David Lavergne

Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naive patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III)

Bortezomib is an active agent in AL amyloidosis and responses to this drug in combination with cyclophosphamide and dexamethasone are both rapid and deep. Here we present an international, multicenter series of 60 patients with Mayo Clinic stage III cardiac amyloidosis to assess the impact of this regimen in improving outcomes in this poor-risk group. The median follow-up for the entire cohort is 11.8 months. The overall response rate was 68%. In a landmark analysis, examining patients who survived more than 3 months, the overall response rate was 86%. A cardiac response was seen in 32% of patients. The estimated 1-year survival rate for the whole cohort was 57% and 24 patients (40%) died while on therapy. Although unable to save the poorest risk patients, the combination of bortezomib, cyclophosphamide and dexamethasone can achieve a high number of hematologic and cardiac responses, likely improving overall survival and justifying a prospective trial.

Left atrial size is an independent predictor of overall survival in patients with primary systemic amyloidosis.

BACKGROUND Primary systemic amyloidosis is a severe plasma cell disorder characterized by the extracellular deposition of amyloid fibrils in different organs. Echocardiography is usually performed to assess cardiac involvement. We hypothesized that in patients with systemic amyloidosis, simple echocardiographic measurement of the left atrial (LA) diameter indexed to the body surface area might provide an important risk marker for this disease. METHODS Between 1997 and 2011, 134 patients were diagnosed with primary systemic amyloidosis and had echocardiography within 28 days; we collected their baseline characteristics and biological and echocardiographic data retrospectively. LA enlargement was defined as recommended as M-mode LA diameter greater or equal to 23 mm/m(2). RESULTS One hundred and eleven patients (83%) had echocardiographic LA dimension data available (mean age 63±11 years; 61% men; 31% previously diagnosed with systemic hypertension). Mean left ventricular ejection fraction (LVEF) and interventricular septum thickness (IVST) were 62±12% and 14±4 mm, respectively. Mean follow-up was 2.8±2.9 years (maximum 12 years). Patients with LA enlargement had a slightly lower LVEF (P=0.08) and a significantly greater IVST (P<0.0001). Overall, 5-year survival was 57±5%. However, 1-year and 5-year survival rates were markedly reduced in patients with LA enlargement versus those without LA enlargement (61±7% and 39±8% vs 83±5% and 72±7%, respectively; P=0.0007). On multivariable analysis, after adjusting for age, sex, LVEF, IVST, presence of hypertension and creatinine concentration, LA enlargement remained an independent predictor of overall mortality at 5 years (hazard ratio 2.47; 95% confidence interval 1.11-5.90; P=0.02). CONCLUSION LA enlargement, a surrogate marker of diastolic dysfunction, is an independent predictor of long-term mortality and may therefore help to enhance risk stratification and management of patients presenting with amyloidosis.

Circulating free light chain measurement in the diagnosis, prognostic assessment and evaluation of response of AL amyloidosis: comparison of Freelite and N latex FLC assays

Abstract Background: The measurement of circulating free light chain (FLC) is essential in the diagnosis, prognostic stratification and evaluation of response to therapy in light chain (AL) amyloidosis. For more than 10 years, this has been done with an immunonephelometric assay based on polyclonal antibodies (Freelite), and cutoffs for staging and response assessment have been validated with this method. Recently, a new assay based on monoclonal antibodies (N latex FLC) has been marketed in Europe. Methods: We evaluated and compared the clinical performance of the two assays in 426 patients with newly diagnosed AL amyloidosis. Results: We found suboptimal agreement between the two methods, with differences between values obtained with the Freelite and N latex FLC assays increasing with the concentration of clonal FLC. The diagnostic sensitivity of the Freelite (82%) and N latex FLC (84%) assays was similar, and both improved to 98% in combination with serum and urine immunofixation. The concentration of FLC measured with both methods had prognostic significance. Less pronounced decreases in FLC best predicted improved survival with the N latex FLC assay (33% vs. 50%), and there was poor concordance (84%) in discrimination of responders. Conclusions: The two assays have similar diagnostic and prognostic performance. However, they are not interchangeable, and follow-up should be done with either one. New response criteria are needed for the N latex FLC assay.

