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Abstract Aims Current European heart failure (HF) guidelines suggest the use of risk score: among them, the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score has demonstrated to be one of the most accurate. However, the risk scores are still poorly implemented in clinical practice, also due to the lack of strong evidence regarding their external validation in different populations. Thus, the current study was designed as an external validation test of the MECKI score in an international multicentre setting. Methods and results The study cohort consisted of patients diagnosed with HF with reduced ejection fraction (HFrEF) across international centres (not Italian), retrospectively recruited. Collected data included demographics, HF aetiology, laboratory testing, electrocardiogram (ECG), echocardiographic findings, and cardiopulmonary exercise testing (CPET) results as described in the original MECKI score publication. A total of 1042 patients across 8 international centres (7 European and 1 Asian) were included and followed up from 1998 till 2019. Patients were divided according to the calculated MECKI scores into three subgroups: (i) MECKI score <10%, (ii) 10–20%, and (iii) ≥ 20%. Survival analysis comparison among the three MECKI score subgroups showed a worse prognosis in patients with higher MECKI score value: median event-free survival times were 4396 days for MECKI score <10%, 3457 days for 10–20%, and 1022 days for ≥20% (P < 0.0001). Receiver operating characteristic (ROC) curves and area under the ROC curves (AUC) were like those reported in the original internal validation studies. Conclusion In patients diagnosed with HFrEF, the power of the MECKI score was confirmed in terms of prognosis and risk stratification, supporting its implementation as advised by the HF guidelines.

AbstractThis guidance document has been prepared on behalf of the International Council for Standardisation in Hematology. The aim of the document is to provide guidance and recommendations on the measurement of factor VIII (FVIII) and factor IX (FIX) inhibitors. After an introduction on the clinical background and relevance of factor VIII and factor IX inhibitor testing, the following aspects of laboratory testing are included: screening for inhibitors, assay principle, sample requirements, testing requirements and interpretation, quality assurance, interferences and recent developments. This guidance document focusses on recommendations for a standardised procedure for the laboratory measurement of FVIII and FIX type I inhibitors. The recommendations are based on published data in peer‐reviewed literature and expert opinion.

7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 109/L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), WBC count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]

7016 Background: Many patients (pts) with myelofibrosis (MF) experience anemia resulting from disease or JAK inhibitor therapy. The open-label, phase 2 ACE-536-MF-001 study (NCT03194542) evaluated the safety and efficacy of luspatercept (LUSPA) for the treatment of MF-related anemia. Methods: Eligible pts comprised 4 cohorts based on transfusion dependence (TD, defined as receiving 4–12 red blood cell [RBC] units/84 days [d] immediately up to cycle 1 d 1) and stable ruxolitinib (RUX) treatment; cohort 1: no TD, no RUX; cohort 2: TD, no RUX; cohort 3A: no TD, RUX; cohort 3B: TD, RUX. Pts received subcutaneous LUSPA 1.0 mg/kg (1.33 mg/kg for pts in cohort 3B expansion) with titration up to 1.75 mg/kg in 21-d cycles. Disease response was assessed at d 169 and treatment extended for pts showing clinical benefit; pts were followed for ≥ 3 years (y) post last dose. The primary endpoint was anemia response (defined as 84 consecutive d: ≥ 1.5 g/dL hemoglobin [Hgb] from baseline without transfusion [cohorts 1 and 3A] or RBC transfusion-free [cohorts 2 and 3B]); secondary endpoints included duration of response (DOR), transfusion frequency, change in Hgb level, and symptom response. Results: Of 95 pts in the ITT group, the most common reason for treatment discontinuation was lack of clinical benefit at d 169 (n = 28). Median (range) age was 71.0 (50–89) y. Most (54.7%) pts had primary MF, intermediate-risk 2 disease (75.8%), and > 2 y since initial diagnosis (74.7%). Median prior RUX therapy was 18.1 months (cohorts 3A/3B) and 84.7% of pts had baseline transfusion burden 6–12 units/84 d (cohorts 2/3B). Mean treatment duration was 42.8 weeks. Cohort 3B had the highest anemia response rate with 26.3% (95% CI, 13.4–43.1) of pts transfusion independent during the primary treatment period and 31.6% (95% CI, 17.5–48.7) transfusion independent during the entire treatment period; median (range) DOR was 448 d (85–1582). In cohort 3B: 19 (50.0%) pts had reduced transfusion burden by ≥ 50% during the primary treatment period; 8 (21.1%) pts achieved mean Hgb increase ≥ 1.5 g/dL from baseline throughout the entire treatment period and 6 (15.8%) achieved a mean ≥ 50% reduction in symptom score from baseline. Overall, 47.4% of pts had ≥ 1 treatment-related adverse event (TRAE), most frequently hypertension (17.9%, 5.3% grade ≥ 3); 3.2% of pts had a serious TRAE. One TRAE led to LUSPA discontinuation. Two (2.1%) pts had transformation to acute myeloid leukemia. Nine pts died on treatment from: post-procedural hemorrhage, pneumonia, intracranial hemorrhage, septic shock, ischemic stroke, multiple organ dysfunction syndrome, renal failure, pneumonitis, and myelofibrosis (n = 1 each); no deaths were considered related to the study drug. Conclusions: In pts with MF, the safety profile of LUSPA was consistent with previous studies and efficacy results showed promising improvements in anemia and transfusion burden in all cohorts. Clinical trial information: NCT03194542 .

