Abstract: This pilot randomized trial examines a FaceTime‐delivered cognitive behavioral intervention for fatigue in fatigued patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor in comparison with a waitlist control. The results show large improvements in fatigue and quality of life.

Abstract: Ponatinib, the only third‐generation pan‐BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic‐phase chronic myeloid leukemia (CP‐CML) resistant to prior second‐generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP‐CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP‐CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1 IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP‐CML treated with ≥1 2G TKI (PACE, n  = 257) and OPTIC ( n  = 93), 45‐mg starting dose cohort, were analyzed for BCR::ABL1 IS response rates, overall survival (OS), progression‐free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1 IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment‐emergent adverse events and serious treatment‐emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response‐based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Abstract: Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.1% by 12 months) and poor responders (failure to meet these criteria). Predictive models based on gene expression demonstrated the best performance (area under the curve =0.76, standard deviation =0.07). All of the top 20 pathways overexpressed in good responders involved immune regulation, a finding validated in an independent data set. This study emphasizes the importance of pretreatment adaptive immune response in treatment efficacy and suggests biological pathways that can be targeted to improve response.

Abstract: Background: Achieving sustained DMR (variably described as ≥ MR4 or ≥ MR4.5) is an emerging treatment goal for patients with CML. DMR is associated with excellent long-term clinical outcomes and a higher likelihood of successful treatment-free remission (TFR) upon discontinuation of tyrosine kinase inhibitor (TKI) therapy. Biological predictors of patients likely to achieve DMR are unknown. Here, we present an exploratory analysis of gene expression signatures in order to predict DMR to TKI therapy, as well as understand the biological underpinnings that allow a DMR, based on patients treated with imatinib or nilotinib in the ENESTnd study (NCT00471497). Methods: ENESTnd is a phase 3, randomized, open-label study comparing nilotinib 300 mg twice daily (BID), nilotinib 400 mg BID and imatinib 400 mg once daily (QD) in patients with newly-diagnosed CML. To maximize the likelihood of defining predictive and biologically relevant gene signatures, samples from a group of poor responders (BCR-ABL1IS & gt; 10% by 3 months of therapy) and good responders (BCR-ABL1IS & lt; 0.01% by 12 months of therapy) were selected across all treatment arms. Whole blood samples collected prior to study treatment initiation were available from 112 such patients from the total 846 patients enrolled in ENESTnd, and were subjected to RNA sequencing. DMR was assessed using quantitative polymerase chain reaction transcript ratios standardized to the international scale (IS) and was defined as BCR-ABLIS ≤ 0.01% (MR4) or ≤ 0.0032% (MR4.5). For statistical analysis, responders were defined as patients having achieved DMR by 5 years, whereas non-responders were in the trial for ≥ 5 years without achieving DMR. Five years was selected to ensure that patients on both imatinib and nilotinib arms had adequate time to reach MR4.5. The association of clinical variables with responder status (good or poor) was assessed via a multivariate logistic regression model. Results: We correlated clinical variables (eg, Sokal risk score, TKI, age, sex) with responder status for 112 ENESTnd study patients who received 400 mg imatinib QD (n = 47), 300 mg nilotinib BID (n = 33), or 400 mg nilotinib BID (n = 32). Of the 112 patient samples, 70 were included in the analysis using MR4.5 as an endpoint, with 47 patients characterized as responders (imatinib: 16; nilotinib: 31), and 23 as non-responders (imatinib: 13; nilotinib: 10). Of the 112 samples, 42 were excluded from analysis because the patients discontinued the trial before 5 years and did not achieve MR4.5 (imatinib: 18; nilotinib: 24). Younger age ( & lt; 35 years) was associated with good response (p & lt; 0.02) in a multivariate analysis. We developed a predictive model of responder status by applying penalized regression to clinical variables and gene expression (13569 genes) in independent (clinical or gene expression) and combined gene and clinical models. The best performing model used patients with MR4.5 vs poor responders, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.87 (Figure; Table). Including clinical variables did not result in markedly different performance (AUC = 0.85). Significantly, both models outperformed a model that included clinical variables only (AUC = 0.65). Relaxing the definition of good responders to include patients with MR4 yielded similar results (Table). Detailed biomarker/pathway analysis to explore the biological pathways that separate good and poor response are underway. Conclusions: We present a gene expression model that distinguishes patients who achieved a DMR from those with a poor response to treatment at 5 years. The approach for sample selection optimized the chances of finding a biological and clinical signal and may be applicable to all CML patients initiating TKI therapy. This work could yield new therapeutic targets that could potentially turn a patient biologically determined to be a poor responder into a good responder who might even achieve a TFR. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy; Agios: Consultancy. Kantarjian:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. DeAngelo:Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Blueprint: Consultancy, Research Funding; Shire: Consultancy. Branford:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Sadek:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Sondhi:Novartis: Employment, Other: Stock; Sanofi: Other: Stock. Mishra:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals: Employment. Shrestha:Novartis: Employment. Obourn:Novartis: Employment. Druker:Cepheid: Consultancy, Honoraria; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; CureOne: Membership on an entity's Board of Directors or advisory committees; Beat AML LLC: Other: Service on joint steering committee; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Aptose Biosciences: Consultancy, Equity Ownership, 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; 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; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Celgene: Consultancy; 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; 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; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; 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.

