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

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.

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A Novel Prognostic Staging System for Light Chain Amyloidosis (AL) Incorporating Markers of Plasma Cell Burden and Organ Involvement.

Blood ◽

10.1182/blood.v114.22.2797.2797 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2797-2797 ◽

Cited By ~ 3

Author(s):

Shaji Kumar ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

Suzzane Hayman ◽

Francis Buadi ◽

...

Keyword(s):

Risk Stratification ◽

Plasma Cell ◽

Light Chain ◽

Cardiac Involvement ◽

Troponin T ◽

Prognostic Score ◽

Staging System ◽

Cardiac Biomarkers ◽

Al Amyloidosis ◽

The Impact

Abstract Abstract 2797 Poster Board II-773 Background: Primary systemic amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in multiple organs leading to varying degree of dysfunction. Cardiac involvement is a common feature of AL, and when significant is highly predictive of poor outcome. The currently used prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro B-type Natriuretic peptide (NT-ProBNP) and is effective at predicting outcome in patients with AL. However, this is driven primarily by the degree of cardiac involvement and does not take into account the degree of plasma cell burden and its impact on the disease course. It is possible that some of the heterogeneity in outcome can be explained by the plasma cell characteristics rather than the degree of the end organ damage. Methods: We examined the baseline clinical and laboratory data from 2119 patients with AL who were seen at our institution with in 90 days of their diagnosis. The data were collected from a prospectively maintained data base, and additional testing was done for free light chain levels (FLC) on stored sera from patients seen before the routine introduction of FLC testing. Cox proportional hazards analysis was performed to estimate the prognostic values of different variables. Results: We first examined the impact of plasma cell clone related characteristics namely, difference between involved and uninvolved FLC (FLC-Diff), bone marrow plasma cell (BMPC) %, plasma cell labeling index (PCLI), beta 2 microglobulin (B2M), and presence of circulating plasma cells, on overall survival (OS) from diagnosis. All variables were dichotomized into high and low based on their median value (FLC-diff: 20 mg/dL, BMPC: 10%, PCLI as a continuous variable, B2M: 3 mg/dL and circulating cells: absent or present). While all were found to be prognostic for OS in univariate analysis; in a multivariate analysis incorporating a stepwise selection only B2M and FLC-diff were significant. We then used these two variables along with the cTnT and NT-ProBNP that are used in the current model to develop a staging system. The median values for all four variables were used for developing the scores. Patients were assigned a score of 1 for presence of each characteristic (FLC difference > 20 mg/dL, troponin-T > 0.02, NT-ProBNP > 1000, and B2M > 3) or 0 if the value was at or below the cutoff. The scores were added to obtain a composite prognostic score that grouped the 370 patients (who had all the variables available for analysis) into 5 groups with very different OS (4.4, 9.3, 24.4, 43, and not reached for stages 4, 3, 2, 1, and 0 respectively; Figure A). However, since the NT-ProBNP did not have independent impact on survival in a multivariable model incorporating all the four variables, we also examined a system that only included FLC-diff, cTnT and B2M. This system again allowed grouping of patients (n=450 with all three variables available) into four distinct groups with divergent outcome with OS of 4.6, 10.5, 36.8, and not reached for stages 3, 2, 1, and 0 respectively; (Figure B). Conclusion: Incorporation of plasma cell related measurements into the existing staging system using cardiac biomarkers allows better risk stratification of patients with AL amyloidosis. The system using FLC, B2M and troponin has the advantage of easily available laboratory values and can be widely adopted. Addition of NT-ProBNP into the system allows better refinement of the intermediate risk groups. This system will allow upfront risk stratification and development of risk-adapted therapies for patients with AL. Disclosures: Gertz: Genzyme: Research Funding.

