Citations

Background In heart failure, the exercise gas exchange Weber (A to D) and ventilatory classifications (VC‐1 to VC‐4) historically define disease severity and prognosis. However, their applications in the modern heart failure population of any left ventricular ejection fraction combined with hemodynamics are undefined. We aimed at revisiting and implementing these classifications by cardiopulmonary exercise testing imaging. Methods and Results 269 patients with heart failure with reduced (n=105), mid‐range (n=88) and preserved (n=76) ejection fraction underwent cardiopulmonary exercise testing imaging, primarily assessing the cardiac output (CO), mitral regurgitation, and mean pulmonary arterial pressure (mPAP)/CO slope. Within both classes, a progressively lower exercise CO, higher mPAP/CO slopes, and mitral regurgitation ( P <0.01 all) were observed. After adjustment for age and sex, Cox proportional hazard regression analyses showed that Weber (hazard ratio [HR], 2.9; 95% CI, 1.8–4.7; P <0.001) and ventilatory classes (HR, 1.4; 95% CI, 1.1–2.0; P =0.017) were independently associated with outcome. The best stratification was observed when combining Weber (A/B or C/D) with severe ventilation inefficiency (VC‐4) (HR, 2.7; 95% CI, 1.6–4.8; P <0.001). At multivariable analysis the best hemodynamic determinants of peak oxygen consumption and ventilation to carbon dioxide production slope were CO (β‐coefficient, 0.72±0.16; P <0.001) and mPAP/CO slope (β‐coefficient, 0.72±0.16; P <0.001), respectively. Conclusions In the contemporary heart failure population, the Weber and ventilatory classifications maintain their prognostic ability, especially when combined. Exercise CO and mPAP/CO slope are the best predictors of peak oxygen consumption and ventilation to carbon dioxide production slope classifications representing the main targets of interventions to impact functional class and, likely, event rate.

ABSTRACT Background With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PD GBA ) under way, we need markers that confirm the impact of genetic variants in patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement. Objective To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI). Methods We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PD GBA patients compared to PD GBA_wildtype patients. Results Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD GBA compared to PD GBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD GBA compared to PD GBA_wildtype . (3) CSF levels of total α‐synuclein were lower in PD GBA compared to PD GBA_wildtype . All of these findings were most pronounced in PD GBA with severe mutations (PD GBA_severe ). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PD GBA_severe . Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PD GBA_severe . Interpretation These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society

