Funding; AI Therapeutics: Research Funding; Forma: Research Funding; Incyte: Research Funding; Kite: Research Funding; Takeda: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Agios: Research Funding, Speakers Bureau. Blum:AmerisourceBergen: Consultancy; Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding. Kovacsovics:Pfizer: Research Funding; Jazz: Consultancy; Novartis: Research Funding; Abbvie: Research Funding; Amgen: Consultancy, Research Funding. Foran:Agios: Honoraria, Research Funding. Druker:Pfizer: Research Funding; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Cepheid: Consultancy, Honoraria; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Beat AML LLC: Other: Service on joint steering committee; CureOne: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding. Byrd:Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S. Levine:C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Prelude Therapeutics: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Lilly: Honoraria; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees. Mims:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction : Cell of origin (COO) determination of diffuse large B-cell lymphoma (DLBCL) is important, as it has prognostic and therapeutic relevance. Patients with germinal center (GC) like DLBCL have more favorable outcomes than those with non-GC DLBCL, when treated with standard immunochemotherapy. In monomorphic post-transplant lymphoproliferative disorder (PTLD), DLBCL subtype, the biologic significance of COO is not well established. The aims of this study were to evaluate the impact of the COO on clinical presentation, outcome and response to different treatment regimens. Methods : We conducted a retrospective review of all monomorphic PTLD of the DLBCL subtype diagnosed and treated at Columbia University from 2000-2018. COO classification into GC and non-GC subtype was determined by immunohistochemistry using the Hans algorithm. In situ hybridization for Epstein-Barr encoded small RNAs (EBER) was performed to evaluate for EBV infection of the neoplastic lymphocytes. Outcomes according to therapeutic regimens were assessed using the revised response criteria for malignant lymphoma (2007). Overall survival (OS) and progression free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log rank test. Results : Cell of origin: Biopsy material for COO subtyping was available for 49 monomorphic PTLD-DLBCL diagnosed during the study period. By immunohistochemistry 20/49 cases (40.8%) were GC and 29/49 cases (59.2%) were non-GC. Median age of presentation was 52 years (range 3-72) and 55 years (range 3-75), for the GC and non-GC respectively. Median time from transplant to PTLD onset was 3 years, range 7 months-25 years vs. 6 years, range 2 months-24 years for GC vs non-GC respectively. There was no significant difference in the incidence of EBV positivity, immunosuppressive therapy, organ transplanted, stage, LDH, ECOG and IPI between the 2 groups. Of note, extranodal involvement, specifically of the gastrointestinal tract was extremely common in both subtypes (16/20 [80%] in GC and 25/29 [86%] in non-GC). While acknowledging the heterogeneity of therapies administered, a trend suggesting better prognosis for the GC type was noted, although not statistically significant. The median PFS was 151.0 months for GC vs 17.0 months in non-GC (p= 0.1095), while the median OS was 151.0 months for GC vs 36.7 months for non-GC (p=0.1006) (Figure 1A, 1B). Impact of Treatment: Of the 49 cases, 44 were adults (age≥18). The two most common first line therapies administered were R-EPOCH (25) and R-CHOP (9). Ten patients received 6 other therapies including Rituximab monotherapy (3), CHOP (2), palliative care (2), RCEOP (1), EPOCH (1), and radiation (1). When focusing on patients who received R-CHOP or R-EPOCH as initial therapy, no significant differences in age, stage, LDH, extranodal disease, ECOG, IPI, immunosuppressive therapy and COO was identified between the 2 groups. The complete response (CR) rate for R-CHOP was 6/9 (66.6%) vs. 21/25 (84%) for R-EPOCH (p= 0.2701). Primary refractory disease was present in a third of the patients receiving R-CHOP vs. (4/25) 16% of the patients treated with R-EPOCH (p=0.2701). Treatment related mortality was low in both groups (1/9 (0.1%) vs 1/25 (0.04%) patients died during first line therapy with RCHOP vs REPOCH respectively). No difference was seen in terms of PFS and OS in the 2 groups. Median PFS and OS for RCHOP was 80.0 and 83.9 months respectively, the medians for R EPOCH were not reached (log-rank test p= 0.5430, 0.2855 for PFS and OS, respectively) (Figure 1C-1D). When the OS and PFS curves for RCHOP and REPOCH were analyzed based on COO, again no difference was noted. Conclusions : Non-GC subtype is more common than GC in monomorphic PTLD DLBCL. Clinical characteristics, EBV infection and time of onset post transplant is not different in the 2 subtypes. There is a trend suggesting better PFS and OS of PTLD DLBCL GC subtype, although not statistically significant, mirroring the outcome of GC vs non-GC COO in DLBCL of immunocompetent patients. With regard to therapy, R-EPOCH did not improve OS or PFS when compared to R-CHOP, but did not result in increased toxicity or treatment related mortality, which in our series was extraordinarily low for both therapies (