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Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis

Blood ◽

10.1182/blood-2018-06-858951 ◽

2019 ◽

Vol 133 (3) ◽

pp. 215-223 ◽

Cited By ~ 36

Author(s):

Brian Lilleness ◽

Frederick L. Ruberg ◽

Roberta Mussinelli ◽

Gheorghe Doros ◽

Vaishali Sanchorawala

Keyword(s):

Brain Natriuretic Peptide ◽

Natriuretic Peptide ◽

Light Chain ◽

Cardiac Involvement ◽

Staging System ◽

Stage I ◽

Stage Iiib ◽

Stage Ii ◽

Al Amyloidosis ◽

Derivation Cohort

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.

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Role of NT-ProBNP to Assess the Adequacy of Treatment Response in AL Amyloidosis.

Blood ◽

10.1182/blood.v112.11.1689.1689 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1689-1689 ◽

Cited By ~ 2

Author(s):

Ashutosh Wechalekar ◽

Giampaolo Merlini ◽

Julian D Gillmore ◽

P. Russo ◽

Helen J Lachmann ◽

...

Keyword(s):

Overall Survival ◽

Cardiac Involvement ◽

Cox Regression ◽

Time Lag ◽

Response To Treatment ◽

Al Amyloidosis ◽

International Consensus ◽

Randomised Study ◽

Response To Chemotherapy ◽

The Impact

Abstract We report the use of NT-ProBNP (N-terminal fragment of brain natriuretic peptide) as an independent marker to identify patients with AL amyloidosis whose clonal response to chemotherapy is inadequate. The aim of chemotherapy is to allow improvement in amyloidotic organ function but the significant time lag often means that patients are either over or under treated. Use of biomarkers (such as BNP and NT-ProBNP) for risk stratification is an area of increasing interest. 200 patients with AL amyloidosis diagnosed between 2004–2007, who had completed one line of treatment and had a complete results available prior to and six month from the start of treatment, were identified from the databases of the Amyloidosis centres in Pavia, Italy and London, UK. Organ involvement and response was assessed according to the international consensus criteria (Gertz et al 2005). NT-ProBNP change was deemed significant if there was a rise or fall of both 30% and >300 ng/L over the starting value. Kaplan-Meier and Cox regression were used for survival analysis as appropriate. The median age was 63 yrs (range 38–83) and the median number of organs involved was 2. 132 (66%) had cardiac involvement, 150 (75%) had renal and 42 (21%) had liver involvement at presentation. 115 (56%) responded to chemotherapy with a complete response (CR) in 34 (17%) and a partial response in 81 (40%). At baseline, median NT-ProBNP was 1865 ng/L (range 50–70144) and was >332 ng/L (the cut-off reported as significant by Dispenzieri et al, J Clin Oncol 2004) in 159 patients (80%). The median follow-up was 23 months. The median overall survival (OS) has not been reached with an estimated 2 yr survival of 71%. Patients with cardiac involvement had worse outcomes (OS 29 mo vs. not reached; p =0.001) whereas renal, liver, neuropathy, soft tissue involvement, the light chain type or presence of a measurable M protein did not significantly impact survival. Haematologic responders had a significantly better overall survival (median not reached) than non-responders (median 22 months; p<0.0001) with those achieving CR having significantly better survival than PR (estimated 4 year survival of 94% and 65% respectively; p=0.005). The NT-proBNP increased and decreased significantly in 45 (22%) and 92 (46%) respectively - with the latter group achieving lower FLC concentration after treatment (27.6 vs. 96.4 mg/L, p<0.0001).16 of the 22 (73%) patients with heart involvement who obtained CR also has decreases in NT-ProBNP. Patients without significant NT-ProBNP decrease (median OS 29 months vs. not reached) or with significant increase (median OS 20 months vs. not reached) had significantly poorer outcome (p<0.0001). The impact of this was most marked in patients achieving a PR – in this group, the estimated 3 year survival was 48% for patients in whom there was an increase in NT-ProBNP (not significantly different from the non-responders) vs. 86% for patient in whom there was a decrease (not significantly different from those who achieved CR) (log rank p<0.0001, see figure). On multivariate analysis, cardiac involvement and change NT-ProBNP were highly significant independent prognostic factors. In summary, patients who have a fall in NT-ProBNP have excellent outcomes irrespective of the degree of haematological response. Conversely, the failure to see a fall or to see an increase in NT-ProBNP clearly identifies a group of patients with AL amyloidosis, who despite a haematologic response to treatment, have significantly poorer outcomes. A prospective randomised study to see the effects of rapidly changing to alternative treatment in the latter groups is being planned. Figure Figure

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A New Staging System for AL Amyloidosis Incorporating Serum Free Light Chains, cardiac Troponin-T and NT-ProBNP.

