Citations

OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1′). Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1′ after maximal exercise (43 [interquartile range, 25–58] versus 25 [interquartile range, 19–34] beats/min; P <0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1′ had an odds ratio of 3.4 (95% CI, 1.6–7.4) of being symptomatic before diagnosis ( P <0.001). In addition, ΔHRR1′ was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22–48] versus 27 [interquartile range, 20–36] beats/min; P =0.01). After diagnosis, patients with a ΔHRR1′ in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles ( P =0.045). Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.

Introduction: Anti-PD-1 monoclonal antibodies (mAbs) are highly active in relapsed/refractory classical Hodgkin lymphoma (cHL), but most patients (pts) will still relapse. Given this, allogeneic stem cell transplantation (alloHSCT) remains an important option for pts after PD-1 blockade, as it offers the possibility of cure. Prior reports have suggested that alloHSCT after PD-1 mAbs may be associated with severe immune-related complications including acute graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytokine release/febrile non-infectious syndrome (CRS). Prior studies of alloHSCT after PD-1 blockade in cHL have been limited by the small number of pts and short follow-up, preventing an accurate assessment of long-term outcomes and complications, risk factors for early toxicity, and the impact of transplant strategies such as choice of GVHD prophylaxis. We therefore assembled a large retrospective international cohort of cHL pts who underwent alloHSCT after PD-(L)1 blockade to better answer these questions, including an assessment of the impact of post-transplant cyclophosphamide (PTCy) on efficacy and toxicity. Methods: Medical records and databases were reviewed at 26 European and United States transplant centers to identify pts with cHL who underwent an alloHSCT any time after receiving a PD-1 or PD-L1 mAb. Response assessment was performed by local investigators according to Lugano 2014 criteria. Overall survival (OS), progression-free survival (PFS), cumulative incidence (CumInc) of relapse (CIR), non-relapse mortality (NRM), acute (a) and chronic (c) GVHD were estimated, as was the association between baseline variables and these outcomes. Results: Between 2014 and 2019, 150 pts were identified who underwent alloHSCT after a median of 10 (range, 1-74) doses of nivolumab (n=118), pembrolizumab (n=31), or avelumab (n=1). The median age was 31 (range 17-68) and pts had received a median of 4 (range, 2-11) lines of therapy prior to PD-(L)1 blockade. 138 pts (92%) had failed BV and 111 (74%) autologous HSCT. The best overall response to PD-(L)1 mAbs was CR for 62 pts (41%), PR for 55 (37%), SD for 17 (11%), PD for 15 (10%) and unknown for 1 (1%). Median time from last dose of PD-(L)1 mAb to alloHSCT was 80 days (range, 17-756) with 70 pts (47%) receiving intervening systemic therapy. At alloHSCT, 90 pts were in CR (60%), 45 in PR (30%), 5 in SD (3%), and 10 in PD (7%). Donors were haploidentical (n=71, 47%), matched sibling (n=29, 19%), matched unrelated (n=39, 26%), mismatched unrelated (n=7, 5%), cord blood (n=2, 1%), or unknown (n=2, 1%). Stem cell source was bone marrow (n=38, 25%), peripheral blood (n=110, 73%), or cord blood (n=2, 1%). GVHD prophylaxis included PTCy in 88 pts (59%) (69/71 (97%) with haploidentical donors; 19/79 (24%) with other donors). With a median post-alloHSCT follow-up for survivors of 23.8 months (range, 1-67), the 2y OS and PFS were 79% (95CI 71-86%) and 65% (95CI 55-73%), respectively, while the 2y CumIncs of relapse and NRM were 21% (95CI 13-29%) and 14%, (95CI, 8-22%), respectively (Fig. 1A-B). 