Byrd, John C.

*equal contribution of AB, RLL, BD and JCB Background: Acute myeloid leukemia (AML) is common with increasing age, and older adults with AML rarely achieve long-term remission with chemotherapy. Gene discovery studies in older adults with AML have shown that this malignancy is characterized by a multitude of somatic genomic alterations beginning with initiating somatic events followed by acquisition of collaborative transforming mutations. Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60 years of age. The Beat AML trial was designed to assess the feasibility of using genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days of the initial diagnosis in a multi-center clinical trial setting, and to delineate the role of molecularly informed first-line treatment of AML with mechanism based novel therapies. Methods: Treatment-naïve patients with AML were enrolled in this prospective trial which offered accelerated cytogenetic and comprehensive mutational testing within 7 days followed by treatment assignment using these molecular data. Pt eligibility included age ≥ 60 years with non-APML AML, no known CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled by local cytogenetics analysis and using a central next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained < 7 days. TA was made centrally using a pre-determined algorithm considering somatic cytogenetic and molecular alterations in the dominant clone, available targeted therapeutics for specific AML subsets, and the likelihood of cure with intensive chemotherapy. Results: From November 2016 to January 2019, 487 pts with a suspected diagnosis of AML had enrolled at 14 clinical sites; 395 were eligible for the study (77% of the patients not eligible for the study had an alternative diagnosis). The median age of eligible patients was 72 years (range: 60 to 92) with 38% being≥ 75 years and 16% with treatment-related AML. From the 395 eligible patients, 374 (94.7%) were centrally assigned to the different cytogenetic/genomic groups within 7 days. The most common groups were TP53 mutated (19%) and marker negative (18%) molecular groups. The Beat AML trial is dynamic by design, thereby allowing different arms to open over time; all trial arms are designed to evaluate for substantial clinical efficacy in small, molecularly defined patient subsets. As shown in Figure 1, 224 patients (57%) had a TA and consented to a BEAT AML sub-study. Of the remaining 171 patients, 103 received standard therapy defined as induction therapy (7+3) or hypomethylation agent (25 before TA and 78 after TA), 28 received an alternative investigational agent (5 before TA and 23 after TA), 38 received palliative care, and 2 had an unknown treatment status and are grouped with the palliative care patients in subsequent analyses; 9 patients died before TA (2 who received standard therapy and 7 in the palliative care group). Demographic, clinical, performance and molecular characteristics were not largely different between pts who elected targeted therapy as part of the BEAT AML trial versus those who elected standard therapy. As shown in Figure 2, the overall survival was significantly longer for patients enrolled in a targeted therapy arm as part of the BEAT AML trial compared to those who elected standard therapy. (p<0.0001). The 30-day estimated death rate was 3.7% (95% CI: 1.9-7.2) for patients electing treatment on a BEAT AML sub-study, 20.4% (95% CI: 13.0-31.2) for those receiving standard therapy, 0% for those receiving an investigational therapy, and 72.6% (95% CI: 57.8-85.7) for the palliative care group. Conclusion: Our data support the feasibility of a rapid precision medicine approach in older patients with previously untreated AML. Patients with AML who elected treatment assigned based upon cytogenetic and molecular alterations in the dominant clone using a novel precision medicine approach had significantly improved overall survival versus those who elected standard of care treatment. Disclosures Levine: Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Lilly: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios 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; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Borate:Novartis: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy. Stein: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; Celgene Corporation: 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; Daiichi Sankyo, 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; Novartis: 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:Takeda: Research Funding; Incyte: Research Funding; Kite: Research Funding; Forma: Research Funding; AI Therapeutics: Research Funding; Abbvie: Research Funding; Astellas: Research Funding. Stock:Daiichi: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: 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. Deininger:Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy; Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Blum:Boehringer Ingelheim: Research Funding; Celgene: Research Funding; Astellas,: Research Funding; Xencor: Research Funding; Forma: Research Funding; AmerisourceBergen: Consultancy. Schiller:Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; 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; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding. Olin:Daiichi Sankyo: Research Funding; Astellas: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Revolution Medicine: Consultancy; AstraZeneca: Research Funding; Clovis: Research Funding; Ignyta: Research Funding; MedImmune: Research Funding; Mirati Therapeutics: Research Funding; Novartis: Research Funding; Spectrum: Research Funding. Foran:Agios: Honoraria, Research Funding. Lin:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria. Traer:AbbVie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Notable Labs: Equity Ownership. Odenike:AbbVie: Consultancy, 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; Incyte: Research Funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Gilead Sciences: Research Funding; Janssen Oncology: Research Funding; Oncotherapy: Research Funding; Agios: Research Funding; CTI/Baxalta: Research Funding. Arellano:Gilead: Consultancy. Vergilio:Roche Holding AG: Equity Ownership; Foundation Medicine: Employment. Brennan:Foundation Medicine: Employment. Vietz:Foundation Medicine: Employment. Druker:ALLCRON: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; 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; Bristol-Myers Squibb: Patents & Royalties, Research Funding; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy, Honoraria; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; Patient True Talk: Consultancy; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; 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; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; 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; Blueprint Medicines: Consultancy, Equity Ownership, 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. Byrd:Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.

