UK National Amyloidosis Centre Research Articles

Deep phenotyping of p.(V142I)-associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. A total of 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR-CM (ATTRv-CM); this equates to 1.6 million carriers in the United States. We undertook deep phenotyping of p.(V142I)-ATTRv-CM and comparison with wild-type ATTR-CM (ATTRwt-CM). A retrospective study of 413 patients with p.(V142I) ATTRv-CM who attended the UK National Amyloidosis Centre (NAC) was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance (CMR) imaging. A total of 413 patients with ATTRwt-CM, matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group. At time of diagnosis, patients with ATTRv-CM had significant functional impairment by New York Heart Association classification (NHYA class ≥ III; 38%) and 6-min walk test distance (median 276 m). Median 5-year survival in ATTRv-CM patients was 31 versus 59 months in matched patients with ATTRwt-CM (p < 0.001). Patients with ATTRv-CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of right ventricular dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv-CM. p.(V142I)-ATTRv-CM has an aggressive phenotype characterized by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR-CM genotypic subgroup.

Prevalence, characteristics and outcomes of older patients with hereditary versus wild-type transthyretin amyloid cardiomyopathy.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR-CM. Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n=421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow-up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro-Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p=0.015), ischaemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv-CM. Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.

189 PREVALENCE, DISEASE CHARACTERISTICS AND OUTCOMES OF HEREDITARY TRANSTHYRETIN AMYLOID CARDIOMYOPATHY AMONG ELDERLY INDIVIDUALS

Abstract Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of variant ATTR-CM (ATTRv-CM) among elderly patients. Methods Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2012 and June 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. Results The study population consisted of 2164 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). ATTRv-CM was diagnosed in 20% (n=431) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) other pathogenic TTR variants. During a median (range) follow up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p&amp;lt;0.001). Univariable and multivariable binary logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.86 per year, p&amp;lt;0.001), female sex (OR 3.0, p&amp;lt;0.001), Afro-Caribbean ethnicity (OR 59.1, p&amp;lt;0.001), atrial fibrillation (OR 0.65, p=0.015), ischemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 3.72, p&amp;lt;0.001) and orthostatic hypotension (OR 3.75, p=0.001) to be independently associated with ATTRv-CM. Conclusions Up to 20% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age.

Cardiac transplantation in transthyretin amyloid cardiomyopathy: outcomes from three decades of tertiary centre experience

Abstract Background Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced heart failure are limited to cardiac transplantation (CT). Despite small case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be an absolute contraindication to CT in some centres. This is in part due to a perceived risk of amyloid recurrence in the cardiac allograft. We report outcomes of patients with ATTR-CM assessed at our centre whom underwent CT over the past thirty years. Methods We retrospectively evaluated all ATTR-CM patients assessed at the UK National Amyloidosis Centre between 1990 and 2020 who underwent CT. Pre-transplantation disease and patient characteristics were determined and outcomes were compared with our large cohort of non-transplanted ATTR-CM patients. Censor date was 11th January 2022. Results Eleven (9 male, 2 female) patients with ATTR-CM underwent CT including 8 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 60.3 years and median follow up post-CT was 65.7 months. Median (range) NT-proBNP concentration pre-transplant was 4478ng/L (1057–8778ng/L), median (range) left ventricular ejection fraction (LVEF) was 39% (27–56%) and mean (IQR) interventricular septal (IVSD) was 18 mm (15.9–20.1 mm). 8 patients were NYHA functional class III, the 3 remaining patients were class II. One, three, and five-year survival was 100%, 89% and 86%, respectively and the longest surviving patient was censored &amp;gt;19 years post CT. Survival is at least comparable to UK and US CT outcome registry data for all non-amyloid patients undergoing CT. No patients had recurrence of amyloid in the cardiac allograft as assessed by endomyocardial biopsy and/or Tc-DPD scintigraphy. Two patients were commenced on Patisiran for amyloid polyneuropathy at 211 and 5 months post-CT. Graft rejection requiring treatment was observed in 2 patients, and successfully treated with intravenous steroids. Renal impairment was common, with 6 patients being left with chronic kidney disease. Three patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly longer than UK patients with ATTR-CM generally (P≤0.006), regardless of NAC ATTR disease stage and including those diagnosed under 65 years of age (P=0.028). (Figure 1) All surviving patients were NYHA functional class I at time of censor. Conclusion Our data indicates that cardiac transplantation is well tolerated, restores functional capacity, and prolongs survival in ATTR-CM with little risk of recurrence of amyloid in the cardiac allograft. We believe that our data argues strongly for ATTR-CM to be routinely included in the list of indications for cardiac transplantation. Funding Acknowledgement Type of funding sources: None.

