Study Population

Eighty-two patients with newly diagnosed biopsy-proven AL amyloidosis who received upfront treatment with HCT at Memorial Sloan Kettering Cancer Center between January 2007 and April 2014 were included in this study. Patients with more than two major organs involved, New York Heart Association class III or IV heart failure, or critical cardiac arrhythmias resulting in unstable hemodynamics were not eligible for HCT. Patients who received chemotherapy before HCT were excluded to eliminate any effect of prior potentially cardiotoxic exposure on baseline echocardiography and post-HCT outcomes. Hence, all baseline echocardiograms were obtained before any treatment. Clinical, laboratory, echocardiographic, and treatment data were extracted from a prospectively maintained database of an ongoing institutional review board protocol that prospectively collects baseline characteristics and outcomes of patients with systemic AL amyloidosis. One of the objectives of the protocol is to assess the prognostic value of cardiac characteristics such as laboratory and echocardiographic data in patients with AL amyloidosis receiving various types of treatment. Although the testing was performed as part of routine care, the data were prospectively collected with the intent of addressing the questions examined in the present study.

Patients were assigned a cardiac stage (mayo I, II, or III) on the basis of the cardiac biomarkers BNP and troponin. Conversion between BNP and NT-proBNP was as follows: log BNP = 0.28 + 0.66 × log NT-proBNP; 86 pg/mO was identified as the appropriate cutoff. Stage I included patients with BNP < 86 ng/mL and troponin I (TnI) < 0.10 ng/mL, stage II included patients with either BNP ≥ 86 ng/mL or TnI ≥ 0.10 ng/mL, and stage III included patients with both BNP ≥ 86 ng/mL and TnI ≥ 0.10 ng/mL.

Echocardiography

Conventional 2D and Doppler echocardiography was performed using commercially available standard ultrasound scanners (Vivid E9 [GE Medical Systems, Milwaukee, WI] and iE33 [Philips Medical Systems, Andover, MA]), according to the standardized American Society Echocardiography protocol. Left ventricular ejection fraction (LVEF) was calculated using the modified Simpson method. Mitral inflow velocity pattern was recorded from the apical four-chamber view with the pulsed-wave Doppler sample volume positioned at the tips of the leaflets during diastole. Peak early filling (E-wave) and late diastolic filling (A-wave) velocities were measured and their ratio (mitral E/A) derived. Doppler tissue imaging of the mitral annulus was performed with measurement of the early (e′) diastolic velocity at the lateral annulus. The studies were performed following a strain protocol. Images from the apical four-chamber, two-chamber, and three-chamber views were acquired sequentially to minimize heart rate variability. Three complete cardiac cycles per loop was recorded for each view to ensure that at least one complete cycle without any truncation was available for analysis. All images were acquired during a breath hold to avoid any breathing artifacts and minimize image translation. A high-quality electrocardiographic trace was obtained to allow proper gating of the images. Settings were optimized with utmost attention paid to the image quality and resolution of the endocardial border. The depth and the sector angle were adjusted to include the left ventricle but minimizing the sector size to achieve a higher frame rate, which was maintained between 40 and 90 frames/sec. All echocardiographic images were digitally archived in Digital Imaging and Communications in Medicine format on the echocardiography information management system and retrieved offline for GLS analysis.

Myocardial Strain Measurement

GLS measurements were performed using vendor-independent offline 2D Cardiac Performance Analysis version 1.1.3 (TomTec Imaging Systems, Munich, Germany). The endocardial border was traced in end-diastole in the three apical views, which allowed the software to track myocardial movement throughout the cardiac cycle. After careful inspection, manual correction was performed if myocardial tracking was suboptimal. Each view was divided into six segments, for a total of 18 segments representing the entire left ventricle. Longitudinal strain curves were generated for each segment. GLS was calculated as the average value of the peak negative systolic strain values for all the segments within the three standard apical views. The negative nature of systolic strain or contraction can lead to confusion when describing increases or decreases in strain, as lower arithmetic value implies more vigorous contraction. For example, GLS of −20% implies better left ventricular (LV) systolic contraction but is lower in value than GLS of −14%. To avoid confusion, the normally negative GLS numbers are manually converted to positive numbers, as recommended in the 2015 American Society of Echocardiography guideline on cardiac chamber quantification, such that the arithmetic value and the amplitude of contraction are concordant, allowing clearer communication of strain changes as an increase or decrease in the absolute value. GLS was measured by two well-trained operators (S.C.P., J.J.). All echocardiographic measurements were made with the operator blinded to the clinical and outcome data.