Abstract: Background Bruton tyrosine kinase (BTK) inhibitors (ie, ibrutinib, acalabrutinib) are approved for treating patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and can mediate durable responses in some patients; however, relapses are common, primarily due to acquired mutations in BTK enzyme and/or phospholipase C gamma 2 (Albitar F, et al. J Cancer. 2015;6[5]:409-411. Maddocks KJ, et al. JAMA Oncol. 2015;1[1] :80-87. Woyach JA. Clin Adv Hematol Oncol. 2016;14[5]:330-333. Woyach JA, et al. N Engl J Med. 2014;370[24] :2286-2294.). Preclinical studies demonstrated successful generation and robust cytotoxicity of an autologous, non-genetically modified, polyclonal T-cell product (IOV-2001) from BTK-inhibitor-treated patients with CLL (Karyampudi L, et al. HemaSphere. 2019; 3[suppl 1; abstract PF447]), consisting of billions of peripheral blood lymphocytes (PBLs). Compared with pre-ibrutinib and treatment-naïve PBLs, those derived from post-ibrutinib blood samples demonstrated higher-fold expansion from peripheral blood and produced higher levels of IFNγ in response to non-specific T-cell receptor stimulation. Methods IOV-CLL-01 (NCT04155710) is an ongoing, first-in-patient, Phase 1/2, open-label, multi-cohort, dose-finding study designed to evaluate the safety and efficacy of IOV-2001 in patients with CLL/SLL who are progressing or have progressed on ibrutinib or acalabrutinib treatment. PBLs are generated by T-cell expansion from 50 mL of the patient's blood in a 9-day manufacturing process at a centralized GMP facility. The PBL product is then cryopreserved and sent back to the treatment center for infusion into the patient. Treatment consists of a preparative regimen of lymphodepleting chemotherapy (cyclophosphamide IV 500 mg/m 2 and fludarabine IV 30 mg/m 2) for 3 days, followed by 2 days of rest, a single infusion of IOV-2001, and 6 doses of either low-dose (9 MIU SC) or high-dose (600,000 IU/kg IV) interleukin-2 (IL-2; Figure 1). Approximately 1 to 5 clinical sites in North America will treat ~39 to 70 patients across 4 cohorts in 2 phases (Table 1). The primary endpoint for Phase 1 (Cohorts 1a and 1b) is to determine the recommended Phase 2 dose (RP2D) of IOV-2001 followed by IL-2, and for Phase 2 (Cohorts 2 and 3) is to evaluate efficacy of the RP2D of IOV-2001 followed by IL-2, as measured by objective response rate per investigator assessment. Patients ages ≥18 years, diagnosed with CLL/SLL with radiographically measurable disease, Eastern Cooperative Oncology Group performance status of 0-1, and meeting prior therapy criteria according to Table 2 are eligible for inclusion. Four US sites are currently active and enrolling patients. Figure 1 Figure 1. Disclosures Pinilla Ibarz: Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; MEI, Sunesis: Research Funding. Lister: Oncology Analytics: Other: Academic Board. Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding. Graf Finckenstein: Iovance Biotherapeutics, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Jagasia: Iovance Biotherapeutics, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Samakoglu: Iovance Biotherapeutics, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Yadav: Iovance Biotherapeutics, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Li: Iovance Biotherapeutics, Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: The use of 2G TKIs in patients with CP-CML who have failed ≥1 2G TKIs is not associated with durable responses; there is limited clinical evidence to support that switching to alternate 2G TKI therapy improves long-term clinical outcomes for these patients. Patients with resistant and intolerant CP-CML with substantial prior 2G treatment demonstrated deep, lasting responses to PON in the pivotal PACE trial. A post hoc modeling analysis of the data from PACE suggested a relationship between dose and safety events (including arterial occlusive events [AOEs]). The OPTIC trial was designed to prospectively evaluate response-based PON dosing regimens with the aim of optimizing its efficacy and safety in patients with CP-CML; the interim analysis (IA) demonstrated clinically manageable safety and AOE profiles with response-based PON dosing regimens. The combined PACE and OPTIC trials comprise the largest patient population in a post-2G TKI setting. We present the efficacy and safety outcomes of these patients