Blood ◽

10.1182/blood.v114.22.2796.2796 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2796-2796 ◽

Cited By ~ 5

Author(s):

Ashutosh D Wechalekar ◽

Nancy L Wassef ◽

Simon DJ Gibbs ◽

Julian Gillmore ◽

Felicia Dike ◽

...

Keyword(s):

Troponin T ◽

Stage Iv ◽

Staging System ◽

The Other ◽

Stage I ◽

Light Chains ◽

Al Amyloidosis ◽

Free Light Chains ◽

Serum Free ◽

Serum Free Light Chains

Abstract Abstract 2796 Poster Board II-772 Background: Risk stratification for patients with AL amyloidosis remains difficult. The Mayo staging system (Dispenzieri et al JCO 2004), based on cardiac biomarkers, is a widely accepted staging method. The Mayo staging cohort was diagnosed over a 21 year period during which the treatment for AL amyloidosis has completely changed. It also does not take into account the underlying clonal disease biology which is emerging as an independent prognostic factor. We propose a new staging for AL amyloidosis incorporating serum free light chains into the Mayo staging system using a much more uniformly treated cohort of patients. Methods: 212 patients with systemic AL amyloidosis attending the UK National Amyloidosis Centre between Jan 2001 and March 2008 with complete data sets (or stored sampled for retrospective testing) for FLC, NT-ProBNP and cardiac Troponin-T prior to any treatment were identified from the database. Patients with overt symptomatic myeloma were excluded from the analysis. Results: Median age was 64 years (range 26-88), male: female ratio was 1.3:1. Median serum creatinine was 149 μmol/L (37-1079), and 24 hour proteinuria 3.9g (<0.1- 20g) with renal involvement being the commonest followed by cardiac. The FLC ratio was abnormal in 180 (85%) patients, with a lambda bias in 136 (64%) cases and a kappa bias in 44 (21%). The concentration of the abnormal class of FLC (iFLC) exceeded 500mg/L in 71 (33%) cases. The median overall survival (OS) of the cohort was 1.8 years with no significant difference in OS for patients with either kappa or lambda as the abnormal component. The cut-off for NT-ProBNP and troponin-T were based on the Mayo staging system (35 pMol/L and 0.03 ng/ml respectively) and iFLC cut-off was selected as 500 mg/L. The median overall survival for patients with values above and below the cut-off were: troponin-T – 0.4 yrs vs. 4.7 yrs (p<0.0001), NT-ProBNP – 1.2 yrs vs. median not reached (p <0.0001) and FLC – 0.9 yrs vs. 3.2 yrs (p=0.02). All patients with a high troponin-T had high NT-ProBNP. For patients with high troponin-T, serum free light chain level at presentation did not significantly affect OS (0.34 vs. 0.48 yrs). When this group was excluded, serum free light chains further stratified patients with a normal or abnormal NT-ProBNP. For the group with normal NT-ProBNP, the median OS was not reached for patients with iFLC <500 mg/L vs. 3.1 yrs for those with iFLC >500mg/L; those with abnormal NT-ProBNP – median OS was 4.6 yrs vs. 1.2 yrs (p=0.015) respectively for low and high FLC. iFLC >500 mg/L independently predicted for poorer OS in a multivariate model (p =0.016). A new staging system is proposed incorporating iFLC using the above mentioned cut-off values for NT-ProBNP, troponin-T and iFLC: Stage I - normal NT-ProBNP/troponin-T with low iFLC (median OS not reached); Stage II - high NT-ProBNP and low iFLC (median OS 4.6 yrs); Stage III - high iFLC (median OS 2 yrs); and Stage IV - abnormal troponin (median OS 0.4 yrs). At 18 months from diagnosis, 8% of stage I, 25% of stage II, 45% of stage III and 76% of stage IV patients had died. Stage IV patients were more likely to have not completed a full course of treatment (42%) compared to other groups (23% stage, 18% and 24% for the other three stages). 6% and 7% of stage I and II patients underwent an autologous stem cell transplant compared to none in the other stages. Conclusion: This new staging system for AL amyloidosis brings clonal markers in the stratification process. Patients with high troponin-T at presentation have a dismal outcome even with recent treatment advances which is unaffected by clonal parameters and need novel rapidly effective approach to treatment. In the other groups, the free light chains at presentation – a surrogate for the clonal burden – are prognostically important. This system offers better stratification of patients over the current system – it upstaged 14% Mayo stage I and 32% stage II patients. Adding the clonal markers may make this useful for addressing new questions in clinical trials. Given the low clonal burden in the good risk stage I patients, is the highest intensity treatment (i.e. ASCT) really needed and could they conceivably achieve the same outcome with less toxic short course treatment? This new staging system needs to be validated in independent patient groups and if validated should be adopted as a new amyloidosis staging system. Disclosures: Bradwell: The Binding Site: Equity Ownership.