Prognostic importance of the 6 min walk test in light chain (AL) amyloidosis

ObjectivesIn AL amyloidosis, organ response assessment is based on surrogates (eg, cardiac biomarkers). An objective functional test, such as the 6 min walk test (6MWT), capturing overall clinical improvement, is...

The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre

Introduction Hereditary apolipoprotein A-I (AApoAI) amyloidosis is a rare heterogeneous disease with variable age of onset and organ involvement. There are few series detailing the natural history and outcomes of solid organ transplantation across a range of causative APOA1 gene mutations. Methods We identified all patients with AApoAI amyloidosis who presented to the National Amyloidosis Centre (NAC) between 1986 and 2019. Results In total, 57 patients with 14 different APOA1 mutations were identified including 18 patients who underwent renal transplantation (5 combined liver-kidney (LKT) and 2 combined heart-kidney (HKT) transplants). Median age of presentation was 43 years and median time from presentation to referral was 3 (0–31 years). Involvement of the kidneys, liver and heart by amyloid was detected in 81%, 67% and 28% of patients, respectively. Renal amyloidosis was universal in association with the most commonly identified variant (Gly26Arg, n = 28). Across all variants, patients with renal amyloidosis had a median creatinine of 159 µmol/L and median urinary protein of 0.3 g/24 h at the time of diagnosis of AApoAI amyloidosis and median time from diagnosis to end-stage renal disease was 15.0 (95% CI: 10.0–20.0) years. Post-renal transplantation, median allograft survival was 22.0 (13.0–31.0) years. There was one early death following transplantation (infection-related at 2 months post-renal transplant) and no episodes of early rejection leading to graft failure. Liver transplantation led to regression of amyloid in all four cases in whom serial 123I-SAP scintigraphy was performed. Conclusions AApoAI amyloidosis is a slowly progressive disease that is challenging to diagnose. The outcomes of transplantation are encouraging and graft survival is excellent.

Abstract 21: Characteristics Of Patients With Transthyretin Amyloid Cardiomyopathy Receiving Tafamidis Therapy: Experience At An Advanced Heart Failure Program

Background: While the safety and efficacy of tafamidis are described in clinical trials, data on its real-world application are lacking. This study summarized the characteristics of patients initiating first-time treatment with tafamidis at the Cardiac Amyloidosis Clinic at Georgia Heart Institute. Methods: A retrospective analysis of the clinical characteristics and treatment progress of patients diagnosed with transthyretin amyloid (ATTR) cardiomyopathy receiving tafamidis therapy from May 6, 2019, to Oct 1, 2021. Results: In total, 18 patients were identified who had received tafamidis. Two patients were excluded from the analysis as they did not receive care from our clinic. Of the remaining 16 patients, 2 African American and 1 Caucasian patients with a mean age of 59.5 years old, carried V122I mutation. The other 13 patients, Caucasian with a mean age of 81.4 years old, possessed wild-type ATTR amyloidosis. No patients with V30M mutation were identified. Of the patients included, 14 male and 2 female, the 2 female patients had wild-type ATTR amyloidosis. At the time of tafamidis initiation, 10 patients were at the UK National Amyloidosis Centre (NAC) stage 1 amyloid cardiomyopathy, 5 patients at NAC stage 2, and 1 patient at NAC stage 3. The median (IQR) levels of NT-proBNP were 2240 (1098 - 4148) pg/mL at baseline, and 1446 (800 - 2795) pg/mL at 12 months after initiation of therapy. The mean eGFR of patients with wild-type ATTR and V122I mutation were 58 and 72 mL/min/1.73 m2, respectively. Four patients received additional therapy with 1) doxycycline, 2) doxycycline and tauroursodeoxycholic acid, 3) diflunisal, 4) patisiran. There were 13.33% patients on beta-blockers, 53.33% received ACEI/ARBs, and 86.67% took aldosterone antagonists. No adverse events were reported nor therapy discontinuation. Conclusion: Our findings are consistent with published data with wild-type ATTR more frequently seen in males and V122I mutation predominantly seen in individuals of African descent. Overall, in a real-world setting, tafamidis was associated with a decline in NT-proBNP and well-tolerated in our patients.