over time. Methods: PACE (NCT01207440) evaluated PON in patients with refractory CML or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). OPTIC (NCT02467270) is a multicenter, randomized Phase 2 trial characterizing the safety and efficacy of PON over a range of 3 starting doses (45, 30, or 15 mg/day); patients with CP-CML receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR-ABL1IS. Data from patients with CP-CML in PACE (n=254) and the 45-mg starting dose cohort (45 mg→15 mg) in OPTIC (n=92) who have been treated with ≥1 2G TKI are presented; OPTIC data are from the IA. Efficacy data includes molecular responses (measured using polymerase chain reaction and performed at the same central lab for both studies) and survival outcomes over time. Safety data, including treatment-emergent AOE rates following adjudication, are also presented. Results: A combined 350 PON-treated patients from the PACE and OPTIC trials who have received ≥1 prior 2G TKI were analyzed; efficacy results are summarized in Table 1. The ≤1% BCR-ABL1IS response rates increased over time and ranged from 42% to 52% in the OPTIC IA 45-mg starting dose cohort and in PACE. Progression-free survival and overall survival were 52% and 73%, respectively, in PACE (up to 5 years) and 81% and 93%, respectively, at the OPTIC IA (up to 2 years) (Table 1). Serious treatment-emergent adverse event (AE) and AOE rates (including exposure-adjusted AOE rates) were lower in OPTIC IA with a response-adjusted dosing regimen compared with PACE (Table 2). Propensity score analyses comparing AOE incidence among all patients in OPTIC vs PACE demonstrate that the relative risk for adjudicated AOEs is 64% lower in OPTIC when compared with PACE after adjusting for baseline differences, duration of exposure, and total PON dose received. Analyses on responses by mutation status also will be presented. Conclusions: In this analysis, comprising the largest patient population of CP-CML patients in a post-2G TKI setting, ponatinib shows high response rates and robust survival outcomes in patients who have failed 2G TKIs. With the response-adjusted dosing regimen in OPTIC (starting at 45 mg and reducing to 15 mg upon response), efficacy outcomes were consistent with that of PACE, while the overall incidences of AOEs and serious treatment emergent-AEs were lower; exposure-adjusted AOEs during the first 2 years were also lower. The ongoing OPTIC study is also evaluating lower starting doses of ponatinib (30 and 15 mg) and primary analysis of this study will provide a refined understanding of the benefit:risk profile of the 3 starting doses of ponatinib in CP-CML patients. Disclosures Kantarjian: Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Jazz: Research Funding. Deininger:Fusion Pharma: Consultancy; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; SPARC: Research Funding; DisperSol: Consultancy; Leukemia & Lymphoma Society: Research Funding; Novartis: Consultancy, Other, Research Funding; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Pfizer: Honoraria, Other, Research Funding; Ariad: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Other, Research Funding. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria. Apperley:Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; BiolineRx: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Arog: Research Funding. Chuah:Pfizer: Other: Travel, Research Funding; Korea Otsuka Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria. DeAngelo:Jazz: Consultancy; Autolos: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Forty-Seven: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy; Glycomimetics: Research Funding; Pfizer: Consultancy; Shire: Consultancy; Incyte Corporation: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Lipton:Takeda: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Nicolini:Sun Pharma Ltd: Consultancy; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Pinilla Ibarz:Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy; TG Therapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau. Rea:BMS: 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; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Shah:Bristol-Myers Squibb: Research Funding. Talpaz:IMAGO: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Srivastava:Takeda: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding.

