Improvement in Global Longitudinal Strain (GLS) Correlates with NT-Probnp Response in Patients with Cardiac Amyloidosis Treated on a Phase 1b Study of Anti-Amyloid Mab Cael-101

Abstract Background: Cardiac AL amyloidosis continues to have poor prognosis with median survival of less than a year from diagnosis and only 3 months in patients with cardiac stage 3b disease (1). Targeting the underlying plasma cell clone can clear circulating light chains but cannot remove deposited protein in the organs. CAEL-101 (11-1F4 mAb) is a monoclonal IgG1 antibody that directly binds to a conformational epitope present on both human kappa and lambda light-chain amyloid fibrils. In preclinical studies the antibody was able to localize to the amyloid tissue and led to decrease in size as well as elimination of the amyloid protein (2). An open-label phase 1b clinical trial of the CAEL-101 showed a promising organ response rate of 63% (3). Global Longitudinal Strain (GLS) is a sensitive measure of functional impairment in cardiac AL Amyloidosis, and may predict survival over and above that of cardiac biomarkers (4). Here, we evaluated the effects of CAEL-101 on the myocardial function using GLS in correlation with NT-proBNP in patients with cardiac amyloidosis treated with CAEL-101. Methods: Patients with relapsed/refractory AL amyloidosis were enrolled and treated in a phase 1b study (N=19) using the anti-amyloid mAb CAEL-101. CAEL-101 was administered weekly for 4 weeks with sequential doses of 0.5, 5, 10, 50, 100, 250 and 500 mg/m2 in a dose-escalation design. All patients underwent transthoracic echocardiograms at screening and 12 weeks. GLS was measured using speckle-tracking (TomTec-Arena 1.2, Germany) and calculated as an average of 4-, 2-, and 3- chamber based measurements. Paired student's t-test was used to compare echocardiographic variables at screening and 12 weeks after therapy start with CAEL-101. GLS was correlated with NT-proBNP using Pearson correlation coefficient. Results: The median age of patients (N=19) was 63 years with 68% male and 32% female. Ten out of 19 patients had cardiac involvement with a median NT-proBNP of 1186 (range 699-3964) at screening. Six out of 10 patients (60%) with cardiac involvement met cardiac response criteria by having a decrease in NT-proBNP >30% (3). Among echocardiographic parameters, mean GLS improved significantly in 9/10 patients from -15.58 ± -4.14% at screening to -17.37 ± -3.53% at week 12, p = 0.004 (Figure 1) of the trial. One patient who did not have improvement in GLS was dosed at low dose level 2 (5mg/m2) in the study. Under the null hypothesis, the probability of 9 or more patients improving without drug effect, is ~0.0107, suggesting that improvement of GLS in 9 of 10 is a highly unlikely outcome unless the there is a drug association. In contrast to the improved GLS in cardiac patients, CAEL-101 had no significant effect (p=0.4829) on GLS in the 9 patients without cardiac involvement (GLS -22.77 ± -3.12 at screening and -22.36 ± -3.02 at end of treatment), suggesting a specific effect of CAEL-101 on cardiac amyloid deposits (Figure 2 and Table 1). Pearson correlation coefficient between NT-proBNP response and GLS response (in 8 cardiac evaluable patients) was 0.345, further confirming the efficiency of Cael-101 in amyloid resolution resulting in structural remodeling of the heart muscle. Conclusion: Improvement in GLS correlates with improvement in NT-proBNP in in patients with cardiac AL Amyloidosis treated with CAEL-101. The short timeframe in which the improvement of the GLS occurred (12 weeks after entering the trial) suggests that this effect is Ab related and GLS along with NT-proBNP should be evaluated in larger studies as markers for early cardiac response in patients with AL Amyloidosis. References:Wechalekar AD, Schonland SO, Kastritis E et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood.2013;121(17):3420-7.Wall JS, Kennel SJ, Stuckey AC et al. Radioimmunodetection of amyloid deposits in patients with AL amyloidosis. Blood. 2010 Sep 30;116(13):2241-4.Edwards CV, Gould J, Langer AL et al. Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis. Blood 2017 130:509.Salinaro F, Meier-Ewert HK, Miller EJ et al. Longitudinal systolic strain, cardiac function improvement and survival following treatment of light-chain (AL) cardiac amyloidosis. Eur Heart J Cardiovasc Imaging.2017 Sep 1;18(9):1057-1064. *Dr. Lentzsch recused herself from the Phase 1a/b trial in 11/2017. Disclosures Maurer: Glaxo Smith kline: Other: personal fees ; Eidos: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees, Research Funding; Prothena: Research Funding; Alnylam: Research Funding; Ionis: Other: Personal fees, Research Funding; Akcea: Other: Personal fees. Lentzsch:BMS: Consultancy; Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences; Bayer: Consultancy; Janssen: Consultancy.