Background The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore the need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 that has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. While other studies have been designed with the goal of discontinuation of ibrutinib through combinations with venetoclax, no other study has been presented using a response-dependent discontinuation strategy. Study Design and Methods A041702 is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the NCI National Clinical Trials Network (NCTN). CLL patients age 70 years or older who are previously untreated and in need of therapy are eligible. Previous treatment of autoimmune complications with steroids or rituximab is allowed. Patients must have intermediate- or high-risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm3 unless due to marrow involvement, and platelets ≥ 30,000/mm3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness that is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted. Patients are initially preregistered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), and are stratified by Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely. The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed. Conclusions A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue for 3 years beginning January 2019, and we welcome participation from sites throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT03737981 Disclosures Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: 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. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.

Monoclonal B cell lymphocytosis (MBL) has been shown to be the precursor condition that precedes overt diagnosis of chronic lymphocytic leukemia (CLL). Whereas CLL is classified with greater than or equal to 5 × 109/L B lymphocytes in the peripheral blood, MBL is a clonal expansion of B-cells below this threshold. MBL can be further divided into high- or low-count based on whether the B-cell count is above or below 0.5 × 109/L. Approximately 10% of the population over 40 is estimated to have MBL, increasing to >50% over the age of 90. While low-count MBL is unlikely to progress, 1-2% of high-count (HC) MBL individuals progress to CLL requiring therapy per year. It is debatable if all patients with detectable MBL should be classified as an entity requiring monitoring by a hematologist, especially for low-count MBL. In addition, the diagnosis of leukemia is distressing to patients; therefore, it is important to identify HC MBL patients that are more likely to progress to disease requiring treatment and thus should be monitored more closely. As the majority of MBL cases phenotypically resemble CLL, established prognostic markers including recurrent chromosomal aberrations, beta-2 microglobulin levels, and the mutational status of the Immunoglobulin heavy-chain variable region locus (IGHV) have been shown to predict time to treatment (TTT) and overall survival (OS) in a large retrospective study of MBL1. CLL patients can also be divided into three distinct epigenetic subtypes that reflect progressive DNA methylation changes that occurs during B cell development. These 'epitypes' termed low-programmed (LP), intermediate-programmed (IP), and high-programmed (HP) independently predict clinical outcomes irrespective of disease stage and treatment2. LP-CLL patients follow a generally unfavorable clinical course compared to the more indolent HP-CLL patients, while IP CLL patients display an intermediate outcome. Here we sought to determine if epitype forecasts progression to CLL and eventual clinical outcome for individuals with MBL. We analyzed 66 individuals diagnosed with HC MBL at the Mayo Clinic with a median follow-up of 6.3 years. Developmental epitype was determined using our novel Methylation-iPLEX technique that interrogates 34 CpGs and assigns epitype using a random forest model2. Seventy-seven percent of the MBL cases were assigned to one of the three epitypes: 42.4% HP, 19.7% IP, and 15.2% LP. The residual 23% remained unclassified due to ambiguous (low confidence) epigenetic patterns or insufficient purity (Figure 1A). The overall proportion of HP and IP epitypes in MBL were significantly greater than proportions observed in CLL cohorts (P<0.01). Epitypes remained stable over time as 20/21 cases for which we obtained a high-confidence epitype classification at multiple time points remained unchanged. Epitype significantly predicted MBL individuals progressing to treatment (P=0.001) with LP individuals progressing in a median of 5.6 years (P=0.049 and P=0.0002 versus IP and HP, respectively); median was not reached in HP or IP (Figure 1B). Epitype also predicted overall survival (OS) in MBL (P=0.04), with LP individuals having a significantly shorter OS (median of 11 years versus not reached in IP and HP; P=0.056 and P=0.048 versus IP and HP, respectively). In this study we evaluated a cohort of 66 HC MBL cases and determined that classification using developmental DNA methylation epitypes can be employed in HC MBL to aid in risk stratification. HC MBL patients classified as LP are more likely to progress to requiring treatment and have a significantly reduced OS. The epigenetic classification may help clinicians decide how closely and frequently a HC MBL individual needs to be monitored. Figure 1: (A) Breakdown of the epigenetic subtype assigned to 66 HC MBL samples. (B) Kaplan-Meier analysis of time to treatment and (C) overall survival of MBL patients separated by epitype. 1. Parikh, S. A. et al. Outcomes of a large cohort of individuals with clinically ascertained high-count monoclonal B-cell lymphocytosis. Haematologica103, e237-e240 (2018). 2. Giacopelli, B. et al. Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia. Blood blood.2019000490 (2019). doi:10.1182/blood.2019000490 Disclosures Byrd: Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding. Shanafelt:Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Merck: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Glaxo-SmithKline: Research Funding; Abbvie: Research Funding; Cephalon: Research Funding; Celgene: Research Funding. Parikh:Genentech: Honoraria; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AbbVie: Honoraria, Research Funding; Acerta Pharma: Research Funding; Ascentage Pharma: Research Funding. Kay:Agios: Other: DSMB; MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board.