Description: Introduction: As an oncoprotein and a transcription factor, C-MYC has been extensively validated as a key driver in many cancers such as Diffuse large B cell lymphoma (DLBCL). C-MYC has been intensely investigated as a therapeutic target in preclinical models. However, no drugs have been successfully developed to target c-Myc, and the c-Myc oncoprotein has been recognized as undruggable. Recent data from our lab and others suggest that the translation of C-MYC and some other oncogenes may be preferentially repressed using inhibitors of the translation apparatus. Translation can be divided into three steps, namely translational initiation, elongation and termination. Translational initiation involves various kinases that stimulate phosphorylation of the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BP) such as 4E-BP1. In its hypo-phosphorylated state 4E-BP1 sequesters eIF4E and acts as a "brake" for translational initiation. mTORC1 has been established as a key activator for hyper-phosphorylation of 4E-BP1. Hyper-phosphorylation of 4E-BP1 allows the release of eIF4E for the assembly of the eukaryotic initiation factor 4F (eIF4F) complex. eIF4F is comprised of 3 subunits, including the mRNA 5ʹ-cap-binding subunit eIF4E, the large scaffolding subunit eIF4G, and the RNA helicase subunit eIF4A. Subsequently, the 40S and 60S ribosomes are assembled on the AUG start codon of mRNA and translational elongation proceeds along the polysomes. Despite the extensive fund of knowledge in translation, there has been limited success in targeting translation as a therapeutic option for cancers. Omacetaxine mepesuccinate (homo-harringtonine) is approved for the treatment of chronic myeloid leukemia (CML), using the mechanism of competing for aminoacyl-tRNA thereby inhibiting translational elongation. No other translation inhibitors have been approved. Insights into novel regulators of translation will be key to successful development of drugs targeting translation for the treatment of cancers. Such drugs may be particularly useful for cancers driven by translationally regulated oncogenes such as C-MYC. Materials and Methods: Gene knockout of molecular targets such as CK1δ was done using CRISPR/Cas9. Assembly of eIF4F was determined by cap-binding assay using m7GTP Sepharose beads. Global and gene-specific translation was determined using (a) surface sensing of translation (SUnSET) assay and (b) polysome profile followed by Western blotting and qPCR. To further investigate the mode of the action and the effect on the translation, we are conducting an unbiased, proteome-wide experiment and RNA-seq studies in 2 cell lines representing DLBCL and MCL. We will determine the binding partners of CK1δ using co-immunoprecipitation followed by LC-MS. Finally, we determined in vitro the pharmacological activity of CK1δ inhibitors using the Cell Titer Glo assay and Annexin V assay; and their in vivo activity is being studied using mouse models of human lymphoma xenografts. Results: Knocking down CK1δ led to marked reduction in the phosphorylation of 4E-BP1 and translational initiation. CK1δ inhibitors phenocopied the effects of CK1δ knockdown on 4E-BP1 or eIF4F, and profoundly inhibited mRNA translation, as demonstrated using the polysome profiling and SUnSET assays. CK1δ inhibitors inhibited the translation of important oncogenes including C-MYC, CCND1, and MDM2 in lymphoma cells. CK1δ inhibitors potently induced cell death in a number of human lymphoma cell lines such as DLBCL and mantle cell lymphoma (MCL). We expect to complete and present the in vivo and omics studies by the time of the ASH meeting in December. Conclusion: Our results suggest that CK1δ is a key regulator of translation and a promising druggable target in lymphoma. CK1δ inhibitors, if successfully developed, will represent a new class of antineoplastic drugs with a completely new mechanism of action. Figure Disclosures Ali: VOR Biopharma: Patents & Royalties. O'Connor:Acetylon Pharma: Other: Travel expenses, Research Funding; Allos Therapeutics: Consultancy; Millenium: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding; Spectrum Pharma: Consultancy, Other: Travel expenses, Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria; Roche: Research Funding.

