Clinical and imaging characteristics of patients with cardiac amyloidosis- a single center observational study.

Amyloidosis is a disease characterized by the deposition of protein fibrils. Cardiac involvement is a significant factor in determining prognosis. This study aimed to examine the clinical profile, outcomes, and long-term mortality rates in patients with transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis. The retrospective cohort study included 94 patients with amyloidosis (69 with AL and 25 with ATTR amyloidosis) diagnosed between 2010 and 2022. The study involved multimodality imaging (ECG, echocardiography and cardiac magnetic resonance (CMR) data and survival analyses. Patients with ATTR amyloidosis were older and had a higher proportion of males compared to those with AL amyloidosis. Cardiac involvement was more prevalent in the ATTR group, including atrial fibrillation (AF), while pleural and pericardial effusion were more frequent in the AL group. Biomarkers such as NT-proBNP and troponin T were significantly elevated in both groups and were associated with all-cause mortality only in univariate analyses. CMR data, especially typical late gadolinium enhancement (LGE) was not associated with increased mortality, while pleural effusion and left atrial dilatation on echocardiography were identified as powerful predictors of mortality. In conclusion, both AL and ATTR amyloidosis exhibited poor outcomes. Cardiac involvement, particularly dilated left atrium and pleural effusion on echocardiography were associated with an increased risk of mortality, while typical LGE on CMR was not.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

AIMS: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. METHODS AND RESULTS: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 µmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 µmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. CONCLUSIONS: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

A new staging system using right atrial strain in patients with immunoglobulin light-chain cardiac amyloidosis.

AIMS: There are minimal data on the prognostic impact of right atrial strain during the reservoir phase (RASr) in patients with immunoglobulin light-chain (AL) cardiac amyloidosis. METHODS AND RESULTS: Among 78 patients who were diagnosed with AL cardiac amyloidosis at Kumamoto University Hospital from 2007 to 2022, 72 patients with sufficient two-dimensional speckle tracking imaging data without chemotherapy before the diagnosis were retrospectively analysed. During a median follow-up of 403 days, 31 deaths occurred. Age and the rate of male sex were not significantly different between the all-cause death group and the survival group (age, 70.4 ± 8.8 years vs. 67.0 ± 10.0 years, P = 0.14, male sex, 65% vs. 66%, P = 0.91). The estimated glomerular filtration rate (eGFR) was significantly lower, and B-type natriuretic peptide (BNP) and high sensitivity cardiac troponin T (hs-cTnT) were significantly higher, in the all-cause death group versus the survival group (eGFR, 48.2 ± 21.0 mL/min/1.73 m2 vs. 59.4 ± 24.4 mL/min/1.73 m2, P < 0.05, BNP, 725 [360-1312] pg/mL vs. 123 [81-310] pg/mL, P < 0.01, hs-cTnT, 0.12 [0.07-0.18] ng/mL vs. 0.05 [0.03-0.08] ng/mL, P < 0.01). Left ventricular (LV) global longitudinal strain (GLS) (LV-GLS), left atrial strain during the reservoir phase (LASr), right ventricular GLS (RV-GLS), and RASr were significantly lower in the all-cause death group versus the survival group (LV-GLS, 8.5 ± 4.3% vs. 11.8 ± 3.8%, P < 0.01, LASr, 8.8 ± 7.1% vs. 14.3 ± 8.1%, P < 0.01, RV-GLS, 11.6 ± 5.1% vs. 16.4 ± 3.9%, P < 0.01, RASr, 10.2 ± 7.3% vs. 20.7 ± 9.5%, P < 0.01). RASr was significantly associated with all-cause death after adjusting for RV-GLS, LV-GLS and LASr (hazard ratio [HR]: 0.91, 95% confidence interval [95% CI]: 0.83-0.99, P < 0.05). RASr and log-transformed BNP were significantly associated with all-cause death after adjusting for log-transformed troponin T and eGFR (RASr, HR: 0.93, 95% CI: 0.87-1.00, P < 0.05; log-transformed BNP, HR: 2.10, 95% CI: 1.17-3.79, P < 0.05). The optimal cut-off values were RASr: 16.4% (sensitivity: 66%, specificity: 84%, area under curve [AUC]: 0.81) and BNP: 311.2 pg/mL (sensitivity: 83%, specificity: 78%, AUC: 0.82) to predict all-cause mortality using ROC analysis. Kaplan-Meier analysis revealed that patients with low RASr (<16.4%) or high BNP (>311.2 pg/mL) had a significantly high probability of all-cause death (both, P < 0.01). We devised a new staging score by adding 1 point if RASr decreased or BNP levels increased more than each cut-off value. The HR for all-cause death using score 0 as a reference was 5.95 (95% CI: 1.19-29.79; P < 0.05) for score 1 and 23.29 (95% CI: 5.37-100.98; P < 0.01) for score 2. CONCLUSIONS: The new staging system using RASr and BNP predicted prognosis in patients with AL cardiac amyloidosis.

Thrombotic and bleeding complications in patients with AL amyloidosis.

Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55-month median follow-up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD-based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24-h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow-up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti-thrombotic or anti-platelet therapy appropriately.