27 pts have died, 3 due to disease and 24 to NRM, including aGVHD (n=7) and VOD (n=2). Veno-occlusive disease (VOD) occurred in 5 pts (day 100 CumInc 4%) and 29 pts (19%) developed CRS (grade 1 n=16; grade 2 n=7; grade 3 n=4; grade 4 n=2). The 6-month CumIncs of grade 2-4, grade 3-4 and grade 4 aGVHD were 39%, 16% and 8%, respectively. Hyperacute GVHD (onset ≤ 14 days after alloHSCT) occurred in 4% of pts and was fatal in 2 pts. The 2y CumInc of cGVHD was 45%. Neither receipt of &gt; 10 doses (median) of anti-PD-(L)1 mAb nor undergoing alloHSCT ≤80 days (median) after last dose of PD-(L)1 mAb were associated with PFS or OS. However, pts with a shorter time to transplant (≤80 days) appeared to have a higher risk of severe (grade 3-4) aGVHD (6m CumInc 24% vs 9%, p=0.006). Recipients of PTCy in this cohort had lower 2y CumIncs of cGVHD (34% vs 58%, p=0.01) and relapse (12% vs 31%, p=0.02), superior 2y PFS (76% vs 54%, p=0.015), and similar rates of severe aGVHD (15% vs 18%, p=0.5), 2y NRM (12% vs 16%, p=0.5), and 2y OS (82% vs 78%, p=0.6). Conclusions: With extended follow-up of a large international cohort, our results argue that alloSCT performed after PD-(L)1 mAbs is a feasible strategy associated with an excellent PFS and a very low CIR for this disease. The use of PT-Cy appears to be associated with improved outcomes and may at present represent the optimal transplant strategy in this pt population. Figure Disclosures Corradini: kite: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Ho:Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Omeros Corporation: Membership on an entity's Board of Directors or advisory committees. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria. Hamadani:Pharmacyclics: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Otsuka: Research Funding; Janssen: Consultancy; Medimmune: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy. Ansell:LAM Therapeutics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Feldman:Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Portola Pharma: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Kyowa Hakko Kirin: Research Funding; Eisai: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Takeda: Honoraria, Speakers Bureau. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Stamatoulas Bastard:Celgene: Honoraria; Takeda: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Manson:Bristol Myers Squibb: Honoraria. Orvain:Incyte: Honoraria; Novartis: Honoraria; Jazz Pharmaceuticals: Other: Travel & accommodations; Pfizer: Other: Travel & accommodations. Bouabdallah:Roche: Consultancy, 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, Speakers Bureau. Frigault:Novartis: Consultancy; Kite/Gilead: Honoraria; Nkarta: Consultancy; Incyte: Consultancy; Juno/Celgene: Consultancy; Foundation Medicine: Consultancy; Xenetic: Consultancy. Chen:Takeda: Consultancy; Kiadis: Consultancy; Magenta: Consultancy; Abbvie: Consultancy; Incyte: Consultancy. Lynch:T.G. Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; Takeda Pharmaceuticals: Research Funding; Juno Therapeutics: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Smith:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding; Acerta Pharma BV: Research Funding; Portola Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Denovo Biopharma: Research Funding; Genentech: Research Funding; Ignyta (spouse): Research Funding; Incyte Corporation: Research Funding; Ayala (spouse): Research Funding; Seattle Genetics: Research Funding. Byrne:Karyopharm: Research Funding. Cohen:Hutchison: Research Funding; Astra Zeneca: Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Genentech, Inc.: Consultancy, Research Funding; UNUM: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; Lymphoma Research Foundation: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Roche: Speakers Bureau; Abb-Vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau; BMS: Consultancy; Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau. Armand:Sigma Tau: Research Funding; Otsuka: Research Funding; Pfizer: Consultancy; ADC Therapeutics: Consultancy; Tensha: Research Funding; Affimed: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Infinity: Consultancy; Genentech: Research Funding. Zinzani:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Carlo-Stella:Servier: Consultancy, Honoraria, Other: Travel, accommodations; Genenta Science srl: Consultancy; Boehringer Ingelheim: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations.