Download Full-text

P309 The use of echocardiographic parameters to predict clinical outcomes in AL-amyloidosis cardiomyopathy

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jez319.162 ◽

2020 ◽

Vol 21 (Supplement_1) ◽

Author(s):

P Geenty ◽

S Sivapathan ◽

T Deshmukh ◽

P Brown ◽

A Boyd ◽

...

Keyword(s):

Ejection Fraction ◽

Primary Endpoint ◽

Cardiac Amyloidosis ◽

Longitudinal Strain ◽

Global Longitudinal Strain ◽

Al Amyloidosis ◽

Predictors Of Outcome ◽

Lv Mass ◽

Echocardiographic Parameters ◽

Al Amyloid

Abstract Background AL-amyloidosis has a rapid clinical progression, with cardiac involvement associated with a particularly poor prognosis. Cardiac amyloidosis is diagnosed by either invasive biopsy or conventional echocardiographic parameters such as increased wall thickness, in the absence of other causes. More recently, novel parameters including 2D longitudinal strain have demonstrated diagnostic utility in a range of infiltrative cardiomyopathies including cardiac amyloidosis. Aim/Method: We sought to evaluate traditional and novel echocardiographic parameters in their ability to predict adverse outcomes in a cohort of AL-amyloid patients. 80 patients who had transthoracic echocardiograms at a single centre were included. Comprehensive echocardiographic assessment was performed, including left ventricular ejection fraction (LVEF), LV Global Longitudinal Strain (GLS), LV mass (indexed to BSA). The primary endpoint was a composite of of major adverse cardiac events (MACE) and all-cause mortality, that was assessed by interrogation of the medical records on a specified censor date. Results At a mean follow-up (time from echo to censor date) of 5.4 ± 2.6years, 38/80 (47.5%) of patients experienced the primary endpoint of MACE or death, of which 25/80 (31%) were deaths. LVEF (59 ± 5.6%vs56 ± 6.4%, p = 0.04), GLS (17.4 ± 3.9%vs14.8 ± 4.9%, p = 0.01) basal longitudinal strain (12.3 ± 3.2%vs9.6 ± 3.9%, p = 0.002), indexed LV mass (107 ± 36g/m2vs130 ± 34g/m2, p = 0.06) and E/E’ (13.7 ± 4.9vs20.6 ± 9.6, p < 0.001) were all significantly different between patients who experienced the primary endpoint and those that didn’t. The strongest predictors of outcome were E/E’ (AUC 0.74), LV mass (AUC 0.73) and the ratio GLS:LV mass (AUC 0.73). An E/E’ of 15 had a sensitivity of 71% and specificity of 69%, while an indexed LV mass of 108 had a sensitivity and specificity of 74% and 67% respectively. GLS to LV mass as a cutoff of 0.16 had a sensitivity and specificity of 70% and 69% respectively. Conclusion In a cohort of 80 patients with AL-amyloid cardiomyopathy, almost half (47.5%) reached the primary composite endpoint. Diastolic dysfunction as expressed as E/E’, and LV mass were the most powerful predictors of outcome, while global longitudinal strain and LV basal strain were also reduced, and showed superiority over LV ejection fraction in predicting prognosis.

Download Full-text

Comparison of Different Techniques to Identify Cardiac Involvement in Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood-2018-99-117627 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3182-3182

Author(s):

Mohammed A Aljama ◽

M Hasib Sidiqi ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Martha Q. Lacy ◽

...