Description: Hematopoietic stem and progenitor cells (HSPCs) have multi-lineage potential and can be used in transplants as a curative treatment for various hematopoietic diseases. HSPC function and behavior is tightly regulated by various cell types and factors in the bone marrow niche. One level of regulation comes from the sympathetic nervous system that innervates the niche and releases neurotransmitters to stromal cells. However, the direct regulation of HSPCs via cell surface expression of neural receptors has not been functionally explored. Using imaging mass spectrometry, we detected strong and regionally specific gamma-aminobutyric acid (GABA) neurotransmitter signal in the endosteal region of mouse bone marrow. GABBR1 is known to be expressed on human HSPCs (Steidl et al., Blood 2004), however its function in their regulation has not been investigated. Based on published mouse HSPC single cell RNA-seq data (Nestorowa et al., Blood 2016), we found that a subset of HSPCs expressed the GABA type B receptor subunit 1 (Gabbr1). We confirmed by surface receptor expression that a subset of mouse bone marrow HSPCs express Gabbr1 protein. Using the same single cell RNA-seq data as above, our own gene set enrichment analysis (GSEA) revealed positive correlation of Gabbr1 expression with genes involved in immune system processes, such as response to type I interferons. We generated a CRISPR-Cas9 Gabbr1 mutant mouse model on a C57/BL6 background suitable for hematopoietic studies. Analysis of Gabbr1 mutant bone marrow cells revealed a reduction in the absolute number of Lin-Sca1+cKit+ (LSK) HSPCs, but no change in the number of long-term hematopoietic stem cells (LT-HSCs). With further hematopoietic profiling, we discovered reduced numbers of white blood cells in peripheral blood that was primarily due to fewer B220+ cells. We show that Gabbr1 null HSPCs display reduced proliferative capacity, as well as diminished reconstitution ability when transplanted in a competitive setting. An in vitro differentiation assay revealed the impaired ability of Gabbr1 null HSPCs to produce B cell lineages. We tested our predicted association with type I interferon response by administration of poly(I:C) and found reduced HSPC proliferation in Gabbr1 null mice. Our results may translate well to humans, as a rare human SNP within the GABBR1 locus was found that correlates with altered leukocyte counts (Astle et al., Cell 2016). Our results indicate an important role for Gabbr1 in the regulation of HSPC proliferation and differentiation, highlighting Gabbr1 as an emerging factor in the modulation of HSPC function and behavior. Disclosures No relevant conflicts of interest to declare.