Introduction: Approximately two-thirds of patients with primary or post-essential thrombocythemia/polycythemia vera myelofibrosis (MF) have anemia, many of whom require red blood cell (RBC) transfusions. In this heavily transfused population there are severely limited treatment options; effective treatment for anemia in MF is a critically unmet medical need. Luspatercept is a first-in-class erythroid maturation agent which binds to select TGF-β superfamily ligands to reduce aberrant Smad2/3 signaling and enhance late-stage erythropoiesis. Here we report the interim results of the ongoing open-label, phase 2 trial evaluating luspatercept in patients with MF and anemia. Methods: Seventy-four patients with MF and anemia were enrolled, including 41 not receiving concomitant ruxolitinib at study entry who received either no RBC transfusions (n = 20; Cohort 1) or 2-4 RBC U/28 d in the 12 wks prior to treatment (n = 21; Cohort 2). Thirty-three enrolled patients were receiving a stable dose of ruxolitinib for at least 16 wks, of which 14 were not receiving RBC transfusions (Cohort 3A) and 19 were (Cohort 3B). Patients in Cohorts 3A and 3B received a median dose of ruxolitinib of 20 mg/d (range, 5-50 mg/d) for a median of 41 and 43 wks, respectively. Patients received luspatercept every 21 d at a starting dose of 1.0 mg/kg in doses escalating up to 1.75 mg/kg. The primary endpoint in patients not receiving transfusions was a hemoglobin (Hb) increase ≥ 1.5 g/L at every assessment from baseline for ≥ 12 consecutive wks, within the first 24 wks on study. In patients receiving RBC transfusions, the primary endpoint was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks, within the first 24 wks on study. Additional endpoints included proportion of patients achieving mean Hb increase ≥ 1.5 g/dL in Cohorts 1 and 3A, and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease from baseline) in Cohorts 2 and 3B, with both responses lasting ≥ 12 consecutive wks, within 24 wks of study entry. Intent-to-treat (ITT) data were analyzed as of May 10, 2019. Results: Median age was 71 y (range, 50-88 y) and 42 (57%) were male. Median interval from MF diagnosis to study entry was 3.3 y (range, 19 d-13.5 y). Seven patients were Dynamic International Prognostic Scoring System (DIPSS) intermediate-1, 58 were intermediate-2, and 8 were high risk. Median Hb concentration at study entry was 8.8 g/dL (range, 6.7-9.8 g/dL) for Cohort 1 and 8.6 g/dL (range, 6.7-9.1 g/dL) for Cohort 3A. Patients in Cohort 2 received a median of 2.7 RBC U/28 d (range, 1-5 U/28 d) and patients in Cohort 3B received a median of 2.3 RBC U/28 d (range, 2-4 U/28 d). Patients received a median of 8 cycles of luspatercept (range, 1-24 cycles). Efficacy data are displayed in the Table, per ITT data. Two of twenty (10%) and 3/14 (21%) patients in Cohorts 1 and 3A, respectively, achieved an absolute Hb increase ≥ 1.5 g/dL at every measurement from baseline over any consecutive 12 wks. Two of twenty-one (10%) and 6/19 (32%) patients in Cohorts 2 and 3B, respectively, achieved RBC-TI over any consecutive 12 wks. Median duration of Hb response was 20 wks (range, 12-27 wks) in Cohort 1 and 12 wks (range, 12-13 wks) in Cohort 3A. Median duration of RBC-TI was 23 wks (range, 16-31 wks) in Cohort 2 and 32 wks (range, 12-65 wks) in Cohort 3B. Three (15%) and 8 (57%) patients in Cohorts 1 and 3A, respectively, achieved a mean Hb increase of ≥ 1.5 g/dL. Eight (38%) and 10 (53%) patients in Cohorts 2 and 3B, respectively, achieved a ≥ 50% reduction in RBC transfusion burden from baseline. Ruxolitinib exposure remained stable throughout the 24-wk treatment period in both Cohorts 3A and 3B. There was no difference in spleen size between responders and non-responders. Four (5%) patients had grade 3-4 treatment-related adverse events (AEs). There were no treatment-related deaths. Treatment-related AEs occurring in ≥ 3% of patients were hypertension (11%), bone pain (8%), and diarrhea (4%). Seven (9%) patients had ≥ 1 AE resulting in treatment discontinuation; 23 (31%) remain on study. Conclusions: The initial results from this ongoing study suggest clinically significant activity of luspatercept in patients with MF-associated anemia, including those receiving concomitant ruxolitinib. A minority of AEs were grade 3-4 in severity, consistent with previous studies in MDS and beta-thalassemia. Disclosures Gerds: CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding. Vannucchi:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Kremyanskaya:La Jolla: Consultancy; Incyte, Celgene, Constellation, Protagonist.: Research Funding. Gotlib:Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Promedior: Consultancy, Research Funding; Kartos: Consultancy, Honoraria, Research Funding; CTI Biopharma: Research Funding. Ribrag:BMS: Membership on an entity's Board of Directors or advisory committees; AZ: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; argenX: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees. Mead:Celgene: Consultancy, Research Funding; CTI: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accommodation expenses, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Consultancy; Pfizer: Consultancy. Harrison:Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau; Roche: Honoraria; Promedior: Honoraria; Janssen: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Shire: Speakers Bureau. Mesa:Shire: Honoraria; Promedior: Research Funding; Genotech: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; LaJolla: Consultancy; AbbVie: Research Funding; NS Pharma: Research Funding; CTI: Research Funding; Gilead Sciences: Research Funding; Samus: Research Funding; Baxalta: Consultancy; Galena Biopharma: Consultancy; Celgene Corporation: Research Funding; Sierra Oncology: Consultancy; PharmaEssentia: Research Funding; Genentech: Consultancy; Pfizer: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Gale:Celgene Corporation: Employment. Laadem:Celgene Corporation: Employment, Equity Ownership. Pariseau:Celgene Corporation: Employment. Gerike:Celgene Corporation: Employment. Zhang:Celgene Corporation: Employment, Equity Ownership. Linde:Abbott Laboratories, Inc.: Equity Ownership; Acceleron Pharma: Employment, Equity Ownership; Fibrogen, Inc.: Equity Ownership. Reynolds:Acceleron Pharma: Employment, Equity Ownership. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Roche: Research Funding; Incyte: Research Funding. OffLabel Disclosure: Luspatercept is an investigational therapy that is not approved for any use in any country. Luspatercept is currently being evaluated for potential use in patients with anemia due to myelodysplastic syndromes, beta-thalassemia, or myelofibrosis.

Introduction. Myeloid leukemia in children with Down syndrome (ML-DS) is a unique subtype of acute myeloid leukemia, distinguished by an earlier age of onset (under 4 years of age); somatic mutations of GATA1; hypersensitivity of leukemic blasts to cytarabine and other chemotherapeutic agents; lack of CNS involvement; and superior event-free survival (EFS, 85-90% at 5 years). Due to these excellent outcomes, successive protocols by the Children's Oncology Group (COG) have aimed for a reduction of treatment intensity but continue to include a course containing high-dose cytarabine (HD-AraC) for all patients, which is associated with the bulk of infectious toxicity. COG AAML1531 is the first study to evaluate differential treatment for ML-DS patients based on risk-stratification. We report the outcomes for patients with Standard Risk (SR) ML-DS enrolled on AAML1531, who were treated without inclusion of HD-AraC (https://clinicaltrials.gov/ct2/show/NCT02521493?term=AAML1531&rank=1). Methods. Patients older than 90 days and younger than 4 years of age with ML-DS were eligible, including those presenting with myelodysplastic syndrome (&lt; 20% blasts in the bone marrow) and trisomy 21 mosaicism. Pathological and cytogenetic data were reviewed centrally. All patients received the same first course of induction therapy (cytarabine 200 mg/m2/24h IV as continuous infusion, day 1-4; daunorubicin 20 mg/m2IV, day 1-4; thioguanine 50 mg/m2/dose PO twice daily, day 1-4; and a single dose of age-based intrathecal cytarabine on day 1). After this first course, measureable residual disease (MRD) in the bone marrow by multi-dimensional flow cytometry in a reference laboratory was used for risk stratification. Patients with negative MRD (&lt;0.05%) were assigned to Standard Risk (SR) therapy, which was modeled after the AAML0431 predecessor study, but with further reduction of treatment by omission of the course containing HD-AraC/E. coli asparaginase (Induction II of AAML0431). Courses #2 and #3 of SR therapy were identical to the first course except that no further intrathecal chemotherapy was administered. Courses #4 and #5 (cytarabine 100 mg/m2/24h IV as continuous infusion day 1-7; etoposide 125 mg/m2 IV, day 1-3) were identical to the corresponding courses of AAML0431. For patients younger than 36 months, chemotherapy doses were calculated based on weight. Use of dexrazoxane during anthracycline-containing courses was at the discretion of the treating center but was captured by the data collection of the study. Patients with positive MRD (&gt;0.05%) after the first course were assigned to the High Risk (HR) Arm and received intensified therapy (equivalent to that used for non-DS AML). Accrual to the HR arm is ongoing. Results. Interim analysis of SR therapy was performed after 50% of expected EFS events had occurred as of June 30, 2018. The observed EFS was 89.3 +/- 6.1% at 2 years from study entry and significantly lower than expected for comparable MRD-negative patients whose treatment in predecessor study AAML0431 included a course of HD-AraC/E. coliasparaginase (p=0.0002). OS at 2 years was 88.7 +/- 6.8%. Among a total of 114 SR ML-DS patients, 11 developed a relapse, all within the first year from study entry (range 136-327 days). OS at 1 year from relapse was 9.1 +/- 17.3%. Based on the results of interim analysis, the SR arm of AAML1531 was closed to accrual due to lack of efficacy. Cytogenetic analysis showed that complex karyotypes (defined as &gt;3 independent abnormalities including &gt;1 structural one) were significantly more frequent in SR patients who relapsed (40%, n=10) compared to SR patients who did not (9%; n=100; p=0.017). The most common abnormalities were trisomies (61% of cases) of chromosomes 3 and 8, and a gain of a fourth copy of chromosome 21. Monosomy 7 was present in 20% of relapsed vs. 5% of patients without a relapse (p=0.122). Conclusions. MRD measured by multi-dimensional flow cytometry is insufficient to identify a subset of ML-DS patients for whom HD-AraC/E.coliasparaginase can be eliminated from treatment. Cytogenetic profiling may aid in further refining risk-based subsets of ML-DS patients. Additional approaches to risk stratification of ML-DS should be pursued, which take into account the emerging genetic events that co-operate with mutant GATA1 in the development of ML-DS. At this time, HD-AraC/E.coli asparaginase should be included in the treatment of ML-DS, regardless of MRD. Disclosures Druley: Washington University: Employment; ArcherDX Inc.: Employment, Equity Ownership. Loken:Hematologics, Inc: Employment, Equity Ownership. Eidenschink Brodersen:Hematologics, Inc: Employment.

Background: Myelofibrosis (MF) is associated with bone marrow fibrosis (BMF), splenomegaly, a high symptom burden, and poor prognosis; the JAK/STAT pathway is the central pathway implicated in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor and the only FDA-approved pharmacotherapy for treatment (Tx) of MF patients (pts), improves splenomegaly, but is unable to control all clinical manifestations of disease. Navitoclax is an orally bioavailable, novel small-molecule that targets and binds with high affinity to multiple antiapoptotic B-cell lymphoma 2 (BCL2) family proteins, including BCL-XL, BCL2, and BCL-W. Preclinical studies have demonstrated cytotoxic activity of navitoclax against myeloproliferative neoplasm-derived cell lines. Herein, the results of a phase 2 study (NCT03222609) evaluating the combination of navitoclax with ruxolitinib in pts with MF are reported. Methods: This phase 2 single-arm, multicenter, open-label study assessed the efficacy and safety of navitoclax combined with ruxolitinib in pts with MF. Eligible pts (≥18 yr, diagnosis of primary MF, post-essential thrombocythemia [PET]-MF, or post-polycythemia vera [PPV]-MF, ECOG 0-2, receiving at least 12 wk of continuous ruxolitinib therapy prior to study Tx initiation) received a starting dose of 50 mg navitoclax once-daily combined with the current stable dose of ruxolitinib (≥10 mg BID). Weekly intra-patient dose-escalation of navitoclax was allowed to a maximum daily dose of 300 mg based on tolerability and platelet count. Tx continued until the end of clinical benefit, unacceptable toxicity, or discontinuation. The primary efficacy endpoint was percentage reduction in splenic volume from baseline. Secondary endpoints included effect on total symptom score (TSS), overall response rate, rate of anemia response, improvement in BMF, and safety profile. Results: As of May 1, 2019, 34 pts (primary MF, n=16; PET-MF, n=5; PPV-MF, n=13) had received ≥1 dose of navitoclax in combination with ruxolitinib. Median age was 68 yr (range 42-86), 68% were male, and 9 pts (26%) had ≥3 prior lines of MF therapy. The median duration of prior ruxolitinib exposure was 745 days (range 134-4549). Of the 34 pts enrolled, 27 (79%) had JAK2 and 7 pts (21%) had CALR mutations. There were no pts enrolled with triple-negative MF. Of 33 pts with available baseline testing, 17 (52%) had high molecular risk, defined by mutations within ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1. The mean baseline platelet count was 231 x 109/L (range 99-706); mean baseline Hgb was 10.8 g/dL; 19 (56%) pts had elevated WBC at baseline (&gt;1.5× ULN). Maximal navitoclax dose of 300 mg was achieved in 23 pts (68%). Of the 25 (74%) pts that enrolled on ruxolitinib doses &gt;10 mg BID, 22 (88%) subsequently had the dose of ruxolitinib reduced to 10 mg BID. At the time of this analysis, 24 pts were evaluable for efficacy, with 20 pts completing ≥24 wk on study and 4 pts with Tx discontinuations prior to 24 wk. At wk 24, 7 of 24 pts (29%) achieved a spleen volume reduction of ≥35% (SVR35) from baseline by MRI as determined by prespecified central review; the median TSS was 7.4 (range 0-23), a 20% improvement from baseline. A SVR35 at any time on study was achieved in 10 pts (42%). Reductions in driver mutation allelic burden of &gt;5% were observed in 10 (42%) pts; 6 pts (25%) had BMF improvement of ≥1 grade. One pt (4%) had an anemia response; the mean Hgb at wk 24 was slightly improved over baseline at 11.3 g/dL. Of the 19 pts with elevated baseline WBC, 16 (84%) reduced to within normal limits during Tx, with a median WBC reduction of 17.7 × 109/L. All pts experienced a Tx-emergent adverse event (TEAE); most common (≥20%) were thrombocytopenia (82%), diarrhea (62%), fatigue (53%), anemia (27%), nausea (27%), contusion (24%), and vomiting (21%). Grade ≥3 TEAEs occurred in 26 pts (77%); most common were thrombocytopenia (n=15, 44%; Grade 4 n=1, 3%) and anemia (n=8, 24%; no Grade 4). Five pts (15%) experienced serious AEs that resolved including anemia, upper abdominal pain, vomiting, chest pain, increased C-reactive protein, and abnormal liver function test (3% each). There were no significant episodes of bleeding and no TEAE-related deaths. Conclusions: Navitoclax in combination with ruxolitinib was well tolerated with clinically