Keyword(s):

Strain Rate ◽

Board Of Directors ◽

Light Chain ◽

Mayo Clinic ◽

Endomyocardial Biopsy ◽

Research Funding ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Al Amyloidosis ◽

Advisory Committees

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Abstract 15734: Left Atrial Reservoir Strain as a Novel Prognostic Marker in Biopsy-proven Light-chain Amyloidosis

Circulation ◽

10.1161/circ.142.suppl_3.15734 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Peter Huntjens ◽

Kathleen Zhang ◽

Yuko Soyama ◽

Maria Karmpalioti ◽

Daniel Lenihan ◽

...

Keyword(s):

Light Chain ◽

Left Atrial ◽

Prognostic Value ◽

Cardiac Amyloidosis ◽

Longitudinal Strain ◽

Global Longitudinal Strain ◽

Strain Imaging ◽

Left Ventricular ◽

Lv Function ◽

Al Amyloidosis

Introduction: Light chain cardiac amyloidosis (AL) has a variable but usually poor prognosis. Left ventricular (LV) function measures including LV strain imaging for global longitudinal strain (GLS) have shown clinically prognostic value in AL. However, the utility of novel left atrial (LA) strain imaging and its associations with LV disease remains unclear. Hypothesis: LA strain is of additive prognostic value to GLS in AL. Methods: We included 99 consecutive patients with AL. Cardiac amyloidosis either confirmed by endocardial biopsy (25%) or by non-cardiac tissue biopsy and imaging data supportive of cardiac amyloidosis. Peak LA reservoir strain was calculated as an average of peak longitudinal strain from apical 2- and 4-chamber views. GLS and apical sparing ratio were assessed using the 3 standard apical views. All-cause mortality was tracked over a median of 5 years. Results: Echocardiographic GLS and peak longitudinal LA strain were feasible in 96 (97%) and 86 (87%) of patients, respectively. There were 48 AL patients who died during follow-up. Patients with low GLS (GLS < median; 10.3% absolute values) had worse prognosis than patients with high GLS group (p<0.001). Although peak longitudinal LA strain was correlated with GLS (R=0.65 p<0.001), peak longitudinal LA strain had additive prognostic value. AL patients with low GLS and low Peak LA strain (<13.4%) had a 8.3-fold increase in mortality risk in comparison to patients with high GLS (95% confidence interval: 3.84-18.03; p<0.001). Multivariable analysis showed peak longitudinal LA strain was significantly and independently associated with survival after adjusting for clinical and echocardiographic covariates (p<0.01). Conclusions: Peak longitudinal LA strain was additive to LV GLS in predicting prognosis in patients with biopsy confirmed AL amyloidosis. LA strain imaging has potential clinical utility in patients with AL cardiac amyloidosis.

Download Full-text

Hematologic Responses and Cardiac Organ Improvement in Patients with Heavily Pretreated Cardiac Immunoglobulin Light Chain (AL) Amyloidosis Receiving Daratumumab

Blood ◽

10.1182/blood.v128.22.4525.4525 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4525-4525 ◽

Cited By ~ 7

Author(s):

Gregory Kaufman ◽

Ronald Witteles ◽

Matthew Wheeler ◽

Patricia Ulloa ◽

Marie Lugtu ◽

...

Keyword(s):