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.

Uproleselan (GMI-1271) is a novel antagonist of E-selectin, an adhesion molecule expressed on endothelial cells. E-selectin is expressed transiently in the normal vasculature during an inflammatory response and constitutively in the bone marrow (BM). Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand (E-sel-L), on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. In preclinical models, blockade of E-selectin with uproleselan disrupts the activation of cell survival pathways and enhanced the efficacy of chemotherapy across multiple AML tumor models. Furthermore, uproleselan protected against chemotherapy-induced mucositis by regulating macrophage trafficking to the site of injury in the gut lining. A previous phase I/II study of uproleselan added to chemotherapy in patients with untreated AML (older adults ≥60 yrs) and relapsed/refractory AML (≥ 18yrs) showed promising remission rates (CR/CRi) and survival outcomes, and reduced rates of mucositis. In the newly diagnosed older patients, high remission rates were achieved overall (CR/CRi 72%) and for the high risk subgroup with sAML (CR/CRi 69%). In this phase 2/3 study, we will test the addition of uproleselan to a standard daunorubicin/cytarabine regimen in older adults with previously untreated AML. The study will enroll patients age ≥ 60 yrs with untreated acute myeloid leukemia. Patients with acute promyelocytic leukemia, activating mutations in FLT3, or evidence of central nervous system involvement are excluded. Subjects are randomized to 7+3 induction (cytarabine + daunorubicin) +/- uproleselan. Subjects achieving a CR/CRi may receive up to 3 cycles of consolidation with intermediate dose cytarabine 2 gm/m2 IV d1-5 +/- uproleselan. The primary phase II objective is to compare the event-free survival (EFS). A sample size of 262 patients was selected for the phase II to detect an improvement in median EFS from 7 months to 11 months (HR= 0.64) with &gt; 95% power, using a log rank test. The phase III primary objective will compare overall survival (OS). For the phase III, a sample size of 335 evaluable patients per arm (670 total inclusive of patients enrolled in phase II) will provide &gt;90% power to detect an improvement in median OS from 12 months to 16 months (HR= 0.75), using a log-rank test. Correlative studies will measure E-selectin ligand on AML blasts and soluble E-selectin and will also measure minimal residual disease after remission induction by multiparameter flow cytometry. A comprehensive geriatric assessment will identify baseline measures associated with EFS and develop a risk model to predict OS among older adults receiving intensive AML therapy. The study is endorsed by SWOG and ECOG-ACRIN and opened to enrollment on 1/16/2019. Figure Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Strickland:Jazz: Consultancy; Sunesis Pharmaceuticals: Research Funding; Pfizer: Consultancy; Kite: Consultancy; Astellas Pharma: Consultancy; AbbVie: Consultancy. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; BeiGene: Research Funding; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Novartis, Agios, Arog: Research Funding. OffLabel Disclosure: Uproleselan in AML

Abstract Introduction: Given the availability of several active treatment (tx) options for CLL, providers frequently make tx recommendations based on their interpretation of objective data from consensus criteria and clinical trials. There are limited data describing patient (pt) experience, values, and insights when encountering multiple tx choices. The CLL Society, a pt-driven, physician-curated nonprofit organization focused on the unmet needs of the CLL community, sought to explore how CLL pts make tx decisions. Methods: A 64 question survey was distributed online and in paper to CLL pts from Oct-Dec 2017. The survey was developed by CLL experts. The research was IRB-approved. Chi square was used for statistical comparison; all other analyses are descriptive in nature. Results: 1147 pts from 48 states completed the survey. Median age was 65 (range 28-86), 46% male, 96% Caucasian. Who Influences Tx: Of the 79% of pts who have seen a CLL expert, defined as a provider focused on CLL at an academic/research center, 95% rated their provider as very/extremely influential. 83% of pts rated their own opinions as influential, and 59% rated the opinion of a general hematologist/oncologist (gen heme/onc), a provider who sees a variety of cancer types, as influential. Only 27% let their provider unilaterally decide on tx. Of these pts, 19% trusted their provider to select the best tx and 5% didn't have enough understanding to be involved in the decision. 