Abstract: BACKGROUND: CSF3R mutations are rare genetic events that have been associated with clinical response to the kinase inhibitors ruxolitinib and dasatinib according to the location and type of mutation observed. Although it has been reported that CSF3R mutations are exclusively associated with chronic neutrophil leukemia (CNL), the clinical relevance and response to therapy across the breadth of myeloid neoplasms is largely unknown. To address this, we report the first case series of CSF3R mutations across a large cohort of myeloid neoplasms. METHODS: This study was approved by scientific and ethical review boards. Cases were profiled for all exons of CSF3R utilizing a CLIA-certified 54 gene myeloid Truseq panel or a commercial panel covering over 400 genes. All cases were sequenced on an Illumina instrument and had a target read depth of 200X and a variant allele frequency cut-off of 5%. Reads were aligned with Novoalign version 3.04.04 and variants called using Varscan version 2.3.6. Detected CSF3R variants were filtered through an analytic pipeline to include only those that have been previously reported as somatic and resulting in activated signaling. Clinical variables were abstracted from the medical record and analyzed using GraphPad Prism and SPSS. Kaplan-Meier curves were utilized to estimate overall survival. All cases were centrally reviewed by two expert hematopathologists. RESULTS: Between April of 2014 and January of 2019, a total of 6182 patients with myeloid neoplasms were subjected to next generation sequencing (NGS) testing and only 18 (0.29%) harbored somatic activating CSF3R mutations. The CSF3R variants observed included T618I in 12 cases, T640N in 2 cases, T615A in 1 case and truncating mutations in 3 cases. CSF3R mutations were seen at diagnosis in 89% (16) of cases. The median age of CSF3R mutated cases was 77 years old (range 32-87 years), and 72% were male. Most cases were pathologically consistent with CNL (44.4%, 8 cases) but two cases were pathologically consistent with chronic myelomonocytic leukemia, one with myelodysplastic syndrome (MDS), one with myeloproliferative neoplasm unclassifiable (MPN-U), and one with MDS/MPN-U. Five patients were diagnosed with acute myeloid leukemia. Most patients were thrombocytopenic with a median platelet count of 69 x103 cells/dL (range 19-428 x103 cells/dL) and anemic with a median Hgb of 9.5 g/dL (range 7.7-14.1). Splenomegaly was observed in four cases (23.5%) by physical exam. The vast majority had normal cytogenetics (94.1%, 16 cases), and the most commonly co-mutated genes were ASXL1 (11 cases), TET2 (11 cases) and SRSF2 (7 cases).The median overall survival of CSF3R mutated cases was 13.8 months. Seven cases were treated with ruxolitinib, 5 of which harbored T618I mutations. When considering bone marrow myeloblast reduction, improvement in transfusion requirements, cytoreduction, improvement in splenomegaly, or improvement in constitutional symptoms, 100% of cases derived clinical benefit from ruxolitinib. This included two patients with clinically meaningful hematologic improvements as well as improvement in splenomegaly in 2 out of 3 patients with baseline splenomegaly. Further, one patient with serial NGS demonstrated CSF3R mutation clearance after 5 months of ruxolitinib therapy. The median overall survival was improved in ruxolitinib treated cases but did not reach statistical significance (16.5 vs. 10.9 months, p=0.27). CONCLUSIONS: To our knowledge, this represents the largest collection of ruxolitinib treated CSF3R mutant myeloid neoplasms reported. Although enriched in CNL, CSF3R can occur in other myeloid neoplasms to include CMML and their overall prognosis is poor. Our data suggest that ruxolitinib should be considered in patients with membrane proximal CSF3R mutations. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios Pharmaceuticals: Consultancy; Daiichi-Sankyo: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; DSI: Consultancy; Agios: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau; Incyte: Consultancy; JAZZ: Consultancy; pfizer: Consultancy. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau. Kuykendall:Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. OffLabel Disclosure: Ruxolitinib for the treatment of CSF3R mutated myeloid malignancies.