Light Chain ◽

Research Funding ◽

Cardiac Involvement ◽

Cardiac Response ◽

Al Amyloidosis ◽

Immunoglobulin Light Chain ◽

Prior Therapy ◽

Hematologic Response ◽

Heavily Pretreated ◽

Organ Response

Abstract Introduction: In immunoglobulin light chain (AL) amyloidosis, cardiac involvement is the primary cause of premature death. Light chain suppression, with therapies targeting the underlying plasma cell clone producing amyloidogenic free light chains, has been difficult to achieve in a relapsed/refractory disease setting. Hematologic response is required to obtain a cardiac organ response, which is predictive of survival and is an important, if not primary, therapeutic goal. We have previously reported rapid and favorable hematologic response rates with the monoclonal anti-CD38 antibody daratumumab in a cohort of heavily pretreated relapsed/refractory AL patients. The aim of this study was to evaluate cardiac organ response following light chain suppressive therapy with daratumumab in patients with relapsed/refractory AL. Materials & Methods:Consecutive patients with biopsy-proven AL and cardiac involvement, followed at the Stanford University Amyloid Center, who received daratumumab were retrospectively evaluated for hematologic and cardiac organ response. In accordance with IRB approval, demographic and clinical information was obtained from medical records. Hematologic and cardiac organ response criteria were defined per consensus guidelines in AL (Comenzo et al, Leukemia 2012). Results: Twelve patients with previously treated AL with cardiac involvement received a median of 12 doses (range 5-18) of single agent daratumumab. The antibody was given intravenously at 16 mg/kg weekly for 8 weeks, followed by every other week infusion for 8 doses and then monthly infusions. The median patient age was 67 and 75% of patients were male. The median number of lines of prior therapy was 3; notably, none of the patients had previously achieved a hematologic complete response to prior therapy including high dose melphalan and autologous stem cell transplant in 2 patients. Ten of 12 patients (83%) achieved a partial hematologic response or better with daratumumab (3 complete responses (25%), 3 very good partial responses (25%), and 4 partial responses (33%)). Median NT-pro BNP was 2516 pg/mL prior to daratumumab therapy. Of all 12 treated patients, seven patients were evaluable for cardiac response based on baseline NT-proBNP >650 ng/L. Of these, 3 patients achieved a cardiac organ response by NT-pro BNP criteria (>30% reduction and >300 ng/l decrease). Two patients had cardiac progression by NT-pro BNP criteria (no echocardiographic progression was observed) despite hematologic response with one patient discontinuing therapy to pursue hospice care. Infusion reactions were observed in 8/12 patients with only 1 grade 3 infusion reaction. Conclusions: Daratumumab yielded rapid and significant hematologic responses in our retrospective single institution cohort of heavily pretreated AL patients. At a median daratumumab duration of therapy of only 4 months, evidence of cardiac organ improvement was observed. Daratumumab represents a well tolerated and exceptionally promising new treatment for patients with AL amyloidosis; larger prospective trials to evaluate this agent are warranted. Disclosures Liedtke: Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding.

Download Full-text

Global longitudinal strain predicts survival and response in patients with systemic AL amyloidosis. analysis of 915 patients from the ALchemy prospective trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.0856 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

O Cohen ◽

A Ismail ◽

R Manwani ◽

S Ravichandran ◽

D Foard ◽

...

Keyword(s):

Cardiac Involvement ◽

Univariate Analysis ◽

Global Longitudinal Strain ◽

Prospective Trial ◽

Mitral Annulus ◽

Cardiac Response ◽

Response To Treatment ◽

Al Amyloidosis ◽

2D Strain ◽

Staging Systems

Abstract Background Cardiac involvement determines prognosis in systemic AL amyloidosis. The extent is assessed by biomarker-based staging systems. This a prospective report of a large cohort of patients assessing the utility of changes in longitudinal function by 2D strain (GLS%), impairment - a hallmark of amyloidosis. Purpose To evaluate the prognostic role of GLS% and other echocardiographic parameters in systemic AL amyloidosis. Methods 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010–August 2017) were included. All patients underwent 6-monthly comprehensive assessments inclusive of echocardiogram. The European modification of the Mayo 2004 staging was used with Mayo stage III patients stratified into IIIa (NT-proBNP <8500ng/L) and IIIb (NT-proBNP ≥8500ng/L). Results 653/915 (71.4%) patients had cardiac involvement. Mayo stage 1, 2, 3a and 3b in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. The median NT-proBNP was 2228ng/L and TNT was 0.54ng/ml. The GLS% significantly worsened with increasing Mayo stage (p<0.0001 between GLS% for each Mayo stage). Poorer baseline GLS% associated with significantly worse OS and stratified patients into three groups: GLS% <−12.8%: OS 69.1 months; GLS% −12.8% to −9%: OS 54.5 months; GLS% >−9%: OS 45.3 months (p<0.0001). On univariate analysis, 11/14 parameters predicted survival (LV wall thickness, LV ejection fraction, systolic velocities of the septal (s'sep) and lateral mitral annulus (s' lat), mitral annulus movement at the lateral corner (e' lat), transmitral early peak flow velocity (E) divided by tissue Doppler mitral annular motion velocity (e') – E/e' and mitral annular plane systolic excursion (MAPSE)). Baseline GLS% >−17% was independent of Mayo stage in predicting survival [Mayo II: Hazard ratio (HR) 2.10 (95% CI: 1.12–3.92) p=0.02, Mayo III: HR 3.94 (95% CI: 2.13–7.32) p<0.0001, Mayo IV: HR 7.49 (95% CI: 3.94–14.21) p<0.0001, GLS <17%: HR 2.14 (95% CI: 1.59–2.88) p<0.0001]. At 12 months, only patients in a haematological complete response (CR) had significant improvement in overall GLS% (p=0.02) as well as baso-lateral (p=0.0004) and baso-septal (p=0.0001) GLS% and MAPSE (p=0.002). The OS was significantly better in patients who achieved a minimum absolute improvement in GLS% of 1.5% improvement (not reached in those with improved GLS% vs. 72 mo in those without) (p=0.034)). Conclusion These data show that baseline GLS% is an independent predictor of survival in AL amyloidosis. GLS% is the first functional marker that is independent of the Mayo staging in predicting outcomes and should be incorporated in prognostic staging for patients with AL amyloidosis. GLS% shows improvement in patients who achieve a complete haematologic response to treatment and improvement in GLS% of 1.5% is associated with improved outcomes. An absolute improvement in GLS% should be considered as a criterion for cardiac response in AL amyloidosis. Funding Acknowledgement Type of funding source: None

