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Abstract Background Wild type transthyretin cardiac amyloidosis (wtATTR-CA) is increasingly recognized as a cause of heart failure with preserved ejection fraction (HFpEF) but prognosis is often limited due to late or misdiagnosis.Longitudinal left ventricular strain and biomarkers are established as markers of disease severity, but the role of RV free wall strain, reflecting RV contractility, is less well understood. Purpose We sought to determine whether RV free wall strain might add incremental prognostic value in wtATTR-CA. Methods Consecutive patients diagnosed with wtATTR-CA with tissue confirmation at Mayo clinic between 2013 and 2015 were included. Patients with TTR gene mutations were excluded. Baseline characteristics and transthoracic echocardiography measurements were obtained from the medical records. Speckle tracking RV free wall longitudinal 2D strain and peak LA longitudinal 2D strain were measured using Tom Tec Imaging System. Survival was determined using Kaplan Meier estimates and using the cox proportional hazard ratio, univariate and multivariable analysis were performed to identify predictors of mortality in patients with wtATTR. Results The study group comprised 139 patients (mean age 74.9±8.6, 92.8% male), of which 102 had adequate image quality for RV strain, and 99 for LA strain. Amongst these, 102 (73.3%) had AF and 118 patients (84.8%) had HF. During 3.23±2.0 years of follow up, 66 patients died. Both mean RV and LA strain were impaired at baseline: RV free wall strain was −14.7±4.9, and peak atrial longitudinal strain (PALS) was 13.2±8.8%. Using ROC analysis, RV strain of −16.8% was an independent predictor of all-cause mortality. In univariate modeling, higher levels of NT-proBNP (HR: 1.1 per 1000 pg.ml; 95%, CI 1.05–1.15, p<0.001) and Troponin T (HR: 2.0 per 0.1ng/ml; 95% CI 1.49–2.61, p<0.001) were associated with increased all-cause mortality. In addition, LV GLS (HR: 1.13 per 1%; 95% CI1.04–1.24, p=0.003), RV free wall LS (HR: 2.16 per 5%; 95%, CI 1.57–3.03, p<0.0001), and PALS (HR: 0.91 per1%; 95% CI 0.85–0.96, p<0.0001) were univariate predictors of all-cause mortality. In multivariate analysis using a stepwise regression model, RV free wall longitudinal strain (HR: 1.81; 95% CI 1.29–2.62, p<0.001) and Troponin T (HR: 1.7; 95% CI 1.25–2.26, p=0.001) remained independent predictors. Kaplan-Meier survival analysis demonstrated a higher mortality rate above −16.8 RV strain cut-off (Wilcoxon <0.0001). All stages were divided into two groups by −16.8% RV strain, and survival in individual stages analyzed. Stage 1 and 2 with <−16.8 RV free wall strain value had higher mortality than ≤-16.8% RV strain (Stage 1: Wilcoxon = 0.0041 and Stage 2: Wilcoxon = 0.023). However, there was not a survival difference between two RV strain groups in stage3 (Wilcoxon = 0.34) Conclusion RV free wall strain is an independent predictor of survival in wtATTR patients and may add incremental prognostic value to NT-proBNP and Troponin. Funding Acknowledgement Type of funding sources: None. Kaplan-Meier curve of all patientsKaplan-Meier curve of stages

Abstract Introduction: Currently, the most extensively tested treatments for immunoglobulin light chain amyloidosis (AL) are high dose melphalan followed by autologous stem cell transplantation (ASCT) and melphalan and dexamethasone (MDex). A recent randomized controlled trial comparing the two regimens showed MDex is at least equivalent if not superior to ASCT. Most patients with symptomatic systemic AL have a low plasma cell load; however, approximately 30% have bone marrow plasmacytosis greater than 20% but do not meet criteria for multiple myeloma with significant anemia or lytic bone disease. This leads to the speculation that the plasma cell biology (and therefore outcomes) might differ between low and high plasma cell burden AL. We undertook this study to address whether these two standard regimens are equally effective in AL patients with low and high plasma cell burden. Methods: Patients with confirmed AL treated with MDex were recruited for this study. Some of the patients treated were not ASCT candidates while others were eligible but favored MDex. Hematologic response was defined as 50% reduction in serum M-protein or 90% reduction in urine M-protein if one was present, otherwise a 50% reduction in serum free light chain levels was used. Organ involvement was defined according to the Consensus