Abstract 12974: Transthyretin Amyloid Cardiomyopathy Associated With the P.V142I Transthyretin Variant is an Inherently Aggressive Form of Transthyretin Amyloid Cardiomyopathy Associated With Significant Functional Impairment and Poor Prognosis

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3-4% of individuals of African descent carry a TTR gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM; this equates to 1.6 million carriers in the USA. We report deep phenotyping in p.V142I ATTR-CM. Hypothesis: The phenotype of p.V142I ATTR-CM is an aggressive form of ATTR CM. Methods: A retrospective study of 395 patients with p.V142I ATTR-CM from the UK National Amyloidosis Centre. Patients were diagnosed at the Centre through a comprehensive evaluation comprising clinical and functional assessment, echocardiography, radionuclide scintigraphy, histology and biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild-type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of diagnosis) were used as a comparator group. Results: At time of diagnosis, patients with p.V142I ATTR-CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38.2%) and impairment of echocardiographic parameters; mean LVEF 43%, global longitudinal strain -9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid (51%) regurgitation. Uni and multivariate cox regression analysis identified troponin T, TR, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters and 5yr survival (27% v 46%, p&lt;0.001) were significantly worse than in wtATTR-CM. Conclusion: p.V142I ATTR-CM has an aggressive phenotype characterised by functional impairment, regurgitant valvular disease and systolic impairment resulting in poor survival. LV systolic impairment, TAPSE, serum troponin and TR were independent predictors of survival, whereas LV wall thickness was not, suggesting as yet unrecognised disease mechanisms.

Safety and Efficacy of Deferred Autologous Stem Cell Transplantation in Patients with Systemic AL Amyloidosis with Significant Cardiac Involvement at Presentation