Background Activating mutations in JAK2 are the molecular hallmark of PV. However, achieving molecular remission is not a validated endpoint in PV, as its correlation with patient-relevant endpoints, such as thrombotic events or disease progression, is not well established. The expression of MDM2, a negative regulator of wild-type p53, is significantly higher in CD34+ cells from patients with PV vs those from healthy controls. Therefore, MDM2 antagonists such as idasanutlin (idasa) may have selective and potentially disease-modifying effects in PV. This exploratory analysis reports baseline mutational profiling and serial measurements of JAK2 V617F variant allele frequency (VAF) from patients treated with idasa in the Phase II NP39761 study (NCT03287245). Methods Patients with PV, as defined by the 2016 World Health Organization criteria, were eligible for inclusion if their disease was HU resistant/intolerant according to European LeukemiaNet criteria and they were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV therapy with ruxolitinib and/or interferon was allowed. Idasa was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg, but dose increase (to 200 mg) or decrease (to 100 mg) was allowed per protocol-defined criteria. The primary efficacy endpoints were hematocrit control (HTC), defined as maintaining acceptable hematocrit levels with ≤ 1 phlebotomy between cycle 1, day 1 (C1D1) and wk 8 and no phlebotomy after wk 8, and complete hematologic remission (CHR), defined as HTC together with platelets &lt; 400 × 109/L and white blood cell count &lt; 109/L on the day of response assessment (or most recent test). JAK2 V617F VAF was analyzed at screening and at C3D28, C5D28 and wk 32. The JAK2 V617F VAF was determined using quantitative polymerase chain reaction. Baseline blood samples were sequenced using the Foundation Medicine FoundationOne Heme next-generation sequencing panel, which interrogates &gt; 400 DNA-sequenced genes, to explore the genetic landscape of PV beyond JAK2 V617F. Results All 27 patients enrolled in the study harbored JAK2 V617F. Baseline and ≥ 1 later JAK2 VAF measurements were available in 23 patients, allowing for analysis. The median age was 56 y (range, 34-74), and 7 patients (26%) had been previously treated with ruxolitinib. Median treatment duration was 257 days (range, 5-677), and the median number of treatment cycles was 8 (range, 1-22). JAK2 V617F VAFs at baseline were highly variable, ranging from 7% to 96% (median, 66%). A reduction in JAK2 V617F VAF was observed as early as after 3 cycles (median reduction, 39%; n = 19) and was sustained in patients receiving treatment, with a median reduction of 58% at C5D28 (n = 17) and of 76% at wk 32 (n = 13). The median reductions in JAK2 V617F VAF were significantly higher for patients with CHR and HTC than in nonresponders on C3D28 (CHR, P &lt; 0.01; HTC, P = 0.04) and C5D28 (CHR, P &lt; 0.01; HTC, P = 0.03), with a similar trend also at wk 32 (CHR, P = 0.06; HTC, P = 0.19) (Figures). Baseline targeted sequencing (n = 16) identified several additional subclonal mutations. However, no TP53 mutations were detected. Variants in TET2 and ASXL1 were detected in 37% (6 of 16) and 20% (3 of 16) of patients, with VAFs of 2%-51% and 38%-50%, respectively. Notably, 68% of the patients had variants detected in 1 to 3 DNA repair genes, including ATM (VAF, 47%-52%), ATR (VAF, 49%), BRCA2 (VAF, 47%-51%), PARP1 (VAF, 52%), PARP3 (VAF, 48%), FANCM (VAF, 47%-50%), BLM (VAF, 48%) and MSH3 (VAF, 49%). In the absence of sequencing of patient-matched non-hematologic tissue and the VAFs being ≈50%, it is possible some of these variants are germline. Whether such variants predispose to PV is unknown. Conclusions Idasa has relevant clinical activity in patients with PV who are resistant to or intolerant of HU and showed rapid JAK2 V617F VAF reduction in a subset of patients as early as after 3 treatment cycles. The median JAK2 VAF reduction was significantly greater in patients who achieved CHR and HTC after 3 and 5 cycles of idasa treatment, suggesting that early molecular response was associated with higher likelihood of clinical response. Baseline mutations were seen in several genes commonly mutated in PV. A high frequency of variants in DNA repair genes has not previously been reported in PV and may contribute to genomic instability in this disease. Figure Disclosures Passamonti: Roche: Other: Support of parent study and funding of editorial support; BMS: Speakers Bureau; Novartis: Speakers Bureau. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; AstraZeneca/MedImmune: Consultancy; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; Sierra Oncology: Research Funding. Gupta:Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Huw:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:Sierra Oncology: Consultancy; Incyte: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; AbbVie: Research Funding; Bristol Myers Squibb: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support; Ardelyx: Current equity holder in publicly-traded company. Mascarenhas:Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution).