64% were influenced by outside sources of information, such as family members, live CLL support groups, or online sources including pt experts and forums. Factors in Deciding Tx: Of the 67% pts surveyed who have been treated, 73% were offered > 1 tx choice by their provider. In deciding on a specific tx, 94% of respondents stated that it was very/extremely important to know there were tx options beyond their current regimen. The most important factors in selecting tx were response rate (91%), overall survival (88%), progression-free survival (86%), long-term side effects (82%), ability to achieve undetectable MRD (80%), cost/insurance coverage (66%), and location of tx (50%) with significant differences between subgroups (Table 1). Tx was impacted by cost or insurance issues for 16% (n=104). Of these 104 pts, cost/insurance issues resulted in tx delay for 34 and change in tx plan for 24 pts. 16 pts reported that an appeal led to coverage and 16 pts received financial assistance. Pts' willingness to accept potentially curable but high-risk tx was heavily influenced by availability of alternate options. For example, 18% of pts would be willing to consider cytotoxic chemotherapy if alternate options were available vs. 72% if no options were available. Similar patterns were seen with CAR-T tx (28% vs. 79%) and bone marrow transplantation (BMT) (15% vs. 66%) with significant differences between subgroups (Table 2). 82% were willing to take a life-long tx for long-term control without potential for cure. Willingness to accept long-term tx was significantly higher in treated vs. untreated pts (84% vs. 77%, p=.006) and men vs. women (84% vs. 78%, p=.008). Clinical Trial Education: Of those treated by a gen heme/onc, 31% received no education on clinical trials. Only 15% reported good understanding of trial opportunities vs. 52% treated by a CLL expert (p<.001). 9% of pts treated by gen heme/onc were offered clinical trial participation vs. 47% treated by a CLL expert (p<0.001). Pts who declined or would have declined participation cited reasons including preference for "proven" tx (38%), distance from trial site (29%), fear (20%), frequent imaging (20%), overall lack of understanding about trials (15%), and lack of information (14%). Summary: Most respondents want to be and are involved in tx decisions. While providers are influential in decision making, CLL pts also rely on outside sources. Gender, age, and tx status influence which factors drive decision making. Pts select tx based on response rate, survival, side effects, and ability to achieve deep response and want a plan in place for sequencing tx. The majority are willing to consider long-term tx without cure. Few want chemotherapy, CAR-T, or BMT unless they have no other options. A significant opportunity for improvement in education on clinical trial opportunities was identified. This description of pt experience, values, and preferences enriches the informed consent process and may lead to more tailored and patient-centered care. Disclosures Kennard: AbbVie, Gilead, Verastem: Consultancy. Furman:TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Sunesis: Consultancy; Verastem: Consultancy; Incyte: Consultancy, Other: DSMB; Genentech: Consultancy; Acerta: Consultancy, Research Funding; Gilead: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Merck: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Roche: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Verastem: Consultancy, Research Funding; BMS: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Roche: Consultancy. Nabhan:Cardinal Health: Employment, Equity Ownership. Kay:Acerta: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees. Siddiqi:Juno Therapeutics: Other: Steering committee. Brander:Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other: DSMB; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding. Hill:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Choi:Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Rigel: Consultancy; Genentech: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau. Mato:AstraZeneca: Consultancy; Prime Oncology: Honoraria; Portola: Research Funding; Johnson & Johnson: Consultancy; Medscape: Honoraria; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Acerta: Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Regeneron: Research Funding.