BackgroundSystemic AL amyloidosis (AL) is associated with an underlying plasma cell dyscrasia and characterised by deposition of abnormally folded monoclonal immunoglobulin light chains. High dose melphalan with autologous stem cell transplantation (ASCT) can lead to durable complete haematologic and organ responses. Early studies reported TRM of >20%. Strategies for careful patient selection have made ASCT safer with TRM 2-5% but exclude ~80% of patients with AL from availing this treatment modality. Modern chemotherapy can lead to high clonal and organ responses but durability of response remains unclear. We describe our experience of deferred ASCT in 22 patients treated at two large European amyloidosis centres who were considered ineligible for ASCT at presentation but achieved clonal and organ responses with induction chemotherapy.Methods22 patients with AL underwent deferred ASCT from September 2011 to July 2017; 8 were treated at Heidelberg University Amyloidosis Centre and 14 were treated at the UK National Amyloidosis Centre. All underwent serial assessment of organ function, biomarkers and clonal response. Organ involvement and response were defined by international amyloidosis consensus criteria. Survival was calculated by Kaplan-Meier analysis. All analyses are on intention to treat basis (ITT).ResultsBaseline characteristics are presented in Table 1. All patients were diagnosed with AL between January 2011 - November 2016. All had cardiac involvement: Mayo Stage 2, 3A and 3B disease in 4 (18%), 16 (73%) and 2 (9%) patients respectively.All patients received bortezomib-based induction chemotherapy, median number of cycles was 6 (range 4-9). 6 (27.2%) were treated with a bortezomib-IMID regimen, the remainder had bortezomib-dexamethasone or a bortezomib-alkylator protocol. Haematologic responses after chemotherapy on an ITT basis were: complete haematologic response (CR) - 11 (50%), very good partial response (VGPR) - 8 (36%) partial response (PR) - 3 (14%). At 6 months, 14 (64%) achieved a cardiac response, 5/9 (56%) with renal involvement achieved a renal response and 3/5 (60%) with liver involvement achieved a liver response.Median time to ASCT from presentation was 14.5 months (range 2-71 months). Indication for ASCT was hematologic progression in 10 (45%) patients and as a consolidation procedure in the remainder. At the time of ASCT, all patients had NYHA class 1-2 symptoms (compared to 86.4% with NYHA Class 1-2 symptoms and 13.6% with NYHA Class 3-4 symptoms at presentation) and ECOG of 0-1 (compared to 95.5% with ECOG 0-2 and 4.5% with ECOG 3-4 at presentation). Median NT-proBNP was 389ng/L (101-2853ng/L)prior to ASCT, having been 2652ng/L (930-28737ng/L) at presentation (p=0.0001) and 1497ng/L (237-5167ng/L) 6 months after diagnosis (p=0.0016). Mean LV wall thickness was 14.5mm, compared to 14.2mm prior to ASCT (p=0.435). Mean LV ejection fraction was 52.5% 6 months after diagnosis, compared to 55.3% prior to ASCT (p=0.478).Median overall survival has not been reached and 3 patients (13.6%) died (at 6, 11 and 26 months post ASCT) (Fig 1).One patient has yet to reach 3 month follow up. Number of patients in an FLC CR, VGPR, PR and no response on an evaluable basis at 3 months was as follows: 11 (52.4%), 5 (23.8%), 3 (14.3%) and 2 (9.5%). Haematologic response was assessed at 6 months post ASCT in 17 patients (5 have yet to reach 6 month follow up (data to be updated at the meeting) and 1 patient died at 6 months). The number of patients in an FLC CR, VGPR and PR at 6 months was as follows: 10/17 (58.8%), 3/17 (17.6%) and 4/17 (23.5%) respectively (Fig 2). Cardiac response at 6 months was assessed in 14 patients. Of the remainder, one had died and others are awaiting 6 month cardiac assessment. 10/14 (71.4%) were in a cardiac response 6 months post ASCT. Median NT-proBNP 6 months post ASCT was 595ng/L (189-2589 ng/L) (Fig 3).ConclusionThis study highlights the potential role of deferred ASCT in both a consolidation or relapse setting in selected patients with cardiac AL who have achieved organ responses. No TRM was observed and ASCT was associated with good haematologic and organ responses. Younger patients (<65 years) with AL should be considered for a stem cell sparing regime to potentially avail this treatment modality if clinically significant organ responses are achieved. Longer follow up and larger studies are needed to confirm these findings and assess durability of response. [Display omitted] DisclosuresHegenbart:Janssen: Honoraria, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prothena: Membership on an entity's Board of Directors or advisory committees. Yong:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Popat:Takeda: Honoraria, Other: Travel support for meetings; Amgen: Honoraria; Celgene: Honoraria, Other: Travel support for meetings; Janssen: Honoraria, Other: Travel support for meetings. Rabin:Janssen: Consultancy, Other: Travel support for meetings, Speakers Bureau; Takeda: Consultancy, Other: Travel support for meetings, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Schönland:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; prothena: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau. Wechalekar:Celgene: Honoraria; Janssen: Honoraria.

Change in N-terminal pro-B-type natriuretic peptide at 1 year predicts mortality in wild-type transthyretin amyloid cardiomyopathy

ObjectivesWild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is a progressive and fatal condition. Although prognosis can be determined at the time of diagnosis according to National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR)...