Introduction: MF is a clonal stem cell disorder characterized by progressive bone marrow failure, extramedullary hematopoiesis, and debilitating constitutional symptoms. Approximately 60% of pts develop anemia within a year of diagnosis; pts who are transfusion dependent have worse survival and quality-of-life outcomes (Tefferi A, et al. Mayo Clin Proc 2012;87:25-33). Treatment for MF-associated anemia remains critically unaddressed, with no approved therapies available. Luspatercept is a first-in-class erythroid maturation agent that has been shown to increase hemoglobin and reduce transfusion burden in pts with myelodysplastic syndromes (Fenaux P, et al. N Engl J Med 2020;382:140-51) and β-thalassemia (Cappellini MD, et al. N Engl J Med 2020;382:1219-31). Pts have also achieved multiple response episodes with luspatercept (Fenaux P, et al. Blood 2019;134:841). We previously reported findings from the ongoing open-label, phase 2 ACE-536-MF-001 trial evaluating luspatercept in pts with MF-associated anemia (Gerds AT, et al. Blood 2019;134:557). Here we report updated study results, focusing on response in pts requiring RBC transfusions. Methods: 79 pts with MF and anemia were enrolled (Figure). Of these, 43 were requiring RBC transfusions, defined as 6-12 U/84 d prior to treatment, or 4-12 U/84 d for the 3 expansion cohort pts. Pts in Cohort 3B received a stable ruxolitinib (RUX) dose for ≥ 16 wks (40 wks for expansion cohort pts), whereas Cohort 2 pts did not (Figure). Pts in Cohort 3B received a median RUX dose of 20 mg/d (range 5-40) for a median of 73 wks (range 29-359) prior to treatment. Pts received luspatercept every 21 d at a starting dose of 1.0 mg/kg (1.33 mg/kg for 3 expansion cohort pts in Cohort 3B), with doses escalating up to 1.75 mg/kg; 81% and 50% of pts in Cohorts 2 and 3B escalated to 1.75 mg/kg. Primary endpoint for pts receiving transfusions was RBC transfusion-independence (RBC-TI) for ≥ 12 consecutive wks within the first 24 wks on study. However, as responses were observed that did not fall within the 24-wk response window, additional assessments were conducted for the entire treatment duration for RBC-TI and ≥ 50% decrease in RBC transfusions (minimum 4 RBC U decrease) from baseline. Intent-to-treat data were analyzed as of March 29, 2020. Results: Pts in Cohorts 2 and 3B received a median of 8 cycles of luspatercept (range 1-39), for a median (mean) duration of 24 (31) and 23 (39) wks, respectively. Pts in Cohorts 2 and 3B received a median of 2.7 RBC U/28 d (range 1-5) and 2.7 RBC U/28 d (range 2-4), respectively. For the primary endpoint, 2/21 (10%) and 6/22 (27%) pts receiving transfusions in Cohorts 2 and 3B achieved RBC-TI over any consecutive 12 wks during the first 24 wks. Median time to start of first RBC-TI response period in Cohorts 2 and 3B was 1.5 days and 37 days; median duration of response was 49 wks (range 16-82) and 42 wks (range 12-111), respectively. When assessing the entire treatment period, 4/21 (19%) and 8/22 (36%) pts in Cohorts 2 and 3B achieved RBC-TI ≥ 12 wks, respectively. 25% of the RBC-TI responders in both cohorts experienced 2 separate episodes of RBC-TI ≥ 12 wks. Median cumulative duration of all individual ≥ 12-wk response episodes of RBC-TI was 59 wks (range 24-82) in Cohort 2 and 55 wks (range 12-116) in Cohort 3B. 8/21 (38%) and 10/22 (46%) pts in Cohorts 2 and 3B achieved a ≥ 50% reduction in RBC transfusion burden (minimum ≥ 4 U reduction) over 12 wks; of these, 38% and 20% of responders in Cohorts 2 and 3B experienced 2 separate ≥ 12-wk response episodes, and 1 pt (13%) in Cohort 2 experienced 3 separate responses. 4/15 (27%) and 8/14 (57%) pts in Cohorts 2 and 3B who reached 24 wks of treatment achieved clinical benefit and therefore continued luspatercept on an ongoing basis. Safety is reported for all 79 pts on study. 5 (6%) pts had grade 3-4 treatment-related adverse events (AEs); these AEs were diarrhea (n = 2), dehydration (n = 1), and hypertension (n = 3). There were no treatment-related deaths. Treatment-related AEs (any grade) occurring in ≥ 5% of pts were hypertension (13%), bone pain (9%), and diarrhea (5%). 8 (10%) pts had ≥ 1 AE leading to discontinuation. 16 (20%) pts remain on treatment. Conclusions: These longer-term findings suggest durable activity of luspatercept in pts with MF-associated anemia. In addition, a quarter of pts receiving transfusions achieved more than one ≥ 12-wk episode of RBC-TI response with luspatercept. The incidence of grade 3-4 AEs with luspatercept was low. Disclosures Gerds: Roche/Genentech: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Research Funding; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Speakers Bureau; BMS: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Kremyanskaya:Constellation Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding. Gotlib:CTI Biopharma: Research Funding; Kartos: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; BMS: Research Funding. McCaul:BMS: Speakers Bureau; Seattle Genetics: Speakers Bureau; Karyopharm: Speakers Bureau; Incyte: Speakers Bureau. Ribrag:argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: 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; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; gustave roussy comprehensive cancer center: Current Employment; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding. Mead:Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Abbvie: Consultancy; CTI: Consultancy; Gilead: Consultancy. Harrison:Roche: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Janssen: Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria. Mesa:Sierra Oncology: Consultancy; LaJolla Pharmaceutical Company: Consultancy; Novartis: Consultancy; Incyte: Research Funding; CTI BioPharma: Research Funding; Genentech: Research Funding; AbbVie: Research Funding; Promedior: Research Funding; Bristol Myers Squibb: Research Funding; Samus Therapeutics: Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Barosi:Bristol Myers Squibb: Consultancy. Gerike:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Shetty:BMS: Current Employment, Current equity holder in publicly-traded company. Pariseau:Bristol Myers Squibb: Current Employment. Miranda:Bristol Myers Squibb: Current Employment. Schwickart:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Giuseppi:BMS: Current Employment, Current equity holder in publicly-traded company. Zhang:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Backstrom:Acceleron Pharma: Current Employment, Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; CTI Biopharma Corp: Research Funding; Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding.