Description: Background: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (〉=VGPR 65.3%, PR 24.5%) than CTD (〉=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P

Description: Small molecule tyrosine kinase inhibitors (TKIs) serve increasingly important roles in the treatment of hematologic malignancies and also have shown efficacy in a range of immunological and inflammatory conditions. However, many successful TKI therapies are associated with problematic effects - particularly on platelets - as bleeding complications have been reported for many TKIs, both on and off clinical trials. Bleeding risk is especially apparent for patients treated with ibrutinib and other irreversible inhibitors of Bruton's tyrosine kinase (BTK), several of which now effectively treat multiple B cell malignancies. Intriguingly, other therapeutic TKIs targeting mechanistic partners of BTK are not associated with platelet-related complications. For instance, inhibitors against the BTK-activating kinase Syk - both with selective (i.e., entospletinib) as well as promiscuous (i.e., fostamatinib) target profiles - are not associated with clinically increased bleeding, despite some reported antiplatelet effects. To gain insight into the multifaceted effects of Syk and BTK inhibitors on platelet function, we analyzed the effects of a panel of eight different clinically relevant Syk- and BTK-directed TKIs (i.e., fostamatinib/R406, entospletinib, ibrutinib, acalabrutinib, AVL-292 and others) on essential platelet responses. We first assessed the effects of TKI treatment on Syk and BTK-mediated signaling events downstream of the platelet immunoreceptor tyrosine-based activation motif (ITAM) receptor GPVI. All Syk and BTK TKIs tested inhibited the phosphorylation of phospholipase C (PLCγ2) Y1217, protein kinase Cδ (PKCδ) Y311 and Akt T308, as well as Akt substrate phosphorylation following platelet stimulation with the GPVI receptor agonist, crosslinked collagen-related peptide (CRP-XL). Independent of TKI target profile, Syk and BTK TKIs differentially inhibited the phosphorylation of DAPP1 Y132, phosphoinositide 3-kinase (PI3K) p85α Y458, Akt S473 and PKC substrates. Syk and BTK TKIs also inhibited platelet adhesion to immobilized CRP-XL in a manner matching the effects of each TKI on ITAM-mediated signaling events. However, platelet signaling and adhesion phenotypes did not match the effects of these same TKIs on GPVI-triggered dense granule secretion, which was inhibited by all TKIs tested with the exception of R406. In contrast, all Syk and BTK inhibitors tested inhibited platelet spreading on immobilized fibrinogen. Based on observations above, we hypothesized that TKIs that irreversibly bind to BTK may disrupt critical molecular interactions around BTK within the PI3K signalosome essential to the proper orchestration of platelet activation programs. To test the effects of Syk and BTK inhibitors on the organization of PI3K signaling in activating platelets, platelets were pretreated with TKIs prior to incubation on immobilized fibrinogen and processing for immunofluorescence microscopy. We found that under control conditions, PI3K p85α regulatory subunit localized to phospholipid PI(3,4)P2-rich regions in adherent platelets associated with active PKC signaling. While Syk and PI3K inhibitors abrogated platelet spreading on fibrinogen, PI3K p85α staining remained strong around undeveloped, nascent adhesions in platelets treated with Syk and PI3K inhibitors. In contrast, PI3K p85α staining was diffuse, diminished or absent in platelets adherent to fibrinogen in the presence of all irreversible BTK inhibitors tested. Our results show that clinically effective kinase inhibitors that target Syk-BTK-PI3K signaling systems have varying effects on platelet function that may offer insights to adverse effects of therapeutic TKIs in different contexts. Moreover, our findings suggest that in addition inhibiting protein kinase activities, the discrepant effects of some TKIs may be attributed to, in part, altered protein relations around BTK, PLCγ2 and other components of the PI3K signalosome in activating platelets. Ongoing studies aim to specify protein:protein interactions affected by reversible as well as irreversible TKIs; to examine patient samples for evidence of PI3K mislocalization - especially in cases of BTK inhibitor-associated bleeding; and, to determine if PI3K signalosome disorganization has roles in other physiological, therapeutic and toxic effects of TKIs. Disclosures Shatzel: Aronora, Inc.: Consultancy.