The Impact of Longitudinal Strain on Haematological and Cardiac Response and Survival in Patients with Systemic AL Amyloidosis

Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac involvement. Mayo stage I, II, IIIa and IIIb in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. Impairment of LS% correlated significantly with increasing Mayo stage (p&amp;lt;0.0001 between LS% for each Mayo stage). At 12 months, only patients with complete haematological responses (CR) had significant improvement in LS% (overall p=0.04; regional baso-lateral p=0.007, and baso-septal p=0.007). The median overall survival (OS) of the whole cohort was 61 months; survival of Mayo stage I and II patients was not reached whilst OS in Mayo stage IIIa and IIIb patients was 30 and 4 months respectively. Patients with cardiac involvement were stratified into 3 baseline LS% groups (≤17%; 10.3-16.9%; and ≥10.2%) with poor baseline LS% being associated with shorter OS (p&amp;lt;0.0001). These groups predicted survival independently of Mayo stage. OS was superior in patients who achieved a minimum absolute improvement in LS% of 1.5% when analysed at either 12 (not reached vs. 72 months, p=0.008) and 24 (not reached vs. 80 months, p&amp;lt;0.0001) months from diagnosis. Patients achieving a LS% response (1.5%) improvement survived longer than those achieving a traditional cardiac response alone or no cardiac response at both 12 and 24 months (p&amp;lt;0.0001). Conclusion: Longitudinal strain is an informative functional marker that is independent of Mayo staging in predicting outcomes in patients with cardiac AL amyloidosis which can be incorporated in prognostic staging for these patients. Improvement in LS% was observed in patients who achieved a CR, and a value of 1.5% was associated with superior outcomes over and above achieving a cardiac response by international consensus criteria. An absolute improvement in LS% should be considered a criterion for cardiac response in AL amyloidosis. Disclosures Wechalekar: Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria.

Global longitudinal strain predicts survival and response in patients with systemic AL amyloidosis. analysis of 915 patients from the ALchemy prospective trial

Abstract Background Cardiac involvement determines prognosis in systemic AL amyloidosis. The extent is assessed by biomarker-based staging systems. This a prospective report of a large cohort of patients assessing the utility of changes in longitudinal function by 2D strain (GLS%), impairment - a hallmark of amyloidosis. Purpose To evaluate the prognostic role of GLS% and other echocardiographic parameters in systemic AL amyloidosis. Methods 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010–August 2017) were included. All patients underwent 6-monthly comprehensive assessments inclusive of echocardiogram. The European modification of the Mayo 2004 staging was used with Mayo stage III patients stratified into IIIa (NT-proBNP &amp;lt;8500ng/L) and IIIb (NT-proBNP ≥8500ng/L). Results 653/915 (71.4%) patients had cardiac involvement. Mayo stage 1, 2, 3a and 3b in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. The median NT-proBNP was 2228ng/L and TNT was 0.54ng/ml. The GLS% significantly worsened with increasing Mayo stage (p&amp;lt;0.0001 between GLS% for each Mayo stage). Poorer baseline GLS% associated with significantly worse OS and stratified patients into three groups: GLS% &amp;lt;−12.8%: OS 69.1 months; GLS% −12.8% to −9%: OS 54.5 months; GLS% &amp;gt;−9%: OS 45.3 months (p&amp;lt;0.0001). On univariate analysis, 11/14 parameters predicted survival (LV wall thickness, LV ejection fraction, systolic velocities of the septal (s'sep) and lateral mitral annulus (s' lat), mitral annulus movement at the lateral corner (e' lat), transmitral early peak flow velocity (E) divided by tissue Doppler mitral annular motion velocity (e') – E/e' and mitral annular plane systolic excursion (MAPSE)). Baseline GLS% &amp;gt;−17% was independent of Mayo stage in predicting survival [Mayo II: Hazard ratio (HR) 2.10 (95% CI: 1.12–3.92) p=0.02, Mayo III: HR 3.94 (95% CI: 2.13–7.32) p&amp;lt;0.0001, Mayo IV: HR 7.49 (95% CI: 3.94–14.21) p&amp;lt;0.0001, GLS &amp;lt;17%: HR 2.14 (95% CI: 1.59–2.88) p&amp;lt;0.0001]. At 12 months, only patients in a haematological complete response (CR) had significant improvement in overall GLS% (p=0.02) as well as baso-lateral (p=0.0004) and baso-septal (p=0.0001) GLS% and MAPSE (p=0.002). The OS was significantly better in patients who achieved a minimum absolute improvement in GLS% of 1.5% improvement (not reached in those with improved GLS% vs. 72 mo in those without) (p=0.034)). Conclusion These data show that baseline GLS% is an independent predictor of survival in AL amyloidosis. GLS% is the first functional marker that is independent of the Mayo staging in predicting outcomes and should be incorporated in prognostic staging for patients with AL amyloidosis. GLS% shows improvement in patients who achieve a complete haematologic response to treatment and improvement in GLS% of 1.5% is associated with improved outcomes. An absolute improvement in GLS% should be considered as a criterion for cardiac response in AL amyloidosis. Funding Acknowledgement Type of funding source: None