Abstract Introduction: The most effective initial therapy for older adults with CLL has not yet been established due to the lack of comparison of chemoimmunotherapy (CIT) and targeted therapy with the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib. CIT has been the gold standard since studies showing that addition of CD20 antibody to chemotherapy prolongs survival. Bendamustine plus rituximab (BR) is one standard, more aggressive CIT regimen for patients (pts) age 65 or older. While ibrutinib has been FDA approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT. Additionally, the benefit of the addition of rituximab to ibrutinib in this setting has not been prospectively studied in a phase 3 trial. As part of a randomized phase 3 trial, the Alliance sought to answer these important clinical questions. Pts and Methods: Alliance A041202 is a multicenter NCI National Clinical Trials Network phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to CIT in terms of PFS. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone. At time of progression, pts on Arm 1 could cross over to Arm 2. Eligible pts were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified based upon Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. With 166 pts per arm, the trial was powered to detect an improvement in 2-year PFS from 61% in Arm 1 to 75% in Arms 2 or 3 (HR=0.586) using two one-sided log-rank tests with type I error rate of 2.5% and 90% power. The Alliance Data and Safety Monitoring Board approved the data release after meeting the protocol-defined efficacy threshold at a planned interim analysis with a one-sided critical value of 0.001538. These data were locked July 2, 2018; updated results will be presented at the meeting. Results: Between 12/9/2013 and 5/16/2016, 547 pts were registered and randomized (Arms 1: 183, 2: 182, and 3: 182). Median age was 71 years and 67% of pts were men. High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28%. Local vs centralized FISH was performed for del(11q) and del(17p) with agreement between local and central results in 94% (Kappa=0.80) and 97% (Kappa=0.76) of pts, respectively. 525 (96%) pts were eligible and included in the primary PFS analysis (Arms 1: 176, 2: 178, and 3: 171). With median follow-up of 32 months (mo), median PFS was 41 mo in Arm 1 and has not been reached in Arms 2 or 3 (HR comparing Arm 2 to 1 is 0.40 with one-sided p&lt;0.0001; HR comparing Arm 3 to 1 is 0.41 with one-sided p&lt;0.0001; HR comparing Arm 3 to 2 is 1.01 with one-sided p=0.48). 2-year PFS estimates were 74%, 87% in 2, and 88% in Arms 1, 2, and 3 respectively. At this time, there are no significant differences in overall survival (OS) among arms (p=0.87), median OS has not been reached for any arm, and 2-year OS estimates were 95%, 90%, and 94% in Arms 1, 2, and 3, respectively. Adverse events (AEs) were compared among arms using Fisher's exact tests. Grade 3+ treatment-emergent AEs were seen in 428 of 537 evaluable pts with 61%, 41%, and 38% of pts experiencing Grade 3+ heme AEs (p&lt;0.0001) and 60%, 72%, and 71% of pts experiencing Grade 3+ non-heme AEs (p=0.03) in Arms 1, 2, and 3 respectively. Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) pts (p=0.07). Unexplained or unwitnessed death over the entire observation period was seen in 2 (1.1%), 7 (3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively. Conclusions: This international phase 3 trial demonstrates that ibrutinib produces superior PFS to standard CIT in older pts with CLL and justifies it as a standard of care treatment for pts age 65 and older. The addition of rituximab does not prolong PFS with ibrutinib. While ibrutinib represents a major therapeutic advance, toxicities and also cost justify future efforts to reduce the need for long-term continuous treatment. Support: K23CA178183, R01CA183444, U10CA180821, U10CA180882, U24CA196171, Clinicaltrials.gov identifier: NCT01886872 Figure. Figure. Disclosures Ding: Merck: Research Funding. Bartlett:Astra Zeneca: Research Funding; ImaginAB: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Bristol-Meyers Squibb: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Parikh:Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Coutre:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Research Funding; Beigene: Consultancy; AbbVie: Consultancy, Research Funding. Lozanski:Novartis: Research Funding; BI: Research Funding; Genentech: Research Funding; Stem Line: Research Funding; Coulter: Research Funding; Beckman: Research Funding. Larson:Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Erba:Amgen: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Juno: Research Funding; Janssen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Juno: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee. Owen:Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Teva: Honoraria. Abramson:Bayer: Consultancy; Novartis: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Abstract Introduction: Several prognostic models for overall survival (OS) in chronic lymphocytic leukemia (CLL) have been developed, but none were derived for patients (pts) with relapsed or refractory (R/R) CLL treated in the era of novel agents. We used a comprehensive approach to derive and validate a novel risk model for OS in 2,475 pts