Description: Background Early trials of long-term lenalidomide (len) use reported an increased incidence of second primary malignancy (SPM), particularly AML and MDS. Later, meta-analysis suggested the link to be secondary to len in combination with melphalan. Myeloma XI is a large phase III randomised trial in-which len is used as an induction and maintenance therapy. We have previously reported on early SPM incidence in the context of this trial and shown that haematological SPM (hSPM) incidence was not increased in association with len (Cumulative incidence 0.7% at 3 years). We have also published data showing that maintenance len is associated with improved survival in post-transplant patients. Here we present for the first time, a long-term analysis of SPM incidence in 4358 patients who have received maintenance therapy versus observation in the context of the Myeloma XI trial. Methods Myeloma XI is a phase III, randomised, multi-centre, parallel group design, open-label trial comparing thalidomide, len, carfilzomib and bortezomib combinations and len as maintenance treatment in NDMM patients. The trial includes transplant eligible (TE) and transplant non-eligible (TNE) pathways. TE patients received high dose melphalan supported by autologous stem cell transplantation if they achieve a very good partial response or better. Patients in both pathways were randomised to maintenance with len (+/- vorinostat) or active observation. Since May 2010, 4358 patients have been treated and assigned to induction. Median follow up is now 68 months (IQ range 49-83), with over 1100 patients enrolled for more than 5 years. A total of 1971 patients have entered maintenance with 1137 randomised to len and 834 observation (median 24 cycles (range 1-97)). Results The median time to SPM development from induction is 41.6 months (range 1.4 - 97.1). Cumulative incidence of all SPMs is 4.1% (95% CI 3.5, 4.7), 7.4% (6.6, 8.3) and 10.8% (9.5, 12.1) at three, five and seven years respectively (figure 1). 378 SPMs have been reported in 318 patients, 180 (57%) treated in the TNE pathway (IR 9.9%) and 138 (43%) in the TE pathway (IR 5.5%). The average age at the time of SPM is 78 and 68 for the TNE and TE pathways, respectively. Of the patients who developed an SPM 195 (61%) did so following maintenance randomisation. The incidence was highest in those receiving len based maintenance (n=145, IR 10.8%). In the observation arm 50 patients developed an SPM (IR 5.6%). The median time to SPM development from maintenance randomisation was 43 months in those receiving len and 40 months in the observation only group. One hundred and ten of the patients who developed an SPM following maintenance randomisation were in the TNE pathway with 77 patients receiving len. The overall incidence of SPM development in TNE patients receiving len maintenance is 15.4% and 9.9% for observation. Within the TE arm 85 SPM cases developed following maintenance randomisation with 68 patients receiving len. The overall incidence of SPM development in the TE patients treated with len maintenance is 7.7% and 3.1% for observation. Of the remaining patients 98, (31%) developed an SPM during induction and twenty five (8%) following induction but prior to maintenance. Forty eight patients developed a hSPM (IR 1.1%), MDS (n=20), AML (n=13), BLCBL (n=6), B-ALL (n=4), CML (n=1), mixed phenotype leukaemia (n=1), T-ALL (n=1), Burkitt lymphoma (n=1) and Hodgkin's Lymphoma (n=1). Of these cases, 35 patients were TE pathway treated, with 25 receiving lenlidomide maintenance (IR 2.8%). The median time to hSPM development in the TE patients was 51.8 months. The remaining 13 cases occurred in the TNE treated patients with 7 receiving lenalidomide maintenance (IR 1.4%). The median time to hSPM development in the TNE patients was 42.3 months. Of the remaining cases, 107 patients developed non-melanoma skin cancers (NMSC) (TE n34, IR 1.3% / TNE n73, IR 4.0%) and 181 patients developed solid tumours (TE n78, IR 3.1% / TNE n103, IR 5.6%). Forty one patients developed 〉1 SPM. Outcome analysis is underway and will be presented at the meeting. Conclusions The overall incidence of SPM is highest in TNE patients receiving lenalidomide maintenance but hSPM rates remain low. This suggests that advanced age is a considerable risk factor for the development of second cancers, particularly NMSC. Second haematological cancers were low in all groups, irrespective of maintenance allocation. Disclosures Jones: Celgene: Honoraria, Research Funding. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Pawlyn:Amgen, Celgene, Takeda: Consultancy; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Mottram:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau. Gregory:Amgen, Merck: Research Funding; Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding. Owen:Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses. Boyd:Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Morgan:Celgene Corporation, Janssen: Research Funding; Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses.