Giulia Zumbo

New and developing therapies for AL amyloidosis

ABSTRACT Introduction: Systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extracellular space. Symptoms and prognosis are governed by which organs are affected, and cardiac involvement is the major determinant of survival. Diagnosis requires demonstration of amyloid deposition and confirmation of the fibril protein type. Areas covered: This review will focus on the available treatments for systemic AL amyloidosis and on new drug targets and therapeutic approaches. Expert opinion: At present, the choice of upfront treatment lies between autologous stem cell transplantation (ASCT) and combination chemotherapy. Chemotherapy agents include dexamethasone, melphalan, cyclophosphamide, thalidomide, bortezomib, lenalidomide, bendamustine in various combinations. Few randomized controlled trials have been performed in AL amyloidosis and treatment has been substantially influenced by clinical practice in myeloma. It has become clear that the best prospects of survival and preservation or improvement in amyloid related organ function require as near complete suppression as possible of the underlying hematological disorder. Future directions include therapies designed to target amyloid deposits directly, in particular anti-amyloid antibodies which are now well advanced in development and are showing great potential.

CMR-Verified Regression of Cardiac AL Amyloid After Chemotherapy

Systemic light-chain (AL) amyloidosis is characterized by interstitial deposition of aggregated misfolded monoclonal immunoglobulin light chains in the form of amyloid fibrils. Cardiac involvement is the main driver of prognosis. Brain natriuretic peptides and echocardiography are currently the

Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time: Extracellular Volume in Amyloidosis

Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus‐only ECV). For large ECV, the bolus‐only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis.

024 Spectrum and significance of CMR findings in cardiac transthyretin amyloidosis

Background Cardiac transthyretin amyloidosis (ATTR amyloidosis) is an increasingly recognised cause of heart failure. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and T1 mapping is emerging as a reference standard for diagnosis and characterisation of cardiac amyloid. Objectives We used CMR with extracellular volume fraction (ECV) measurement to characterise cardiac involvement in relation to outcome in ATTR amyloidosis. Methods Subjects comprised 263 patients with cardiac ATTR amyloidosis corroborated by grade 2–3 99mTc-DPD cardiac uptake, 17 with suspected cardiac ATTR amyloidosis (grade 1 99mTc-DPD) and 12 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations. Fifty patients with cardiac AL amyloidosis acted as disease controls. Results In contrast to AL amyloidosis, asymmetric septal hypertrophy was present in 79% of ATTR patients (70% sigmoid septum and 30% reverse septal curvature), whilst symmetric left ventricular hypertrophy (LVH) was present in only 18%; 3% of patients has no LVH. In patients with cardiac amyloidosis, the pattern of LGE was always typical for amyloidosis (29% subendocardial, 71% transmural) including right ventricular LGE (96%). 65 patients died during follow-up (19±14 months). ECV independently correlated with mortality and remained independent after adjustment for age, N-terminal pro-brain natriuretic peptide, ejection fraction, E/E’ and left ventricular mass index (hazard ratio, 1.164; 95% confidence interval, 1.066–1.271; p<0.01). Conclusions Asymmetric hypertrophy, traditionally associated with hypertrophic cardiomyopathy, is the commonest pattern of ventricular remodelling in ATTR amyloidosis. LGE imaging is typical in all patients with cardiac ATTR amyloidosis. ECV correlates with amyloid burden and provides incremental information on outcome even after adjustment for known prognostic factors. Abstract 024 Figure 1 Left: four-chamber SSEP cine image in diastole and corresponding late gadolinium enhancement (LGE) images of four patients; asymmetric hypertropy with sigmoid septal contour and transmural LGE (top); asymmetric hypertrophy with reverse septal contour and transmural LGE (second from top); symmetric hypertrophy pattern and transmural LGE (third from top); eft ventricular hypertrophy and subendocardial LGE (bottom). Right top; Kaplan-Meier curve for ECV. Right bottom: four-chamber SSFP cine image in diastole and corresponding LGE images, native T1 maps and ECV maps of there patients, showing no LGE (top), subendocardial LGE (middle) and transmural LGE (bottom).