meaningful spleen responses, allelic burden reductions, TSS improvements, and encouraging improvements in BMF in pts with MF who have received prior Tx with ruxolitinib. Disclosures Harrison: CTI: Speakers Bureau; Promedior: Honoraria; Roche: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau. Garcia:Genentech: Research Funding; Abbvie: Research Funding. Mesa:CTI: Research Funding; Galena Biopharma: Consultancy; Samus: Research Funding; Genotech: Research Funding; AbbVie: Research Funding; NS Pharma: Research Funding; Baxalta: Consultancy; LaJolla: Consultancy; Shire: Honoraria; PharmaEssentia: Research Funding; Genentech: Consultancy; Celgene Corporation: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Promedior: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Incyte: Other: travel, accommodations, expenses, Research Funding; Gilead Sciences: Research Funding; Pfizer: Research Funding; Sierra Oncology: Consultancy. Somervaille:Novartis: Consultancy. Komrokji:pfizer: Consultancy; celgene: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Pemmaraju:sagerstrong: Research Funding; celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; samus: Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; affymetrix: Research Funding. Papadantonakis:Agios: Consultancy, Honoraria. Foran:Agios: Honoraria, Research Funding. O'Connell:Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Holes:AbbVie Inc: Employment, Other: Stock/stock options. Jia:AbbVie: Employment, Other: Stock/stock options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Hutti:AbbVie: Employment, Other: Stock/stock options.

AbstractObjectiveTo conduct a systematic literature review of dorsal root ganglion (DRG) stimulation for pain.DesignGrade the evidence for DRG stimulation.MethodsAn international, interdisciplinary work group conducted a literature search for DRG stimulation. Abstracts were reviewed to select studies for grading. General inclusion criteria were prospective trials (randomized controlled trials and observational studies) that were not part of a larger or previously reported group. Excluded studies were retrospective, too small, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsDRG stimulation has Level II evidence (moderate) based upon one high-quality pivotal randomized controlled trial and two lower-quality studies.ConclusionsModerate-level evidence supports DRG stimulation for treating chronic focal neuropathic pain and complex regional pain syndrome.

Abstract BACKGROUND Aneurysm recurrence after coiling has been associated with aneurysm growth, (re)hemorrhage, and a greater need for follow-up. The second-generation HydroCoil Embolic System (HES; MicroVention, Inc) consists of a platinum core with integrated hydrogel and was developed to reduce recurrence through enhancing packing density and healing within the aneurysm. OBJECTIVE To compare recurrence between the second-generation HES and bare platinum coil (BPC) in the new-generation Hydrogel Endovascular Aneurysm Treatment Trial (HEAT). METHODS HEAT is a randomized, controlled trial that enrolled subjects with ruptured or unruptured 3- to 14-mm intracranial aneurysms amenable to coiling. The primary endpoint was aneurysm recurrence using the Raymond-Roy scale. Secondary endpoints included minor and major recurrence, packing density, adverse events related to the procedure and/or device, mortality, initial complete occlusion, aneurysm retreatment, hemorrhage from target aneurysm during follow-up, aneurysm occlusion stability, and clinical outcome at final follow-up. RESULTS A total of 600 patients were randomized (HES, n = 297 and BPC, n = 303), including 28% with ruptured aneurysms. Recurrence occurred in 11 (4.4%) subjects in the HES arm and 44 (15.4%) subjects in the BPC arm ( P = .002). While the initial occlusion rate was higher with BPC, the packing density and both major and minor recurrence rates were in favor of HES. Secondary endpoints including adverse events, retreatment, hemorrhage, mortality, and clinical outcome did not differ between arms. CONCLUSION Coiling of small-to-medium aneurysms with second-generation HES resulted in less recurrence when compared to BPC, without increased harm. These data further support the use of the second-generation HES for the embolization of intracranial aneurysms. Video Abstract