Download Full-text

The Impact of Longitudinal Strain on Haematological and Cardiac Response and Survival in Patients with Systemic AL Amyloidosis

Blood ◽

10.1182/blood-2020-137391 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-40

Author(s):

Oliver C Cohen ◽

Andreia Ismael ◽

Richa Manwani ◽

Sriram Ravichandran ◽

Steven Law ◽

...

Keyword(s):

Longitudinal Strain ◽

Cardiac Involvement ◽

Troponin T ◽

Staging System ◽

Stage I ◽

Cardiac Response ◽

Al Amyloidosis ◽

International Consensus ◽

The Uk ◽

The Impact

Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac involvement. Mayo stage I, II, IIIa and IIIb in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. Impairment of LS% correlated significantly with increasing Mayo stage (p<0.0001 between LS% for each Mayo stage). At 12 months, only patients with complete haematological responses (CR) had significant improvement in LS% (overall p=0.04; regional baso-lateral p=0.007, and baso-septal p=0.007). The median overall survival (OS) of the whole cohort was 61 months; survival of Mayo stage I and II patients was not reached whilst OS in Mayo stage IIIa and IIIb patients was 30 and 4 months respectively. Patients with cardiac involvement were stratified into 3 baseline LS% groups (≤17%; 10.3-16.9%; and ≥10.2%) with poor baseline LS% being associated with shorter OS (p<0.0001). These groups predicted survival independently of Mayo stage. OS was superior in patients who achieved a minimum absolute improvement in LS% of 1.5% when analysed at either 12 (not reached vs. 72 months, p=0.008) and 24 (not reached vs. 80 months, p<0.0001) months from diagnosis. Patients achieving a LS% response (1.5%) improvement survived longer than those achieving a traditional cardiac response alone or no cardiac response at both 12 and 24 months (p<0.0001). Conclusion: Longitudinal strain is an informative functional marker that is independent of Mayo staging in predicting outcomes in patients with cardiac AL amyloidosis which can be incorporated in prognostic staging for these patients. Improvement in LS% was observed in patients who achieved a CR, and a value of 1.5% was associated with superior outcomes over and above achieving a cardiac response by international consensus criteria. An absolute improvement in LS% should be considered a criterion for cardiac response in AL amyloidosis. Disclosures Wechalekar: Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria.

Download Full-text

Botezomib Containing Regimens Provide a Rapid Hematological and Cardiac Response in Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v120.21.4064.4064 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4064-4064

Author(s):

Victor H Jimenez-Zepeda ◽

Donna Reece ◽

Suzanne Trudel ◽

Christine I. Chen ◽

Rodger E. Tiedemann ◽

...