028 Routine identification of hypoperfusion in cardiac amyloidosis by myocardial blood flow mapping

Background Cardiac involvement is the main driver of outcome in systemic amyloidosis, but the relationship between amyloid deposits and cellular injury is not well understood. The simple explanation of physical, mechanical replacement of parenchymal tissue seems insufficient, and preliminary studies support the hypothesis that myocardial hypoperfusion could contribute to cell damage in amyloidosis. The aim of this study was: 1) To assess feasibility of fully automated pixel-wise rest myocardial blood flow (MBF) mapping in cardiac amyloidosis during routine clinical scans; 2) To assess the prevalence of myocardial hypoperfusion and correlation with amyloid deposits and disease severity. Methods Patients (n=56) with systemic amyloidosis and healthy volunteers (n=16) were recruited. All subjects underwent CMR at 1.5T (Siemens) with standard SSFP cine imaging, Phase Sensitive Inversion Recovery Reconstruction Late Gadolinium Enhancement (PSIR-LGE), T1 mapping, Extracellular Volume (ECV) mapping and rest MBF mapping. Results The pixel-wise MBF maps for all slices were generated automatically in all patients within 2.5 min after image acquisition. Myocardial perfusion was globally reduced in patients with cardiac amyloidosis compared to healthy volunteers (0.66±0.26 ml/min/g vs 0.84±0.19 ml/min/g, p<0.05). Myocardial perfusion inversely correlated with amyloid burden measured as extracellular volume fraction (r=−0.46, p<0.001) (figure 1) and with the transmurality of LGE (no LGE 0.88±0.18 ml/min/g, subendocardial LGE 0.73±0.28 ml/min/g and transmural LGE 0.58±0.20 ml/min/g, p<0.01) (figure 2). There was a correlation between myocardial perfusion and markers of systolic dysfunction (EF, r=0.39, p<0.01) as well as blood biomarkers (NT-proBNP, r=−0.41, p<0.01 and Troponin T, r=−0.41, p<0.01), current reference prognostic markers in cardiac amyloidosis. There was no significant correlation between myocardial perfusion and native T1 values (r=−0.07, p=0.59). Conclusions Myocardial perfusion can be measured in cardiac amyloidosis during routine clinical scans with fully automated MBF mapping. Myocardial hypoperfusion at rest is highly prevalent in subjects with cardiac amyloidosis, and correlates with the degree of amyloid infiltration and disease severity.

008 Demonstration of cardiac AL amyloidosis regression after succesful chemotherapy. a CMR study

Background Cardiac involvement in immunoglobulin light chain (AL) amyloidosis is the major determinant of survival; Cardiac response to chemotherapy is conventionally assessed by serum brain natriuretic peptide (NT-proBNP) and echocardiography, but neither quantify amyloid burden. The aim of this study was to evaluate cardiac AL amyloid serially using cardiovascular MR (CMR) including extracellular volume measurement (ECV), which is the site of the amyloid deposits. Methods 31 patients with cardiac AL amyloidosis who had chemotherapy were studied serially using ECG, echocardiography, 123I-labelled serum amyloid P component (SAP) scintigraphy, NT-proBNP measurements and CMR with T1 mapping and ECV measurements (mean interval 20±11 months). Nineteen patients achieved a complete or very good partial haematological response (CR n=10; VGPR n=9). Twelve patients attained a partial response (PR) or no response (NR). Results At follow-up (mean 20±11 months), the amyloid burden had decreased substantially in 6 of the 10 (60%) attaining a CR, 6 of the 9 (67%) in VGPR and 1 of the 8 (13%) in PR. Changes in the ECV consistent with regression of amyloid were concordant with the changes in native T1, reduction in amyloid volume and in 5 patients with changes in late gadolinium enhancement pattern (figure 1). Overall there was significant reduction in NT-proBNP concentration, LV mass, left atrial area and improvement in diastolic function in patients whose amyloid burden decreased. Regression of cardiac amyloid by CMR correlated with regression of amyloid in other organs measured by SAP scintigraphy. Abstract 008 Figure 1 Top: four chamber SSFP cine images in disatole, corresponding late gadalinium anhancement (LGE) images and ECV mapping before and after chemotherapy in a patient who had regression of amyloid burden after chemotherapy. Bottom: four chamber SSFP cine images in disatole, corresponding LGE images and ECV mapping before and after chemotherapy in a patient who had progression of amyloid burden after chemotherapy.