with R/R CLL who received therapy in randomized phase 3 trials evaluating ibrutinib (IBR), idelalisib (IDELA), and venetoclax (VEN) vs control arms, or the Mayo Clinic CLL Database (MCCD). Methods: In collaboration with Janssen, Gilead, Pharmacyclics, and Genentech/Roche, the analysis included 2,475 pts from 6 multicenter randomized phase 3 trials or the MCCD. Trials included were: IBR plus bendamustine-rituximab (BR) vs placebo plus BR (HELIOS: NCT01611090), IBR vs ofatumumab (RESONATE: NCT01578707), IDELA plus BR vs placebo plus BR (Study 115: NCT01569295); IDELA plus rituximab vs placebo plus rituximab (Study 116: NCT01539512); IDELA plus ofatumumab vs ofatumumab (Study 119: NCT01659021); VEN plus rituximab vs BR (MURANO: NCT02005471). All pts had R/R CLL and required treatment by iwCLL criteria. The model-building dataset (n=969) included pts from HELIOS and RESONATE, and was randomly assigned to the IBR/chemoimmunotherapy (CIT) training dataset (n=727) and IBR/CIT internal-validation dataset(n=242). Three independent external validation datasets included IDELA/CIT (n=897), VEN/CIT (n=389), and MCCD (n=220). We applied univariate and multivariate analyses (MVA) to 28 candidate clinical/laboratory and genetic prognostic factors to derive the risk model in the training dataset. The primary endpoint was OS. We assessed the need for separate models for targeted agents by interactions with treatment in univariate analyses. We proceeded to develop a single model for all pts with R/R CLL, as only one candidate factor (del(13q), interaction p value <0.1) demonstrated a marginal differential effect. We evaluated cutoffs for dichotomized covariates and for definition of risk groups after the final factors were selected. We fit a Cox regression on the training and internal/external validation datasets using the risk categories as the covariate to test the difference among the groups, and calculated the C-statistic as a measure of discrimination. Results: Of 11 selected factors with a significant univariate effect on OS (p<0.1), 6 were independently prognostic in the MVA of OS (p<0.05): Baseline β2-microglobubulin (B2M), lactate dehydrogenase (LDH), hemoglobin (HGB), IGHV mutational status, number of prior therapies, and time from initiation of last therapy. We excluded number of prior therapies from the model, reasoning that its optimal cutoff might change with advances in CLL therapies. IGHV did not remain significant (p=0.0592) in MVA of 5 remaining prognostic factors. Notably, del(17p) was not independently prognostic for OS. The final risk model consisted of 4 prognostic factors: B2M ≥5 mg/L, LDH elevated, HGB <110 mg/L for women or <120 mg/L for men, and time from initiation of last therapy <24 months. Because hazard ratios for each factor were similar (range, 0.55-0.68) with overlapping confidence intervals, 1 point was assigned to each factor. The resulting score separated pts into low (score 0-1), intermediate (score 2-3), and high risk (score 4) groups. Our risk model was prognostic for OS in the IBR/CIT training dataset (C-statistic 0.74 [95% CI 0.60-0.85]; log-rank p<0.0001) and was validated in the IBR/CIT internal validation (C-statistic 0.79 [95% CI 0.56-0.97]; log-rank p<0.0001), as well as in all 3 external validations: IDELA/CIT dataset (CS=0.71, 95% CI 0.59-0.81; log-rank p<0.001); VEN/CIT dataset (CS=0.76, 95% CI 0.66-0.85; log-rank p=0.01); MCCD (CS=0.61, 95% CI 0.56-0.66; log-rank p<0.001). Conclusions: We present the first validated risk model for OS in R/R CLL in the era of targeted therapies. Our model consists of 4 readily available factors (B2M ≥5 mg/L, LDH elevated, HGB <110 mg/L for women or <120 mg/L for men, and time from initiation of last therapy <24 months), identifies 3 prognostic groups with significantly different OS, and has been validated for pts treated with all FDA approved targeted therapies: IBR, IDELA, and VEN. This identifies a well-defined cohort of pts with R/R disease with an unmet clinical need who are suitable for prospective trials targeting these pts. An exploratory analysis regarding prediction of MRD is ongoing. Figure. Figure. Disclosures Darif: Jannsen: Employment. Londhe:Jannsen: Employment. Xing:Gilead Sciences, Inc.: Employment. Mun:Genentech: Employment, Equity Ownership. Kay:Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Celgene: Research Funding. Furman:Loxo Oncology: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Incyte: Consultancy, Other: DSMB; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Hillmen:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Novartis: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Sharman:Acerta: Consultancy, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding. Seymour:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding. Jones:Celgene: Employment, Equity Ownership. Ferrante:Jannsen: Employment. Dreiling:Gilead: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Stark:Genentech: Employment. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Howes:Janssen: Employment. James:Pharmacyclics: Employment. Bhargava:Gilead: Employment. Zelenetz:Novartis/Sandoz: Consultancy; Abbvie: Research Funding; Celgene: Consultancy; Amgen: Consultancy; Gilead: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech/Roche: Consultancy, Research Funding.