Left ventricular myocardial work improves in response to treatment and is associated with survival among patients with light chain cardiac amyloidosis.

AIMS: Complete haematologic response to treatment for light chain cardiac amyloidosis (AL-CA) may lead to improvement of myocardial function and better outcomes. We sought to evaluate the effect of response to treatment for AL-CA on echocardiographic indices of myocardial deformation and work and their prognostic significance. METHODS AND RESULTS: Sixty-one patients treated for AL were enrolled and underwent echocardiographic assessment at baseline and at 1 year. Patients were stratified according to haematologic response as complete or not complete responders. A significant reduction in median N-terminal pro-brain natriuretic peptide (NT-proBNP) (2771-1486 pg/mL; P < 0.001) and posterior wall thickness (13-12 mm; P = 0.002) and an increase in global work index (GWI) (1115-1356 mmHg%; P = 0.018) was observed at 1 year. Patients with complete response (CR) had a more pronounced decrease in intraventricular septum thickness (14.2-12.0 mm; P = 0.006), improved global longitudinal strain (GLS) (-11.6 to -13.1%; P for interaction = 0.045), increased global constructive work (1245-1436 mmHg%; P = 0.008), and GWI (926-1250 mmHg%, P = 0.002) compared with non-CR. Furthermore, deltaGLS (ρspearman = 0.35; P < 0.001) and deltaGWI (ρspearman = -0.32; P = 0.02) correlated with delta NT-proBNP. Importantly, patients with GLS and GWI response had a better prognosis (log-rank P = 0.048 and log-rank P = 0.007, respectively). After adjustment for Mayo stage, gender, and response status, deltaGLS [hazard ratio (HR) = 1.404, P = 0.046 per 1% increase] and deltaGWI (HR = 0.996, P = 0.042 per 1mmHg% increase) were independent predictors of survival. CONCLUSION: Complete haematologic response to treatment is associated with improved left ventricular myocardial work indices, and their change is associated with improved survival in AL-CA.

A real-world study on diagnosis and prognosis of light-chain cardiac amyloidosis in Southern China.

BACKGROUND: Light-chain cardiac amyloidosis (AL-CA) has been highly valued in developed countries, but in developing countries, the recognition and diagnosis of this condition is still limited. There are currently few reports on a large number of Chinese patients with AL-CA. The present study aimed to report real-world clinical characteristics and prognosis of AL-CA in China. METHODS AND RESULTS: Consecutive patients with AL-CA diagnosed at the Second Xiangya Hospital of Central South University between June 2012 and September 2020 were reviewed. A total of 170 patients with AL-CA have been recruited, whose mean ages were 60.81 ± 10.46. 70.59% of the patients were male. They were from eight provinces in southern China, 55.7% were referred patients, and 37.3% had been misdiagnosed previously. 64 (37.6%) patients received chemotherapy. The median survival time for patients with AL-CA was 8.00 months, and survival time for patients who received chemotherapy was 13.00 months, which was significantly longer than that of patients with palliative treatment (13.00 vs 6.00, p = 0.004). CONCLUSIONS: Although clinicians have improved their understanding of AL-CA in recent years, the prognosis of AL-CA is still poor, and the misdiagnosis rate and missed diagnosis rate are still very high in China. It is imperative to improve the recognition and early diagnosis of this condition, which may require multidisciplinary collaboration among cardiologists, hematologists and nephrologists.

Dexamethasone is associated with early deaths in light chain amyloidosis patients with severe cardiac involvement.

BACKGROUND: Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib (Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment. METHODS AND FINDINGS: We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p<0.05), supporting a potential negative inotropic effect of dexamethasone in AL-CA patients with severe cardiac involvement. CONCLUSION: Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation.

Marked progress in AL amyloidosis survival: a 40-year longitudinal natural history study.

The recent decades have ushered in considerable advancements in the diagnosis and treatment of systemic light chain (AL) amyloidosis. As disease outcomes improve, AL amyloidosis-unrelated factors may impact mortality. In this study, we evaluated survival trends and primary causes of death among 2337 individuals with AL amyloidosis referred to the Boston University Amyloidosis Center. Outcomes were analyzed according to date of diagnosis: 1980-1989 (era 1), 1990-1999 (era 2), 2000-2009 (era 3), and 2010-2019 (era 4). Overall survival increased steadily with median values of 1.4, 2.6, 3.3, and 4.6 years for eras 1-4, respectively (P < 0.001). Six-month mortality decreased over time from 23% to 13%. Wide gaps in survival persisted amid patient subgroups; those with age at diagnosis ≥70 years had marginal improvements over time. Most deaths were attributable to disease-related factors, with cardiac failure (32%) and sudden unexpected death (23%) being the leading causes. AL amyloidosis-unrelated mortality increased across eras (from 3% to 16% of deaths) and with longer-term survival (29% of deaths occurring >10 years after diagnosis). Under changing standards of care, survival improved and early mortality declined over the last 40 years. These findings support a more optimistic outlook for patients with AL amyloidosis.

Lenalidomide and dexamethasone in relapsed/refractory immunoglobulin light chain (AL) amyloidosis: results from a large cohort of patients with long follow-up.

Lenalidomide and dexamethasone (RD) is a standard treatment in relapsed/refractory immunoglobulin light chain (AL) amyloidosis (RRAL). We retrospectively investigated toxicity, efficacy and prognostic markers in 260 patients with RRAL. Patients received a median of two prior treatment lines (68% had been bortezomib-refractory; 33% had received high-dose melphalan). The median treatment duration was four cycles. The 3-month haematological response rate was 31% [very good haematological response (VGHR) in 18%]. The median follow-up was 56·5 months and the median overall survival (OS) and haematological event-free survival (haemEFS) were 32 and 9 months. The 2-year dialysis rate was 15%. VGHR resulted in better OS (62 vs. 26 months, P < 0·001). Cardiac progression predicted worse survival (22 vs. 40 months, P = 0·027), although N-terminal prohormone of brain natriuretic peptide (NT-proBNP) increase was frequently observed. Multivariable analysis identified these prognostic factors: NT-proBNP for OS [hazard ratio (HR) 1·71; P < 0·001]; gain 1q21 for haemEFS (HR 1·68, P = 0·014), with a trend for OS (HR 1·47, P = 0·084); difference between involved and uninvolved free light chains (dFLC) and light chain isotype for OS (HR 2·22, P < 0·001; HR 1·62, P = 0·016) and haemEFS (HR 1·88, P < 0·001; HR 1·59, P = 0·008). Estimated glomerular filtration rate (HR 0·71, P = 0·004) and 24-h proteinuria (HR 1·10, P = 0·004) were prognostic for renal survival. In conclusion, clonal and organ biomarkers at baseline identify patients with favourable outcome, while VGHR and cardiac progression define prognosis during RD treatment.

The Role of Autologous Stem Cell Transplantation in Amyloidosis.

Autologous stem cell transplantation (ASCT) has been an essential part of the treatment armamentarium in light chain (AL) amyloidosis for several decades. Patients who achieve a complete hematologic response following ASCT have a long overall survival. However, only 1 randomized controlled trial compared ASCT with the standard of care used at the time, which was melphalan and dexamethasone, and the results did not support the use of ASCT in AL amyloidosis. These results are of limited significance due to the unexpected high transplant-related mortality (TRM) (24%). TRM is a major concern in AL amyloidosis, but its incidence can be lessened by better patient selection and by patients receiving ASCT in specialized centers. ASCT in AL amyloidosis is performed only in selected patients; approximately 20% of patients with AL amyloidosis are transplant eligible up front or after bortezomib (Velcade) based conditioning. The introduction of newer agents such as bortezomib and daratumumab (Darzalex), which lead to deep responses and have good safety profiles, encourage revisiting the benefit and timing of ASCT in the modern era. This review provides a comprehensive assessment of eligibility criteria for ASCT in AL amyloidosis, conditioning dosing, efficacy in terms of hematologic and organ response, and future areas of research.

Evolving Role of Autologous Stem Cell Transplantation for Light Chain Amyloidosis in the Modern Era.

Muhamed Baljevic, MD, considers the role of autologous stem cell transplantation for light chain amyloidosis in a peer perspective accompanying an article by Iuliana Vaxman, MD, and Angela Dispenzieri, MD.

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib.

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p < 0.005). At 1-month, patients with CR and iFLC < 20 mg/l had a significantly better survival compared to CR and iFLC > 20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement.

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis.

BACKGROUND: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODS: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTS: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONS: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).

Impact of time to diagnosis on Mayo stages, treatment outcome, and survival in patients with AL amyloidosis and cardiac involvement.

OBJECTIVE: To study the impact of time to diagnosis on cardiac Mayo stages, treatment outcome, and overall survival. METHODS: We retrospectively analyzed 77 consecutive patients diagnosed between 2015 and 2020 with AL amyloidosis and cardiac involvement. Medical history was recorded in standardized form with the help of a questionnaire. RESULTS: Time from onset of symptoms of cardiac failure to diagnosis was correlated with the severity of cardiac involvement in modified Mayo 2004 and revised Mayo 2012 staging systems (rs  = 0.30, 95% CI: 0.07-0.50, P = .007 and rs  = 0.25, 95% CI: 0.01-0.45, P = .03). Patients with advanced Mayo 2004 stages received reduced-intensity regimens and had a lower probability to achieve adequate hematologic- and cardiac response after first-line treatment than patients with early stages (rs  = 0.28, 95% CI: 0.04-0.48, P = .01 and rs  = 0.72, 95% CI: 0.55-0.82, P < .0001) and poorer overall survival (P = .0004). Compared with patients diagnosed within the first year, patients diagnosed after 13-18 or ≥19 months from first symptoms had a 3- to 5 times higher risk of dying. Our data indicate that there is a 12-month window within which the diagnosis of AL amyloidosis needs to be established to avoid early deterioration and death. CONCLUSIONS: Sensitizing physicians and raising awareness for the disease are crucial for timely diagnosis and may improve the outcome of the disease.