Opinion from the 10th International Symposium on Amyloid and Amyloidosis. Patients were separated into a high and a low marrow plasma cells (PC) group based on their percentage of bone marrow plasma cells. Cutoff for the bone marrow plasmacytosis was calculated using receiver-operator characteristic (ROC) curve. Overall survival (OS) and progression free survival (PFS) were compared using Kaplan-Meier method. OS was also calculated for 342 AL patients treated with ASCT for comparison. Results: Seventy-three patients with AL received MDex between 05/01 and 05/07. Median follow-up was 16.8 months. At the time of the study, 42.5% had died. Calculating for OS and PFS, the best cutoff for bone marrow plasmacytosis was found to be 20%. In our cohort, 28.8% had >20% bone marrow plasmacytosis. Age (64.8 yr vs 61.0 yr, p = 0.61) and sex (81% male vs 63.4% male, p = 0.13) were similarly distributed between patients with high and low PC. Cardiac troponin T (cTnT) was also comparable between the 2 groups (0.03 ng/ml (high) vs 0.06 ng/ml (low), p = 0.41). Cardiac involvement were similar between high and low PC groups (78.9% vs 85.7% respectively, p = 0.49) but renal involvement was less common in the high PC group (70.6% vs 38.1%, p = 0.01). No differences were noted in the gastrointestinal and neurological involvement. Patients with high PC received a median of 4 cycles of MDex vs 5 in the low PC group (p = 0.68). Hematologic response was achieved in 75% of patients with high PC and 54.9% of the low’s (p = 0.11). A significant difference was noted in the PFS and OS between the 2 groups. The PFS and OS were 13.5m and 15.3m, respectively for patients with high PC but neither was reached in those with < 20% plasmacytosis (p=0.02 and p = 0.03 respectively). In the multivariate analysis, hematologic response, cardiac involvement and plasmacytosis >20% were independent predictors of PFS and OS. To determine if plasmacytosis had the same affect on survival of ASCT treated patients, 342 patients were analyzed. No relationship between OS and % of plasmacytosis was found. Conclusion: Our study suggests that ASCT and MDex may not be equivalent for all AL patients. Even though hematologic response rates were similar, patients with plasmacytosis >20% had a worse OS and PFS when treated with MDex. This disparity in survival was not evident in patients treated with ASCT. This effect was independent of cardiac involvement. If confirmed, this could have a significant impact on the choice of therapy for AL patients. The best therapy may be determined by the extent of marrow plasmacytosis, with higher plasma cells favoring high dose therapy.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder associated with varying degree of organ infiltration with light chain derived amyloid protein and consequent organ dysfunction. Various acquired coagulopathies, predominantly Factor X (FX) deficiency have been previously described in AL. The factor deficiencies are thought to be due to the direct binding of blood coagulation proteins to amyloid fibrils. Little is known regarding the prognostic significance of abnormal coagulation parameters in AL patients (pts). Methods: After Institutional Review Board approval, we performed a retrospective review of the medical records of 625 consecutive pts who had presented within 3 months of a diagnosis of AL to be evaluated at Mayo Clinic from June 2001 to June 2006. 540 pts had coagulation studies performed within 2 months of presentation. 51 of those pts were on oral anticoagulation and were excluded from the analysis. Results: Of the 489 pts included in the analysis, the median age was 62 years and 61% were male. The median overall survival (OS) of the entire cohort was 26.8 months. Table 1 lists the prevalence of abnormal coagulation tests in the remaining 489 patients. Prothrombin time (PT) was available in the majority of pts. 61 pts (12.6%) had elevated PT, and 63 pts (20.4%) had a decreased FX. 37 of the 61 pts with elevated PT had available FX levels, of which 31 (84%) of those had a decreased FX, suggesting that the cause of elevated PT was mostly due to a low FX. Indicators of hepatic involvement such as alkaline phosphatase and bilirubin levels were higher among the patients with prolonged PT and low FX. An elevated PT (more than 12.4 seconds) was strongly predictive of an adverse outcome, with a median OS of 8.7 months compared to a median OS of 29 months (p<0.0001) in pts with normal PT (Figure 