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression

ObjectivesThe purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM). BackgroundAdministration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain. MethodsPatisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a “TTR-stabilizing” drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results. ResultsPatisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: −6.2% [95% confidence interval [CI]: −9.5% to −3.0%]; p = 0.001) accompanied by a fall in N-terminal pro–B-type natriuretic peptide concentrations (adjusted mean difference between groups: −1,342 ng/l [95% CI: −2,364 to −322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%). ConclusionsReductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.

Disease progression in cardiac transthyretin amyloidosis is indicated by serial calculation of National Amyloidosis Centre transthyretin amyloidosis stage.

AimsCardiac transthyretin amyloidosis (ATTR‐CM) is a progressive and fatal condition. Prognosis can be determined at diagnosis according to the National Amyloidosis Centre (NAC) transthyretin amyloidosis (ATTR) stage. We sought to examine how NAC ATTR stage changes during follow‐up and whether it maintains its prognostic value throughout the disease course.Methods and resultsWe performed a retrospective study of 945 patients with wild‐type ATTR‐CM (wtATTR‐CM) or hereditary ATTR‐CM associated with the V122I variant (V122I‐hATTR‐CM) who were diagnosed and serially evaluated at the UK NAC. Patients who commenced any disease‐modifying therapy for amyloidosis were censored at the time of doing so. Landmark Kaplan–Meier survival analyses were performed at diagnosis (n = 945) and at 6 ± 1 (n = 432), 12 ± 3 (n = 562), and 24 ± 3 (n = 316) months and stratified by recalculated NAC ATTR stage at the relevant time point. Cox regression analyses were performed to assess the prognostic significance during follow‐up of an increase in NAC ATTR stage from Stage I at diagnosis. Mortality in ATTR‐CM was predicted by NAC ATTR stage at each time point [Stage II vs. I, hazard ratios (HRs) 1.95–2.67; P < 0.001; Stage III vs. II, HRs 1.64–2.25; P < 0.001–0.013]. An increase from NAC ATTR Stage I, which occurred in 21%, 32%, and 44% of evaluable patients at 6, 12, and 24 months of follow‐up respectively, was highly predictive of ongoing mortality at each time point (HRs 2.58–3.22; P < 0.001) and in each genotypic subgroup (HRs 1.86–4.38; P < 0.05). Increase in NAC ATTR stage occurred earlier in V122I‐hATTR‐CM than in wtATTR‐CM (43% vs. 27% at 12 months of follow‐up; P = 0.003).ConclusionsNational Amyloidosis Centre ATTR stage predicts ongoing survival throughout the disease natural history in ATTR‐CM, and an increase from NAC ATTR Stage I at diagnosis to a higher NAC ATTR stage predicts mortality throughout follow‐up. Serial calculation of NAC ATTR stage suggests a more aggressive phenotype in V122I‐hATTR‐CM than in wtATTR‐CM.

The value of screening biopsies in light-chain (AL) and transthyretin (ATTR) amyloidosis.