3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]

TPS1115 Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients progress during maintenance therapy with T + P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in patients with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T + P as maintenance therapy for HER2+ MBC. Approximately 650 patients will be enrolled. Eligible patients will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, Eastern Cooperative Oncology Group Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Patients will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T + P once every 21 days. Patients with hormone receptor-positive disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), PFS by Blinded Independent Central Review (BICR), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, Canada, Brazil, APAC and EU countries with additional sites planned. Clinical trial information: NCT05132582 .

TPS8064 Background: Multiple myeloma (MM) remains an incurable disease. Combinations of established agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies, are used in all lines of therapy, but re-exposure to previously received classes of therapy is associated with decreasing response rates and duration of response (Moreau et al. 2021). BCMA-targeted agents have recently been approved for the treatment of patients with RRMM whose disease has been exposed or become refractory to PIs, IMIDs and anti-CD38 antibodies (triple-class exposed or refractory MM). Although effective, the majority of patients who respond to anti-BCMA agents eventually relapse. Proven salvage therapies for these patients are currently lacking and represent a new unmet medical need. Cevostamab is an immunoglobulin G1-based T-cell-engaging bispecific antibody that targets Fc receptor-homolog 5 (FcRH5) on myeloma cells and CD3 on T cells. Dual binding results in T-cell activation and potent killing of MM cells. In an ongoing Phase I study (GO39775; NCT03275103), cevostamab monotherapy showed promising activity in heavily pre-treated patients with RRMM, including those with prior exposure to anti-BCMA agents (Trudel et al. 2021). Methods: CAMMA 2 (CO43476; NCT05535244) is an open-label, multicenter Phase I/II trial evaluating cevostamab monotherapy in patients with RRMM who are triple-class refractory and have previously received an anti-BCMA agent. Prior anti-BCMA antibody-drug conjugates or chimeric antigen receptor (CAR) T cells are permitted in Cohorts A1 and B1, while prior anti-BCMA bispecific antibodies are allowed in Cohorts A2 and B2. In A1 and A2, cevostamab is administered by intravenous infusion and is initiated with step dosing (0.3mg on Cycle [C] 1 Day [D] 1 and 3.3mg on C1D2, D3, or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] after the initial administration), with the target dose of 160mg given on C1D8 and on D1 of each subsequent 21-day cycle. Patients are hospitalized for the C1 administrations only and treatment is continued until disease progression or unacceptable toxicity occurs. CRS is managed per protocol based on the clinical presentation and may involve corticosteroid and tocilizumab treatment. Primary objectives are evaluation of efficacy (primary endpoint: objective response rate by investigator assessment using IMWG criteria) and safety. Secondary objectives include assessment of quality of life, pharmacokinetics, pharmacodynamics, and immunogenicity. Cohorts B1 and B2 will evaluate the efficacy and safety of cevostamab at the recommended Phase II dose in this setting. As of February 2023, enrolment into Cohorts A1 and A2 is ongoing. Clinical trial information: NCT05535244 .

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

Abstract Aims In this protocol-predefined substudy of the RHAPSODY trial, the primary aim was to assess whether pericardial late gadolinium enhancement (LGE) was associated with time to pericarditis recurrence. Methods and results RHAPSODY was a Phase 3 double-blind, placebo-controlled, randomized-withdrawal trial that demonstrated the efficacy of rilonacept in recurrent pericarditis (RP). Patients with a history of multiple RP and an active recurrence were enrolled and had the option to participate in a cardiac magnetic resonance (CMR) imaging substudy. CMRs were interpreted by a blinded independent core laboratory with prespecified criteria to define pericardial LGE. Compared to patients with trace or mild pericardial LGE (n = 9), patients with moderate or severe pericardial LGE (n = 16) generally had a higher number of recurrent episodes per year (5.3 vs. 3.9) and a higher mean CRP level (3.6 vs. 1.1 mg/dL). Overall, 10/14 (71.4%) who received a placebo had a recurrence compared to 0/11 (0%) who received rilonacept. In patients randomized to placebo who had moderate or severe pericardial LGE, the median time to recurrence was 4.2 weeks compared to 10.7 weeks in patients who had trace or mild pericardial LGE. At the conclusion of the event-driven randomized-withdrawal period, among patients receiving a placebo, 5/7 (71.4%) with trace or mild pericardial LGE and 5/7 (71.4%) with moderate or severe pericardial LGE had a recurrence. Conclusions Among patients with multiple RP, these preliminary findings support the concept of pericardial LGE as an imaging biomarker that may inform the duration of treatment and risk of recurrence with cessation of therapy and larger studies should be considered. ClinicalTrials.gov Identifier NCT03737110

Abstract Aims To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA). Methods and results We analyzed mild stenosis (25–49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02–3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09–2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07–2.22; P = 0.020). Conclusion In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs. Clinical trial registration ClinicalTrials.gov NCT02803411