Abstract Introduction Transformation of chronic lymphocytic leukemia (CLL) into Hodgkin lymphoma (HL) is a rare, but recognized complication of CLL. The prognosis of CLL with HL Transformation (HT) appears significantly worse than de novo HL, but most series are small and there are limited published data. These reports have prompted several groups to recommend aggressive therapy with stem cell transplantation (SCT) in first complete remission (CR1). We describe the largest reported series of HT patients (pts) with analyses of the clinicobiologic characteristics, treatment patterns, and clinical outcomes based upon our multi-institutional clinical experience. Methods Pts diagnosed with HT from 01/2000 - 01/2018 were retrospectively identified in 13 tertiary cancer centers. Clinicobiologic characteristics, treatment type, and survival outcomes for each pt were analyzed. Overall survival (OS) was measured from the time of HT diagnosis until time of death. OS estimates were calculated using the Kaplan-Meier method. The log-rank test was used to calculate differences in survival. Results Ninety-four pts with HT were identified. Median age at HT was 67 years (yrs; range, 38-85) and 81% of the pts were male. Median time from CLL diagnosis to HT was 5.5 yrs (range, 0-20.2; 7 pts with simultaneous diagnosis of CLL and HL). At initial CLL diagnosis, 31%, 34%, 21%, 10%, and 4% were Rai Stage 0, 1, 2, 3, and 4, respectively. At CLL diagnosis, 67% (25/37) had an un-mutated IgVH gene, 36% (21/59) had del(13q), 32% (14/44) had trisomy 12, 24% (14/59) had del(11q), and 15% (9/61) had del(17p). Prior to HT diagnosis, pts had a median of 2 (range, 0-12) therapies for CLL. Seventeen (18%) had no prior CLL treatments. Forty-three (46%) and 25 (27%) patients had received purine analogue- and ibrutinib-based therapy prior to HT, respectively. Baseline characteristics at HT are described in Table 1. As initial therapy for HL, the majority of pts (61%, n = 62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine) at full (n = 48) or reduced (n = 14) doses. Of these, CD20 monoclonal antibody was added in 6 and Bruton-tyrosine kinase inhibitor was added in 2. Ten (11%) received a brentuximab-based regimen. Seven (7%) received an RCHOP-based regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Six patients (6%) received no therapy for HT due to frailty. Subsequent therapy included autologous SCT and allogeneic SCT in 7 (7%) and 11 (12%) of patients, respectively. Two (2%) and 5 (5%) pts received their autologous and allogeneic SCT while in CR1, respectively. The median number of treatments for HT per pt was 1 (range, 0-5) with 59 (61%) pts only receiving one line of therapy. After HT diagnosis, pts had a median follow-up of 1.6 yrs (range, 0.0 - 15.1). Two-yr OS after HT diagnosis was 72% (95%CI 62 - 83%). The pts who received any CLL directed therapy (n = 80) prior to HT had a significantly lower estimated 2-yr OS of 69% (95%CI 58 - 82%) compared with pts who did not receive any prior CLL-directed therapy (n = 17; 93%; 95%CI 82-100%; p 0.02; Figure 1). Pts who received purine-analogue-based therapy for their CLL prior to HT had a significantly lower estimated 2-yr OS of 60% (95%CI 46 - 79%) compared with pts who did not receive purine-analogue-based CLL-directed therapy prior to HT (n = 51; 83%; 95%CI 73 - 96%; p 0.009; Figure 2). Although limited by small sample size, the pts who underwent SCT for HT in CR1 had a similar 2-yr OS (n = 7; 67%; 95%CI 38-100%) to pts who did not undergo SCT for HT in CR1 (n = 87; 72%; 95%CI 63 - 84%; p 0.46; Figure 3). Conclusions In this retrospective analysis, we describe the largest reported series of pts with HT from CLL. Two-yr survival in pts with HT was shorter than what is historically expected in patients with de novo HL, but longer than what is expected in CLL pts who transform to diffuse large B-cell lymphoma. Pts with HT who have received prior CLL-directed therapies (specifically purine-analogue-based treatments) are estimated to have a shorter 2-yr OS, likely due to underlying immunosuppression. The majority of pts (61%) only received 1 line of HL therapy and only 20% went on to receive SCT (7% while in CR1), indicating that these patients can have prolonged OS after achieving response to first-line therapy for HT and may not require SCT in CR1. Further study of this rare population is required to determine optimum management. Disclosures Kander: AstraZeneca: Consultancy. Parikh:Gilead: Honoraria; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Shadman:Acerta Pharma: Research Funding; Verastem: Consultancy; Celgene: Research Funding; Gilead Sciences: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Consultancy; Beigene: Research Funding; Genentech: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; Genentech: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mato:Portola: Research Funding; AstraZeneca: Consultancy; Acerta: Research Funding; Prime Oncology: Honoraria; Regeneron: Research Funding; Celgene: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Medscape: Honoraria; TG Therapeutics: Consultancy, Research Funding; Johnson & Johnson: Consultancy; AbbVie: Consultancy, Research Funding. Hill:Amgen: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Danilov:Verastem: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding. Phillips:Abbvie: Research Funding; Bayer: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Brander:Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Smith:BMS: Consultancy; Portola: Honoraria. Davids:Surface Oncology: Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; MEI Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Research Funding; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Celgene: Consultancy; BMS: Research Funding; Surface Oncology: Research Funding; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding.