Reproducibility

Interobserver and intraobserver variability was assessed using the intraclass correlation coefficient. Bland-Altman plots were constructed by plotting the average of the two readings on the x axis versus the difference between the two readings on the y axis. The mean and SD of the differences were calculated. Because of the small sample size, the t distribution was used as the reference distribution to calculate the 95% limits of agreement. A P value < .05 was considered to indicate statistical significance. All statistical analyses were performed using either SAS version 9.2 (SAS Institute, Cary, NC) or R version 2.13.1 (R Core Development Team, Vienna, Austria). Interobserver variability was calculated by comparing the original GLS calculation with that calculated by a blinded second observer in 20 randomly selected patients. Intraobserver variability was calculated by repeated measurements in 20 patients by the primary reviewer 3 weeks after the initial measurement.

Statistical Analysis

Prospective follow-up began on the date of HCT. OS was the primary outcome. No patient was lost to follow-up during the study. Comparisons between groups were made using the Fisher exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. The Spearman rank correlation coefficient was used to estimate the correlation between continuous variables. Differences between echocardiographic parameters and biomarkers before and after transplantation were evaluated using the Wilcoxon signed rank test. OS and survival stratified by categorical variables was estimated using the Kaplan-Meier method. The associations of baseline characteristics on OS were examined using the log-rank test for categorical variables and Cox proportional-hazards regression for continuous variables. There were too few events for a multivariate survival analysis. The cut point for GLS to predict OS was chosen using the maximally selected log-rank statistic (i.e., the cut point chosen best separates outcomes according to the maximum test statistic).

Baseline Patient Characteristics

Demographics and clinical features of 82 patients are summarized in Table 1 . Sixty-four percent of the patients had elevated troponin and/or BNP, with 15% classified as Mayo stage III (elevated troponin and BNP). Baseline standard 2D echocardiographic parameters as well as GLS are shown in Table 2 . The mean LVEF was 65%, with only three patients having LVEFs < 50%. Although the mean GLS was 17%, which is the lower limit of normal, 20% of patients (16 of 82) had GLS < 12%, consistent with significant LV dysfunction, which has been associated with an adverse prognosis in other clinical settings. The Spearman correlation coefficient of GLS with BNP was r = −0.46 ( P < .0001) and with LVEF was r = 0.50 ( P < .0001). GLS was not significantly correlated with TnI ( r = -0.17, P = .15).

Pretreatment Predictors of Survival

Among 82 patients, 21 (25%) died. The median follow-up time for survivors was 58 months. GLS as well as cardiac biomarkers and mitral E/A ratio were identified as the strongest predictors of survival in the univariate analysis ( P < .0001; Table 3 ). Other variables, including patient sex, difference in the involved and uninvolved free AL, and echocardiographic parameters of LV morphology and function, were also significantly associated with survival. Mayo cardiac stage was significantly associated with survival, with 5-year estimates of 93%, 72%, and 31% in cardiac stage I, II, and III patients, respectively ( Figure 1 ). GLS of 17% was identified as the value that best discriminated survivors from nonsurvivors. For the entire study population, patients with baseline GLS > 17% had 5-year survival of 95% compared with 47% in patients with GLS ≤ 17% ( Figure 2 ). Among the 12 patients with Mayo stage III disease, nine patients (75%) had GLS ≤ 17%, and three patients had GLS > 17%. By 5-year follow-up, only those three patients with GLS > 17% were alive, suggesting additional value of GLS for prognostication in this high-risk subgroup. Similarly for patients in Mayo stages I and II, GLS ≤ 17% was associated with worse prognosis than GLS > 17% ( Table 4 ). Multivariate analysis was not possible given the limited number of deaths.

OS in patients with AL amyloidosis represented by Kaplan-Meier survival curves according to the biomarker-based Mayo stage ( P = .0001).

OS in patients with AL amyloidosis represented by Kaplan-Meier survival curves according to GLS cutoff value of 17% ( P < .0001).

Table 4

Survival according to Mayo stage stratified by GLS

	Stage I			Stage II			Stage III
GLS	n	5-year OS	P ∗	n	5-year OS	P ∗	n	5-year OS	P ∗
≤17%	5	80%	.41	23	55%	.01	9	0%	.01
>17%	23	95%		16	100%		3	100%

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