1). Similarly, pts with decreased FX (less than 60% activity), was associated with significantly worse outcomes with a median OS of 14.9 months versus a median OS of 33 months (p<0.0001) in pts with normal FX (Figure 2). In a Cox proportional hazards model containing cardiac troponin (cTnT), NT-Pro BNP, serum alkaline phosphatase, and free light chain difference (involved minus uninvolved), prolonged PT or FX deficiency were independently prognostic for overall survival. Conclusion: Abnormalities of PT and FX are seen in a sizable proportion of pts with newly diagnosed AL. An elevated PT and or FX deficiency appear to adversely affect the outcome of these patients. It is likely that the elevated PT in these patients relate to FX deficiency in the majority which in turn may reflect the amyloid ‘burden’. The effect of other organ involvement like the hepatic involvement may also have an impact on FX and PT. Table 1. Prevalence of abnormal coagulation testing in patients with newly diagnosed primary systemic amyloidosis. Coagulation study N (Test results available) N of abnormal results (%) Elevated prothrombin time 486 61 12.6 Elevated activated partial thromboplastin time 312 48 15.4 Elevated thrombin time 315 84 26.7 Elevated fibrinogen 140 118 84.3 Decreased Factor II activity 62 26 41.9 Decreased Factor V activity 63 9 14.3 Decreased Factor VII activity 63 17 27 Decreased Factor X activity 309 63 20.4 Elevated D-dimer 130 72 55.4 Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 1. Survival grouped by normal versus elevated Prothrombin time. Figure 2. Survival grouped by normal versus low Factor X levels. Figure 2. Survival grouped by normal versus low Factor X levels.

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder with a poor survival, especially in patients (pts) with multiple organ involvement. For pts with limited organ involvement, high dose chemotherapy with autologous stem cell (SCT) support is an effective approach. However, the toxicity of SCT limits its widespread use. Melphalan and dexamethasone has been previously shown to be effective in pts ineligible for SCT. Methods: We reviewed our experience with melphalan and dexamethasone for treatment of AL. Eighty one pts were treated between 2001 and 2003; median age at start of therapy was 63 years (range, 38–80) and 56 pts (69%) were males. Among these, 46 pts (57%) had 2 or more major organs (cardiac, renal, hepatic) involved. Intravenous melphalan (IV) was used in 45 pts (56%), 32 (40%) received oral melphalan (PO) and the rest received cycles of both. The most common doses were 16 mg/m2 for IV administration (every 4–6 weeks) and 0.22 mg/kg for PO administration (every 4 weeks). Dexamethasone was usually given at a dose of 40 mg for the first 4 days of each cycle. Results: Patients received a median of 5 cycles (range; 1–17). At the time of analysis, 53 (65%) pts were alive with a median follow up of 10.8 months (range, 1.4–47.1).The estimated median overall survival (OS) was 25.6 months for the entire group, with the number or type of organs involved not impacting survival. Hematological response (HR) was defined by a 50% reduction in either serum M-spike, urine M-spike, or the absolute difference between the involved and uninvolved immunoglobulin free light chains. A HR was observed in 43 pts (67%) of the 64 pts measurable for HR by conventional criteria. Achievement of HR was associated with a superior OS with a median post-therapy OS that was not reached, while non-responders had a median OS of 11.1 months (p<0.0001) (Figure 1). Among these pts, an organ response as defined by conventional criteria, was seen in 14 pts (22%), which was significantly correlated with obtaining a hematological response (33% vs. 5%, p=0.01). A 25% reduction in the difference between the involved and uninvolved FLC strongly predicted prolonged OS, with a median post-therapy OS that was not reached for responders vs. 11.3 months for non-responders (p<0.0001) (Figure 2). A decrease in post-therapy brain natriuretic peptide (BNP) also predicted for a survival improvement, with the median OS not reached for responders vs. a median OS of 17 months for non-responders (p<0.016). Conclusion: Treatment with melphalan and dexamethasone is effective and a significant survival advantage is achieved in patients with a hematological response. FLC and BNP response can help identify patients that are likely to benefit from this therapy. Figure Figure Figure Figure