Identification of prognostic markers in transthyretin and AL cardiac amyloidosis

Abstract Background: The prognosis of amyloidosis is known to depend heavily on cardiac function and may be improved by identifying patients at highest risk for adverse cardiac events. Aims: Identify predictors of mortality in patients with cardiac light-chain amyloidosis (AL), hereditary transthyretin amyloidosis (m-TTR), or wild-type transthyretin amyloidosis (WT-TTR) to prompt physician to refer these patients to dedicated centers. Methods and results: Observational study. About 266 patients referred for suspected cardiac amyloidosis (CA) in two French university centers were included. About 198 patients had CA (AL = 118, m-TTR = 57, and WT-TTR = 23). Their median (25th–75th percentile) age, NT-proBNP left ventricular ejection fraction were, respectively, 68 years (59–76), 2339 pg mL−1 (424–5974), and 60% (48–66). About 31% were in NYHA class III–IV. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (p < 0.0001). Median follow-up in survivor was 26 months (15–44) and 87 (44%) patients died. By multivariate analysis, independent predictors of mortality for AL amyloidosis were the following: age, cardiac output and NT-proBNP; for TTR amyloidosis was: NT-proBNP. When all amyloidosis were combined NT-proBNP, low cardiac output and pericardial effusion were independently associated with mortality. Conclusion: NT-proBNP is a strong prognosticator in the three types of cardiac amyloidosis. High NT-proBNP, low cardiac output, and pericardial effusion at the time of screening should prompt physician to refer the patients to amyloidosis referral center.

Comparison and identification of early clinical, biological and echocardiographic prognostic markers in cardiac amyloidosis

Results NYHA class was III-IV in 31% of patients. Median (25th75th percentile) values were 69 (60-76) years for age, 3027 (673-7155) pg•mL-1 for NT-proBNP, and 60% (48-66) for left ventricular ejection fraction. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (P<0.0001). NTproBNP correlated with IVST (R=0.34; P=0.0001). The 6-month mortality rate was 24% (42 patients). The AL group had higher values for both NT-proBNP (P=0.0001) and 6-month mortality (P=0.0001). By multivariate analysis, independent predictors of 6-month mortality were higher NT-proBNP (Q4), NYHA class (III-IV), lower cardiac output (<4 L.min-1), and pericardial effusion.

Left atrial function in patients with light chain amyloidosis: A transthoracic 3D speckle tracking imaging study ☆ ☆☆

BACKGROUND Systemic light chain amyloidosis (AL) is characterized by the extracellular deposition of amyloid fibrils. Transthoracic echocardiography is the modality of choice to assess cardiac function in patients with AL. Whereas left ventricular (LV) function has been well studied in this patient population, data regarding the value of left atrial (LA) function in AL patients are lacking. In this study, we aim to examine the impact of LA volumes and function on survival in AL patients as assessed by real-time 3D echocardiography. METHODS A total of 77 patients (67±10 years, 60% men) with confirmed AL and 39 healthy controls were included. All standard 2D echocardiographic and 3D-LA parameters were obtained. RESULTS Fourteen patients (18%) were in Mayo Clinic (MC) stage I, 30 (39%) in stage II, and 33 (43%) in stage III at initial evaluation. There was no significant difference among the MC stages groups in terms of age, gender, or cardiovascular risk factors. As compared to patients in MC II and MC I, those in MC III had significantly larger indexed 3D-LA volumes (MCIII: 46±15mL/m2, MC II: 38±12mL/m2, and MC I: 23±9mL/m2, p<0.0001), lower 3D-LA total emptying fraction (3D-tLAEF) (21±13% vs. 31±15% vs. 43±7%, respectively, p<0.0001), and worse 3D peak atrial longitudinal strain (3D-PALS) (11±9% vs. 18±13% vs. 20±7%, respectively, p=0.007). Two-year survival was significantly lower in patients with 3D-tLAEF <+34% (p=0.003) and in those with 3D-PALS <+14% (p=0.034). Both parameters provided incremental prognostic value over maximal LA volume in multivariate analysis. CONCLUSION Functional LA parameters are progressively altered in AL patients according to the MC stage. A decrease in 3D-PALS is associated with worse outcome, independently of LA volume.

Hepatocyte growth factor measurement in AL amyloidosis

Abstract Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95–max: 200.4] versus 1.4 ng/mL [min: 0.82–max: 6.2] (p < 0.0001). The threshold value of 2.2 ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies.

Effectiveness of second-line treatment in AL amyloidosis patient's refractory to M-Dex.