Systemic amyloidosis is a histological diagnosis, often achieved via critical organ biopsy. Screening biopsies represent a low-risk approach to diagnosis. All patients with systemic AL and ATTR amyloidosis who underwent abdominal fat aspiration (AFA) and either a bone marrow (BM) or gastrointestinal (GI) biopsy at the UK National Amyloidosis Centre (2006-2019) were identified. We sought to determine diagnostic sensitivity in relation to whole body amyloid burden, amyloid type and organ involvement. Diagnostic sensitivity established in 471 patients with AL (n=321) and ATTR (n=150) amyloidosis, respectively, was 73.2% and 27.3% for AFA (P<.001), 59.7% and 42.2% for BM (P<.001), and 74.6% and 44.6% for GI biopsy (P<.001). ATTR amyloid deposits were detected in 35.4% BMs and 33.3% of GI biopsies when AFA did not demonstrate amyloid. In AL amyloidosis, sensitivity of combined AFA and BM biopsy in AL amyloidosis was 82.9%. There was a strong association between whole body amyloid burden and sensitivity of each screening biopsy method. The diagnostic sensitivity of screening biopsies ranged from 80.0% to 90.5% for patients with a large amyloid load on 123 I-SAP scintigraphy in comparison with 53.9%-79.0% in those with no visceral amyloid visible on imaging. Performing both AFA and BM biopsy should be considered in suspected AL amyloidosis to substantially reduce the clinical risk associated with critical organ biopsy. The sensitivity of screening biopsies in ATTR amyloidosis is poor.

Diagnostic amyloid proteomics: experience of the UK National Amyloidosis Centre.

Systemic amyloidosis is a serious disease which is caused when normal circulating proteins misfold and aggregate extracellularly as insoluble fibrillary deposits throughout the body. This commonly results in cardiac, renal and neurological damage. The tissue target, progression and outcome of the disease depends on the type of protein forming the fibril deposit, and its correct identification is central to determining therapy. Proteomics is now used routinely in our centre to type amyloid; over the past 7 years we have examined over 2000 clinical samples. Proteomics results are linked directly to our patient database using a simple algorithm to automatically highlight the most likely amyloidogenic protein. Whilst the approach has proved very successful, we have encountered a number of challenges, including poor sample recovery, limited enzymatic digestion, the presence of multiple amyloidogenic proteins and the identification of pathogenic variants. Our proteomics procedures and approaches to resolving difficult issues are outlined.

Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

Ixazomib, lenalidomide and dexamethasone in relapsed AL amyloidosis – a first report

Ixazomib is a next generation oral proteasome inhibitor with proven efficacy in relapsed AL amyloidosis. Whilst the combination of ixazomib, lenalidomide and dexamethasone (IRd) is established in multiple myeloma, its role in AL amyloidosis is undetermined. We present the UK experience of this regimen in the treatment of relapsed refractory AL amyloidosis. Method Forty patients treated with IRd, between 2016 and 2019, were identified from the database at the UK National Amyloidosis Centre. Haematological and disease responses were defined as per the international amyloidosis consensus guidelines.

A Novel Mass Spectrometry Method to Identify the Serum Monoclonal Light Chain Component and Infer Organ Involvement in Systemic Light Chain Amyloidosis