Keyword(s):

Research Funding ◽

Cardiac Involvement ◽

Troponin I ◽

Cardiac Biomarkers ◽

Cardiac Response ◽

Cardiac Complications ◽

Al Amyloidosis ◽

Novel Therapy ◽

Cardiac Reserve ◽

Cardiac Responses

Abstract Abstract 4064 The spectrum and severity of organ involvement, especially cardiac involvement, usually dictate early outcome, with cardiac biomarkers such as cTnT, NT-ProBNP, and serum uric acid; median survival is only 5.8 months in patients (pts) with high-stage cardiac biomarkers. Since novel therapies have been now been tried in AL amyloidosis, we performed a retrospective review of two different treatment approaches to explore whether the more rapid hematological (HR) that can result from novel therapy produces improved cardiac responses (CardR) and organ responsse (OR) and translates into a greater benefit for pts with poor cardiac reserve. Methods: Pts with documented symptomatic AL with cardiac involvement based on functional studies and/or serum biomarkers who received treatment with bortezomib–containing (Bor) regimens or melphalan and dexamethasone (MD) were identified from our institutional amyloidosis database. TnI and BNP values at baseline, 3, 6 and 12 months were recorded. HR, CardR and OR were assessed according to the more recent validation of the criteria response (Leukemia, 2012). Results: Thirty-eight pts meeting inclusion criteria were identified, with 25 pts treated with Bor and 13 pts treated with MD from 12/2005 to 10/2011. Clinical characteristics are shown in Table 1. Bor was given as upfront therapy in 9 pts, as second-line in 13 pts and third-line in 3. After a median of 7 cycles of Bor regimens (1–56) and 6 cycles of MD (1–9), a HR was seen in 23 cases (92%) and 13 cases (100%), including: CR in 32% and 31%, VGPR in 56% and 54% and PR in 4% and 15%, respectively, (p=0.491). Pts treated with Bor achieved HR at a median of 6 weeks compared to 10 weeks for MD (p=0.001); 16 patients treated with Bor had already achieved ≥PR at 6 weeks. OR at 6 months was documented in 20 cases treated with Bor (80%) and 3 cases with MD (23%). With respect to cardiac response, a ≥50% decrease of Troponin-I was seen in 9 of 13 and 4 of 11 evaluable patients treated with Bor and MD respectively, while a decrease of BNP of ≥50% was observed in 11 of 13 evaluable cases treated with Bor and 10 of 13 treated with MD at a median of 6 and 5 months in the Bor group and 12 and 12 months in the MD group, respectively (p=0.001). In the Bor group, 23 patients remained progression-free, versus 7 patients in the MD group (p=0.01). In conclusion, Bor is a safe and well-tolerated therapy for AL patients and shows faster HR and cardiac responses assessed by BNP and TnI than MD. Although this retrospective study has the limitations of selection bias, small numbers, variable entry criteria, and slight differences in treatment regimen, we show that the overall HR and OR rates are similar with both Bor and MD regimens but, importantly, the rapidity of response is better with bortezomib therapy. This is meaningful for patients with poor cardiac reserve in whom a fast response is needed to avoid cardiac complications/early death. Further prospective comparative studies are required with a focus on longer-term outcomes such as overall survival. Disclosures: Jimenez-Zepeda: MMRF: Research Funding; Janssen Ortho: Honoraria. Reece:Otsuka: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millinneum Pharmaceuticals: Research Funding; Merck: Consultancy, Honoraria, Research Funding. Chen:Roche: Honoraria; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Kukreti:Roche: Honoraria.

Download Full-text

Cardiac involvement Is Underdiagnosed in Patients with Biopsy-Proven Systemic AL Amyloidosis

International Cardiovascular Forum Journal ◽

10.17987/icfj.v6i0.172 ◽

2016 ◽

Vol 6 ◽

Author(s):

Haoyi Zheng ◽

Amitabha Mazumder ◽

Stuart Katz

Keyword(s):

Clinical Diagnosis ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Clinical Care ◽

Response To Therapy ◽

Cardiac Response ◽

Al Amyloidosis ◽

Limited Data ◽

Nccn Guidelines

Background: Clinical recognition of cardiac involvement and cardiac response to therapy is an important element of clinical care in patients with AL amyloidosis. The new criteria including NT-proBNP, troponin, and echocardiography for assessment of cardiac involvement in patients with systemic AL amyloidosis were proposed in 2004, but there are limited data on the utilization of these in clinical practiceMethods: We retrospectively reviewed the clinical data of 28 patients with AL amyloidosis. Clinical diagnosis of cardiac amyloidosis was based on medical record documentation of symptomatic heart failure without other causes. Then we use the criteria from the current NCCN Guidelines to reassess cardiac involvement.Results: 14 cases (50%) had clinical diagnosis of cardiac amyloidosis at the time of diagnosis and also met the NCCN criteria. An additional 6 cases without clinical diagnosis of cardiac amyloidosis met the NCCN criteria. In total, 20 patients (71.4%) met the NCCN criteria for cardiac involvement. No routine follow-up testing with echocardiography and biomarkers was documented during treatment for any of the patients.