Oral melphalan and dexamethasone (MDex) is now widely considered to be the standard conventional treatment for patients with AL amyloidosis. With M-Dex median survival is around 5 years but survival of non-responders is poor in the absence of rescue treatment. We examined whether utilization of new drugs in non-responders to M-Dex is associated with an improved survival. We included 32 patients who received, as salvage therapy, thalidomide (n1⁄4 5), lenalidomide (n1⁄4 7), or bortezomib (n1⁄4 20). Hematological response occurred in 71%, with 34% complete response (CR). Partial response was obtained in 4/5 patients with thalidomide and 2/7 with lenalidomide; 17/20 patients (85%) in the bortezomib group responded with 11 CR (55%). With a median follow-up of 21 months, 23 patients (72%) are alive. Introduction of new drugs in refractory patients to MDex gives a high level of response leading to a better survival. Bortezomib seems to be particularly attractive with response rate of 85%, and 55% CR. Introduction: Since the randomized trial published in 2007 [1] comparing intensive treatment with stem cell support (melphalan 140 or 200 mg/m depending on age and clinical status supported with autologous stem cell transplant (ASCT) collected with granulocyte colony-stimulating factor (G-CSF) alone) and the oral regimen melphalan and dexamethasone (MDex) (melphalan 10 mg/m and dexamethasone 40 mg for 4 days each months, up to 18 months), M-Dex is our reference front-line therapy in patients with AL whatever be the risk group. With M-Dex, median survival is longer than with MP (melphalan and prednisone), being around 5 years, in our study as well as in the Italian series [2]. Patients with hematologic response (at least 50% drop in the monoclonal protein) after M-Dex have a very good median survival but survival was very poor for refractory patients in our study. The 12 nonresponder patients in the M-Dex arm (patients who received at least three cycles of M-Dex and had a measurable disease) had a median survival of only 6 months (Figure 1), in the absence of valuable rescue treatment between 2000 and 2005. The new drugs used in myeloma, thalidomide, lenalidomide, and bortezomib have been reported to be effective in patients with AL amyloidosis [3–8]. We examined whether utilization of these drugs in patients refractory to M-Dex has translated into improved outcome. Method: We performed a retrospective multicentric study in 11 centers belonging to the French network for AL amyloidosis. Patients with AL amyloidosis, treated front line with M-Dex, since June 2006 were included if they were considered as refractory by their referent physician and had received, as salvage treatment, thalidomide, lenalidomide, or bortezomib, associated to sequential dexamethasone and/or alkylating agents. We recorded the hematological response, monitored by the free light chain (FLC) assay, with second-line treatment. All patients but one enrolled in this study had measurable disease, only one patient had a monoclonal light chain level below 30 mg/l with an abnormal serum-free light chain ratio, he was considered as non-responder after the second-line treatment and normalized the ratio after third-line treatment with bortezomib and dexamethasone. Survival was analyzed from the first day Figure 1. Randomized trial (high-dose melphalan versus melphalan plus dexamethasone), 2000–2005 [1]. Survival according to the hematologic response in the 38 patients in the M-Dex arm who could be evaluated. Blue curve: patients with at least a 50% response. Red curve: patients with less than a 50% response, median survival: 6 months. 145

Comparison of echocardiographic parameters in Fabry cardiomyopathy and light-chain cardiac amyloidosis

Fabry cardiomyopathy (FC) and light‐chain amyloid cardiomyopathy (AL) present with concentric left ventricular (LV) hypertrophy/remodeling and diastolic rather than systolic dysfunction. Direct comparisons are difficult due to rarity and confounded by variability of LV thickness.

0224: Prevalence and prognostic significance of left-sided valvular thickening in patients with systemic light-chain amyloidosis

Background Cardiac involvement is frequent in systemic light chain amyloidosis (AL). Left-sided valvular thickening (LVT) have been described in AL reflecting heavy infiltration of the valvular endocardium by amyloid proteins. However, the exact prevalence at diagnosis and the prognostic significance of LVT in AL patients have never been investigated. Aims to study the prevalence and the impact on long-term survival LVT in AL patients. Methods and results Between 1998 and 2013, 150 AL patients were included at diagnosis (mean age was 68±11 ans, 59% were male). A comprehensive transthoracic echocardiography was performed at baseline. The presence of LVT was assessed visually and was found in 42% of patients. Compared to patients without LVT, those with LVT have more frequently advanced NYHA functional class. They also had significantly higher left ventricular (LV) wall thickening (p=0.01), LV mass (p=0.02), and mitral E/e’ (p=0.0009) and larger left atrial size (p Conclusion The presence of LVT is a common finding in patients with AL and is associated with impaired both LV systolic and diastolic function, poorer functional status and advanced stage of the disease. In addition, LVT appeared as a powerful marker of mortality. Download : Download full-size image Abstract 0224 – Figure: 5-year survival of AL-patients according to LVT