▪IntroductionLight chain (AL) amyloidosis is caused by progressive organ dysfunction due to the deposition of structurally abnormal monoclonal light chains (LC) as amyloid fibrils. Serial free light chain measurement is the cornerstone of AL diagnosis but is limited by current methods which measure normal polyclonal and abnormal monoclonal LCs. Since each individual monoclonal LC has a unique amino acid sequence, mass spectrometry (MS) has the ability to detect serum monoclonal LCs.We report a novel MS method for monoclonal LC detection in AL amyloidosis.MethodsTwenty patients with systemic AL amyloidosis, diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC), were randomly selected. This included 16 newly diagnosed patients, 2 patients in a complete haematological remission (CR) post-treatment and 2 patients with no amyloidosis (acting as negative controls). All patients had detailed baseline assessments of organ function and serum FLC measurements. Organ involvement was defined according to the international amyloidosis consensus criteria. Magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free k) and free lambda light chains (anti-free l). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute free light chains in monomeric form. Mass spectra were acquired on a Microflex LT/SH smart matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS; Bruker, GmbH).ResultsThe median number of organs involved was 2 (range 1-4); cardiac involvement was most common in 70% (14/20) patients, followed by renal 40% (8/20), autonomic and soft tissue in 15% (3/20) and peripheral nerve involvement in 5% (1/20). No patients had liver involvement. The median N-terminal pro b-type natriuretic peptide (NT-proBNP) and cardiac troponin T were 3761.5 (range 245-25348 ng/L) and 35.5 (8-170 ng/L) respectively. The median presenting serum albumin was 37 (19-45 g/L) and eGFR 62 (10-100 mls/min). The amyloid deposits were typed as AL lambda in 14(70%), kappa in 2(10%) patients and amyloid of uncertain type in two cases (10%). The median involved FLC was kappa 76 mg/L (range 71-440) and lambda 185 mg/L (44-1023), with difference involved to uninvolved (dFLC) 118 mg/L (33-1015). An intact monoclonal protein was present in 70% (14/20).In all cases, MS correctly identified the presence and type of monoclonal LC, identifying a monoclonal lambda in 14/14 (100%) and a monoclonal kappa in 2/2 (100%); the two patients where a clear monoclonal component could not be identified were patients whose amyloid fibrils failed to be typed by immunohistochemistry or MS. The assay also confirmed normal polyclonal expression of both kappa and lambda LCs in the two control samples. In the two lambda patients in a CR, the MS method identified monoclonal lambda LC expression; in one of these patients next-generation sequencing (NGS) confirmed minimal residual disease (MRD). A clear shift in the LC mass spectra was seen relating to the specific pattern of organ involvement: in patients with renal amyloid the monoclonal LC predominantly displayed a “heavy” molecular mass, (with a mean molecular mass of 11596+/- 436 daltons), whereas in patients with cardiac involvement the monoclonal LC mainly exhibited a “light” mass (with a mean molecular mass of 11443 +/- 102 daltons).ConclusionThis small study shows that monoclonal light chains can be accurately detected by MS and be concordant to the tissue amyloid type. A monoclonal LC was detected in 2 patients in serological “CR” - in one case presence of persistent disease was demonstrated by NGS-MRD. Even in this small sample size, there appears to be a marked difference in LC mass for patients with cardiac (“light” LC) vs. renal (“heavy” LC) involvement, raising the interesting possibility that “heavy” LC are trapped by the glomerulus causing renal AL but are unable to penetrate the tight cardiac capillary gap junctions, and vice versa. The unique molecular location of LC on MS offers the possibility of exploiting this technique as a tool to detect amyloidogenic FLC and potentially predict organ involvement in patients with gammopathies. We plan to expand this study to a large cohort of patients to confirm these findings and assess the impact on survival and organ response outcomes. [Display omitted] DisclosuresWechalekar:Janssen: Honoraria.

Real world outcomes of pomalidomide for treatment of relapsed light chain amyloidosis

Pomalidomide is a next-generation immunomodulatory agent with activity in relapsed light chain (AL) amyloidosis, but real world outcomes are lacking. We report the experience of the UK National Amyloidosis Centre. All patients with AL amyloidosis treated with pomalidomide between 2009 and 2017 were included. Data was collected on treatment toxicity and clonal response. Survival was calculated by the Kaplan-Meier method and outcomes reported on an intent-to-treat (ITT) basis. A total of 29 patients treated with pomalidomide were identified. Haematological responses at 3months were: complete response (CR) nil, very good partial response (VGPR) 10 (35%), partial response (PR) 9 (31%), stable or progressive disease 7 (24%), unevaluable 3 (10%). On an ITT basis (n=28), responses at 6months were: CR- nil, VGPR-11 (39%), PR-2 (7%) and the remaining patients were non-responders 15 (53%). Median overall survival was 27months (95% confidence interval 15·7-38·1months). Median progression free survival (PFS) was 15months (95% confidence interval 6·24-23·77). In conclusion, pomalidomide has activity in patients with relapsed AL amyloidosis. Responses are rapid and early responses may be predictive of a sustained overall response. Deep responses (VGPR or better) are seen in only a third of all patients and combination therapy needs to be explored.