Abstract Introduction: Aggressive chemo-immunotherapy followed by peripheral blood stem cell autografting (ASCT) in CALGB (Alliance) 59909 achieved a median progression-free survival (PFS) in MCL of 5 years (Damon et al JCO, 2009), but late recurrences occurred. Using the CALGB 59909 treatment backbone, we evaluated tolerability and efficacy of adding post-transplant bortezomib consolidation (BC) or maintenance (BM)in a randomized phase II trial. Interim results of CALGB (Alliance) 50403 were previously presented (ASH 2015) demonstrating 5 yr PFS 70% and 69% for the BM and BC arms respectively. We now report final 8 year follow up results from this trial and compare outcomes to CALGB 59909, which differed from CALGB 50403 only by the absence of post-transplant bortezomib. Methods: The primary endpoint was PFS measured from randomization for each treatment arm. Induction therapy was with 2-3 cycles of augmented R-CHOP (2000 mg/m2 cyclophosphamide) and methotrexate (300 mg/m2) followed by high-dose cytarabine/etoposide/rituximab(R)/filgrastim (EAR) stem cell mobilization and cyclophosphamide/carmustine/etoposide (CBV) ASCT. After 2 doses of post-transplant R, patients were randomized to BC (1.3 mg/ m2 IV days 1, 4, 8, 11 of a 3-week cycle for 4 cycles) or BM (1.6 mg/m2 IV weekly x4 every 8 weeks for 18 months) beginning at approximately day 90. Minimal residual disease (MRD) was analyzed using patient-specific PCR probes for the bcl-1 / IgH junction or the IgH CDR3 region. Results: 151 patients were enrolled from 10/2006 - 6/2010 at 14 sites; 147 who received treatment are included in this analysis. Median age was 59 years (29-69); stage II (2.7%), III (11.6%), IV (85.0%); MIPI low (52.4%), intermediate (30.6%), high (17.0%); blastoid histology (12.9%); bone marrow involvement (81.0%); Ki67 was evaluated in 86 and was >30% in 17.4% of patients. 118 (80%) underwent ASCT and 102 (68%) were randomized. Most withdrawals (45) were for progression (10) or adverse events (AEs) (19) including 4 treatment-related deaths. Fifty-two patients were randomized to BM and 50 to BC. Following randomization, 34 (65%) completed BM and 33 (66%) completed BC. Withdrawal for AEs occurred in 14 (28%) of BC and 7 (13%) of BM patients (p = 0.09), most for cytopenias or peripheral neuropathy. With a median follow-up 7.8 years from randomization (8.3 from registration), the median PFS from randomization for the BM arm was not reached and was 8.9 years (95% CI 7.2 to not reached) for the BC arm. Both arms had median PFS significantly greater than the null hypothesis setting median PFS to 4 years (p < 0.001; 1-sided test of exponential parameter)The 8-year PFS estimates in the BM and BC arms were 77% (95% CI 66-90%) and 58% (95% CI 44-76%), respectively. Among all 147 patients treated on CALGB 50403, 8-year PFS from time of registration was 43.6% (35.6-53.3%). PFS from registration was not significantly extended in CALGB 50403 compared with CALGB 59909 (log rank p=0.24), but using a landmark analysis from time of transplant, PFS was significantly extended in CALGB 50403 (log rank p=0.005)(fig 1). Baseline patient characteristics in the two studies were not significantly different. In CALGB 50403, 8-year PFS from registration by MIPI was 52.0% (95% CI 41.1-66.0%) in MIPI low risk, 37.5% (95% CI 25.3-55.4%) in intermediate risk, and 28.2% (95% CI 13.7-57.9%) in high-risk. Bone marrow MRD results were collected for 42 patients post-induction therapy; 8-year PFS estimates were 80.2% (95% CI 62.2-100%) (n=17) and 43.2% (95% CI 27.3-68.2%) (n=25) for MRD-negative and MRD-positive patients, respectively (p=0.009). Conclusions: Induction chemotherapy followed by ASCT and either BC or BM was efficacious and tolerable, although BC was associated with more withdrawals for toxicity. PFS was not significantly different between BC and BM. The comparison between studies 50403 and 59909 with long-term follow up continues to suggest a PFS benefit from the addition of BC or BM among patients undergoing transplant. This did not translate into a PFS benefit from time of study enrollment possibly due to the higher pre-transplant dropout rate in 50403. MRD-negativity following induction chemo-immunotherapy is highly associated with improved PFS and the role of ASCT in post-induction MRD-negative patients is currently under investigation in a randomized clinical trial. Support: U10CA180821, U10CA180882, U24CA196171; ClinicalTrials.gov Identifier: NCT00310037 Disclosures Kaplan: Bayer Pharmaceuticals: Consultancy. Maurer:Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Bartlett:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blum:Acerta: Consultancy; Astra-Zeneca: Consultancy. LaCasce:Seattle Genetics: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria; Research to Practice: Speakers Bureau; Bristol-Myers Squibb: Other: Data safety and monitoring board. Leonard:AstraZeneca: Consultancy; Juno: Consultancy; BMS: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Biotest: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; MEI Pharma: Consultancy; Celgene: Consultancy; United Therapeutics: Consultancy; Sutro: Consultancy; Genentech/Roche: Consultancy; Pfizer: Consultancy; Bayer: Consultancy. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy.