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Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed/refractory IDH-mutant AML and are approved for use in this setting, while investigations in combination with chemotherapy are underway in de novo AML. The prognostic significance of IDH mutations remains controversial. We hypothesize that refining our understanding of IDH-mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeted agents. The objective of our study was to identify characteristics that affect outcome in de novo IDH-mutated AML across the age spectrum utilizing a large cohort of patients enrolled on several pediatric and adult trials. Methods: The total cohort (N=3588) included patients age <1 month - 88 years. Pediatric and young adult (YA) patients were treated on recent CCG/COG AML trials (CCG2961, COG 03P1, 0531, 1031, N=2231) and YA/adult patients were treated on SWOG S0106 (N=396), ECOG E1900 AML trials (N=398), Beat AML (N=363), or included in the TCGA biology study (N=200; outcomes not evaluated for this group). Patients were analyzed according to three defined age groups: "younger" 0-29 years of age (N=2401), "intermediate" 30-59 years of age (N=819) and "older" 60 years of age and above (N=319). Data regarding clinical characteristics and treatment outcomes were collected and evaluated according to the standard practices of each cooperative or research groups for the respective studies. Mutational profiling was performed by targeted sequencing for patient samples from COG trials, Beat-AML, ECOG, and SWOG; whole-genome or whole-exome sequencing for the TCGA cohort. Prevalence of IDH mutations, co-occurring mutations, and outcomes (5-year event-free survival [EFS]) were analyzed across the defined age groups. Results: The prevalence of IDH mutations among the entire cohort was 8.6% (N=276). Analysis according to mutation type demonstrated that IDH2 mutations comprised 57% (N=158) and IDH1 mutations 43% (N=118). The prevalence of IDH mutations was strongly correlated with increased age (Fig 1A); according to the age-defined cohorts was 4.0% (N=82) in younger, 15.2% (N=126) in intermediate, and 20.3% (N=65) in older patients (p<0.001). The co-occurring mutational profile demonstrated that IDH mutations commonly co-occurred with NPM1,DNMT3A, and FLT3-ITD mutations (Fig 1B). Among IDH-mutant patients, 48% (N=132) harbored dual mutations (IDHmut/NPM1mut); 11.6% (N=32) triple mutations (IDHmut/NPM1mut/DNMT3Amut), the latter particularly prevalent in intermediate-aged adults (N=27/32, 85%). Analysis of the cohort with outcome data (N=2824) demonstrated that IDHmut and IDH-WT patients experienced similar EFS of 39% vs. 40%, respectively (p=0.723). Given the favorable prognostic significance of NPM1, we subsequently analyzed outcomes of this dual mutant group and found that NPM1 mutations retained favorable prognostic impact in the context of IDH mutant patients (Fig 2A). Notably, this effect was age-dependent, as those with IDHmut/NPM1mut had a favorable EFS compared to IDHmut/NPM1-WT for younger (76% vs. 24%, p<0.001) and intermediate patients (43% vs. 15%, p=0.001, Fig 2B) but this favorable effect was lost in older patients (29% vs. 34%, p=0.456, Fig 2C). Among intermediate age patients, outcome was further stratified by DNMT3A status, and IDHmut/NPM1mut/DNMT3Amut patients experienced an inferior EFS of 25% vs. 57% in IDHmut/NPMmut (p=0.003, Fig 2D). Conclusion: Analysis of this large patient cohort provides the most comprehensive description of IDH mutations in AML across the age spectrum. We confirm age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutation in all ages and in further combination with DNMT3A mutation in intermediate-aged adults. We definitively demonstrate that IDH mutation status is not an independent prognostic determinant of outcome in any age group. Co-occurrence of NPM1 and IDH mutations favorably impacts outcome in patients < 60 years of age with AML, particularly in the absence of DNMT3A mutation. Our data support that IDH inhibitors may be of particular interest in older adults and in patients <60 according to co-occurring NPM1 and DNMT3A mutations. Disclosures Othus: Marck: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Radich:Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Tallman:UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding. Atallah:Jazz: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Hoffman La Roche: Research Funding. Levine:Novartis: Consultancy; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Gilead: Honoraria; Lilly: Consultancy, Honoraria; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).

Introduction: Daratumumab (DARA) is a human, CD38-targeting, IgG1κ monoclonal antibody approved as monotherapy in relapsed/refractory multiple myeloma (RRMM) and in combination with standard of care for RRMM and NDMM. The addition of DARA to standard-of-care regimens in phase 3 studies has consistently improved progression-free survival (PFS) and led to deep and durable responses, including higher rates of minimal residual disease (MRD) negativity compared with standard of care. In the primary analysis of the phase 3 MAIA study (median follow-up, 28.0 mo), D-Rd vs Rd significantly improved PFS and MRD-negativity rates in transplant-ineligible NDMM (Facon T, N Engl J Med 2019). With longer follow-up (36.4 mo), D-Rd maintained a PFS benefit and deeper and more durable responses vs Rd alone (Bahlis N, Blood 2019. 134[Suppl 1]:1875). Here, we report updated efficacy and safety findings from MAIA after approximately 4 years of follow-up. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age ≥65 years or comorbidities were randomly assigned (1:1) to receive Rd ± DARA. Stratification factors included International Staging System stage (ISS [I vs II vs III]), region (North America vs other), and age (<75 vs ≥75 years). All patients received 28-day cycles of Rd (R: 25 mg orally once daily on Days 1-21; d: 40 mg orally on Days 1, 8, 15 and 22). In the D-Rd arm, DARA (16 mg/kg intravenously) was given weekly for Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. Patients were treated until disease progression or unacceptable toxicity in both treatment arms. The primary endpoint was PFS. Key secondary endpoints included overall response rate (ORR), MRD-negativity rate (10‒5 sensitivity, clonoSEQ® version 2.0), and safety. PFS on the next line of therapy (PFS2), defined as the time from randomization to progression on the next subsequent line of therapy or death, was also measured. Results: A total of 737 patients were randomized (D-Rd, n = 368; Rd, n = 369). Patient baseline characteristics were well balanced between the two treatment arms. Median (range) age was 73 (45-90) years, with 44% of patients ≥75 years of age. 27%, 43%, and 29% of all patients were ISS stage I, II, and III, respectively. Among 642 patients evaluable for FISH/karyotyping analysis, 86% had standard and 14% had high cytogenetic risk. After a median follow-up of 47.9 months, 176 (48%) and 273 (75%) patients discontinued study treatment in the D-Rd vs Rd groups, respectively, with 85 (23%) and 113 (31%) patients discontinuing treatment due to progressive disease. PFS remained improved for D-Rd vs Rd (median, not reached [NR] vs 34 mo; HR, 0.54; 95% CI, 0.43-0.67; P<0.0001; Figure). The estimated 48-month PFS rate was 60% with D-Rd vs 38% with Rd. The PFS benefit of D-Rd in prespecified subgroups, including patients with high cytogenetic risk, was generally consistent with overall results. Adding DARA to Rd continued to result in deeper responses with higher rates of ≥CR and ≥very good partial response (VGPR; Table). Median duration of response among responders was NR with D-Rd vs 44 months with Rd. Median PFS2 was NR vs 51 months with D-Rd vs Rd, respectively (HR, 0.65; 95% CI, 0.52-0.83; P=0.0005); follow up is ongoing. 107 (29%) patients in the D-Rd group and 132 (36%) in the Rd group have discontinued the study due to death. Grade 3/4 treatment-emergent adverse events (TEAEs; D-Rd/Rd) occurring in ≥10% of patients were neutropenia (53%/37%), pneumonia (18%/11%), anemia (16%/21%), lymphopenia (16%/11%), hypokalemia (12%/10%), leukopenia (11%/6%), and cataract (11%/10%); grade 3/4 infection rates were 40%/29%. The most common serious TEAE was pneumonia (17%/11%). 11% of patients in the D-Rd arm and 22% in the Rd arm discontinued treatment due to an adverse event. The complete updated data set will be presented at the meeting with additional efficacy endpoints, including MRD-negativity rate. Conclusion : After 48 months follow up, the addition of DARA to Rd continues to demonstrate a superior PFS benefit. More patients continued to have deeper and more durable responses with D-Rd vs Rd alone. No new safety concerns were observed with longer follow-up. These results continue to support the use of D-Rd in the first line of treatment for patients with transplant-ineligible NDMM. Disclosures Kumar: Sanofi: Research Funding; Carsgen: Other, Research Funding; Cellectar: Other; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Adaptive Biotechnologies: Consultancy. Facon:Celgene, Janssen, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, BMS, Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Usmani:Abbvie: Consultancy; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Other; GSK: Consultancy, Research Funding; Merck: Consultancy, Research Funding; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding. Plesner:Janssen: Consultancy. Orlowski:Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding. Bahlis:BMS/Celgene and Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Research Funding; Genentech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Goldschmidt:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Incyte: Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Mundipharma GmbH: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Molecular Partners: Research Funding; Merck Sharp and Dohme (MSD): Research Funding. O'Dwyer:Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Weisel:Adaptive: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Karlin:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene: Other: Personal fees; Sanofi: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Preis:Janssen: Other: for factor XI inhibitor. Broyl:Janssen, Celgene, Takeda, Amgen: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Krevvata:Janssen: Current Employment. Wang:Janssen: Current Employment. Van Rampelbergh:Janssen: Current Employment. Ukropec:Janssen: Current Employment, Current equity holder in publicly-traded company. Uhlar:Janssen: Current Employment, Current equity holder in publicly-traded company. Kobos:Janssen: Current Employment, Current equity holder in publicly-traded company. Perrot:Amgen, BMS/Celgene, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding.

The NCCN Guidelines for Colorectal Cancer (CRC) Screening describe various colorectal screening modalities as well as recommended screening schedules for patients at average or increased risk of developing sporadic CRC. They are intended to aid physicians with clinical decision-making regarding CRC screening for patients without defined genetic syndromes. These NCCN Guidelines Insights focus on select recent updates to the NCCN Guidelines, including a section on primary and secondary CRC prevention, and provide context for the panel’s recommendations regarding the age to initiate screening in average risk individuals and follow-up for low-risk adenomas.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.

Abstract Background: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE’s Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient’s disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.

PURPOSE NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile–driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable aberration(s) in fibroblast growth factor receptor ( FGFR) 1-3 were treated with AZD4547, an oral FGFR1-3 inhibitor. METHODS Patients’ tumors were screened by next-generation sequencing for predefined FGFR amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising. RESULTS Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients’ tumors harbored FGFR1 or FGFR2 amplification (n = 20), FGFR2 or FGFR3 single-nucleotide variants (n = 19), or FGFR1 or FGFR3 fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored FGFR1-3 point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring FGFR fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%). CONCLUSION Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary end point. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence.

8547 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor that has synergistic activity with bortezomib (B) and dexamethasone (d). In the Phase 3 BELLINI trial, addition of Ven to Bd significantly improved median progression-free survival (PFS) and response rates, including minimal residual disease (MRD) negativity, but resulted in increased mortality vs placebo (Pbo). Here, we determine whether MRD negativity was associated with longer PFS and OS in relapsed/refractory multiple myeloma (RRMM) patients treated with Ven+Bd in the BELLINI dataset. Methods: In BELLINI (NCT02755597), RRMM patients (pts) sensitive or naïve to proteasome inhibitors with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo plus B (1.3 mg/m2) and d (20 mg). Next-gen sequencing MRD assessments were done on bone marrow aspirates at the time of suspected CR/sCR, and 6- and 12-months post confirmation of CR/sCR. Patients with a missing or indeterminate assessment were considered MRD positive. Evaluation of MRD in biomarker-defined subgroups (cytogenetics and BCL2 expression) was also performed and will be presented. Results: In total, 291 pts were randomized; 194 to Ven, 97 to Pbo. As of 13 Sep 2019, the median follow-up was 29 months. Ven + Bd demonstrated significantly higher MRD negativity rates ( < 10−5), including a higher proportion of pts achieving sustained MRD negativity (Table). In the Ven arm, the median (m)PFS was not reached for MRD negative pts vs 16.2 months for MRD positive pts (HR = 0.23, 95% CI: 0.10-0.54, p < 0.001). While the mOS was not reached in the Ven arm, OS was significantly longer for MRD negative vs MRD positive pts (HR = 0.25, 95% CI: 0.08-0.80, p = 0.0194). Conclusions: The addition of Ven to Bd resulted in deep and durable responses, including higher rates of MRD negativity. MRD negativity in the context of Ven was associated with prolonged survival in patients with RRMM, consistent with the broader MRD body of evidence with other therapies in MM. Clinical trial information: NCT02755597 . [Table: see text]

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2 , pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.