Background PV is a clonal myeloid neoplasm characterized by activating mutations in JAK2 and increased red blood cell production. Reduction of thrombosis risk through lowering of hematocrit (Hct) and thus blood viscosity is critical, but management of constitutional symptoms is also important. HU is an effective and well-tolerated first-line treatment (tx) for PV, but pts who develop resistance to or intolerance of HU have limited tx options. A Phase I study of idasanutlin, an MDM2 antagonist leading to increased p53 activity, showed encouraging efficacy and potential disease-modifying effects via rapid reduction in JAK2 V617F variant allele frequency in 11 pts with PV. These results prompted the larger, international Phase II study of idasanutlin in HU-resistant/intolerant PV (NCT03287245); data from the initial phase of the study are reported here. Methods Pts meeting the 2016 WHO criteria for PV were eligible for inclusion if they had HU-resistant/intolerant disease according to the European LeukemiaNet (ELN) criteria and were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV tx with ruxolitinib (rux) or interferon was allowed. Idasanutlin was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg; increase to 200 mg was allowed for non-responders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for pts treated beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles. The primary endpoint (wk 32) was the composite response of Hct control (HTC) and spleen volume reduction &gt; 35% by CT/MRI in pts with splenomegaly (&gt; 450 cm3) and HTC alone in pts without splenomegaly. Key secondary endpoints included safety, complete hematologic response (CHR; defined as HTC and normalization of platelets/leukocytes) and ELN response. Results A total of 27 pts were included in this study and received tx with idasanutlin. Median age was 56 years (range, 34-74) and 16 pts (59.3%) were male (Table 1). All pts had JAK2 V617F mutation; 7 had previous exposure to rux. Median tx duration was 257 days (range, 5-677); the median number of treatment cycles was 8 (range, 1-23). Dose modifications occurred in 17 pts (63.0%; Table 2). A total of 3 serious AEs occurred: atrial flutter, atrial fibrillation and nausea/vomiting (n = 1 each). The serious cardiac AEs occurred in pts with pre-existing hypertension and a past incident of heart failure not symptomatic upon enrollment, respectively. No deaths, transformation to acute myeloid leukemia, progression to myelofibrosis or thrombotic events occurred during the study. AEs occurring in ≥ 15% of pts are listed in Table 3; gastrointestinal toxicity and fatigue were the most common events. The population for primary endpoint evaluation consisted of pts with response assessed at wk 32 (n = 16). One of 13 pts with baseline splenomegaly achieved a composite response (7.7%; Table 4). Nine of 16 pts (56.3%) among all evaluable pts achieved HTC: 6 of 11 rux-naive pts (54.5%) and 3 of 5 rux-exposed pts (60.0%). Eight of 13 pts (61.5%) among all pts had HTC duration ≥ 12 wk beyond wk 32: 5 of 9 rux-naive pts (55.6%) and 3 of 4 rux-exposed pts (75.0%). At wk 32, 8 of 16 pts (50.0%) achieved a CHR, with 6 of 13 (46.2%) having a CHR duration ≥ 12 wk beyond wk 32. Overall response rates per modified ELN response criteria in pts with baseline splenomegaly, pts without baseline splenomegaly and in all pts were 69.2% (9 of 13), 66.7% (2 of 3) and 68.8% (11 of 16), respectively; 9 of 15 pts (60%) among all pts had a response duration ≥ 12 wk beyond wk 32. Median (range) laboratory value changes at wk 32 were: platelets, −253 × 109/L (−2083 to +175) and leukocytes, −4.8 × 109/L (−25.3 to +3.4). At wk 32, 6 of 14 pts (42.9%) had a ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Conclusions Idasanutlin showed relevant clinical activity in pts with HU-resistant/intolerant PV and also in a subset of pts with prior rux tx. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations. These results iterate the importance of tolerability of novel therapies administered over the long term for pts with PV. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Burbury:Roche: Other: Support of parent study and funding of editorial support. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gupta:Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kovic:Roche: Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: 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. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

AbstractAimsTreatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF).Methods and resultsA total of 218 treatment naive patients with symptomatic PAF were randomized (1 : 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was ≥1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) &gt;30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P &lt; 0.001).ConclusionsCryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.

TPS252 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2+ metastatic breast cancer (MBC), is being developed as a novel therapy for patients (pts) with metastatic colorectal cancer (mCRC) and other GI tumors. While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ gastric or gastroesophageal junction adenocarcinoma (GEC), no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy in 2nd-line, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras in HER2+ mCRC. The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC in combination with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC and Tras with the 2nd-line standard of care, Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC, have received a HER2-directed antibody, and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose finding stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-12 patients, and evaluate the safety and activity of the regimen in Cohorts 2A and 2B (30 patients each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ~235 patients) vs. placebo (Arm 3B; ~235 patients), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ~30 patients). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment is ongoing in the U.S. Clinical trial information: NCT04499924.

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts have RAS wild-type and HER2+ mCRC, and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.