Download Full-text

Another Obesity Paradox: In Cardiac AL Amyloid a Higher BMI Is Associated with a Lower Rate of Cardiac Response

Blood ◽

10.1182/blood-2019-123890 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5502-5502

Author(s):

So Yeon Kim ◽

Amanda Vest ◽

Raymond L Comenzo ◽

Cindy Varga

Keyword(s):

Heart Failure ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Cardiac Amyloidosis ◽

Cardiac Response ◽

Al Amyloidosis ◽

Advisory Committees ◽

Hematological Response ◽

High Bmi

Background:Light-chain amyloidosis (AL) is a clonal plasma cell disorder in which Ig light chains cause organ-specific disease due to toxic misfolded light-chain aggregates and extracellular deposition of amyloid fibrils derived from light chain proteins. The majority of amyloid patients present in various stages of heart failure and survival is largely driven by the extent of cardiac involvement. In the general heart failure population, overweight and mild/moderate obesity is associated with lower mortality, termed the obesity survival paradox. Conversely for patients with multiple myeloma, a disease similar in pathophysiology to AL, obesity is a risk factor for hematological progression. Hypothesis:We hypothesized that patients with cardiac amyloidosis would exhibit an obesity survival paradox and sought to determine the impact of BMI on hematological and cardiac responses to anti-plasma cell treatment. Methods:We conducted a single tertiary center retrospective study of consecutive patients with cardiac AL amyloidosis, referred between 1/1/2009 and 09/30/2018. We collected demographics and BMI prior to treatment. We recorded the date of diagnosis and subsequent dates of hematological and/or cardiac response, mortality or end of follow-up. We constructed a Cox proportional hazards model examining the association between BMI and mortality with a restricted cubic spline function curve. Three logistic regression models were constructed to examine the association between high BMI (>/=25 kg/m2) and cardiac or hematological response, and mortality. Models were adjusted for age, sex and cardiac stage at the time of diagnosis. Results:Of 79 patients, 17 patients had BMI of 17-22.5, 19 a BMI of 22.6-25, 23 a BMI of 25.1-29.7, and 20 a BMI of >/=30 kg/m2. Crude mortality was 31/79 (39%). There was no relationship between BMI as a continuous variable and mortality (HR 0.98, 95% CI 0.91-1.06, p=0.625, adjusted for age and sex), although a survival paradox trend was suggested by the spline curve. While there was no relationship between high BMI and hematological response (adjusted OR 1.00, 0.37-2.75, p=0.996), there was a relationship between high BMI and lower likelihood of achieving cardiac response (adjusted OR 0.23, 0.07-0.71, p=0.011). Conclusions:In this small cohort of patients with AL cardiac amyloidosis, there was no significant relationship between BMI and mortality. Hematological response was unrelated to BMI, but patients with a higher BMI were significantly less likely to achieve a cardiac response. These findings suggest that obesity might be associated with poorer cardiac outcomes in AL amyloidosis, highlighting the importance of a multidisciplinary approach involving oncologists, cardiologists, and nutritionists in the treatment of this complex multi-organ disease. Disclosures Comenzo: Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding.

Download Full-text

Outcomes By Cardiac Stage in Newly Diagnosed AL Amyloidosis: Results from Andromeda

Blood ◽

10.1182/blood-2020-139754 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 44-45

Author(s):

Monique C. Minnema ◽

Angela Dispenzieri ◽

Giampaolo Merlini ◽

Raymond L. Comenzo ◽

Efstathios Kastritis ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Involvement ◽

Cardiac Response ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

Publicly Traded ◽

Advisory Committees ◽

Hazard Ratios ◽

Organ Response

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.

Download Full-text