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The Utility of High Sensitivity Cardiac Troponin Among Patients with Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood.v118.21.2887.2887 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2887-2887 ◽

Cited By ~ 1

Author(s):

Angela Dispenzieri ◽

Morie A Gertz ◽

Amy K Saenger ◽

Martha Grogan ◽

Shaji Kumar ◽

...

Keyword(s):

Light Chain ◽

Cardiac Involvement ◽

High Sensitivity ◽

Staging System ◽

Cardiac Response ◽

Al Amyloidosis ◽

Immunoglobulin Light Chain ◽

Light Chain Amyloidosis ◽

Staging Systems ◽

Immunoglobulin Light Chain Amyloidosis

Abstract Abstract 2887 Introduction: Cardiac involvement is the major cause of death in patients with immunoglobulin light chain amyloidosis (AL). Detection of cardiac involvement and risk stratification has been facilitated by cardiac biomarkers like troponin T (cTnT) and N-terminal brain natriuretic peptide (NT-proBNP). A novel high sensitivity cTnT (hs-cTnT) assay has been developed, and we evaluated its diagnostic use with three questions in mind: 1) How do the cTnT and hs-cTnT perform in the AL amyloid staging system? 2) Does higher sensitivity add significant additional value in terms of prognosticating outcomes for patients with AL amyloidosis? 3) Can the current AL amyloidosis staging system be further improved upon? Methods: Stored serum samples (-20°C) from 224 pts with AL were analyzed for concentrations of hsTnT, TnT, and NT-proBNP on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). 99th percentile reference limits were <0.014 and <0.010 mcg/L for hsTnT and TnT, respectively. Results: Median values for hsTnT, TnT, and NT-proBNP were 38 ng/L (range 0–075.4), 0.017 mcg/L (<0.0–0.904), and 1230 ng/L (0–32, 226), respectively. The correlation coefficient between hsTnT and TnT was 0.972. Those classified by echocardiographic parameters as having (n=143) or not having (n=81) cardiac involvement had TnT concentrations of 0.04 and 0.01 mcg/L and hsTnT levels of 52.2 and 15.6 ng/L, respectively. The direct numeric result from the hs-cTnT result CANNOT merely be substituted for a cTnT result in the Mayo AL staging system since 14% of patients would be misclassified. The performance of the receiver operation curve derived hs-cTnT cut-point of 54 ng/L is a slight improvement over the direct substitution of 35 ng/L if replacement of one assay for another is required. An alternate staging option using hs-cTnT alone—using the two thresholds14 ng/L and 54 ng/L (figure)—performs as well as either the original Mayo AL staging system or a derivative system incorporating hs-cTnT with respective relative risks of death (95%CI) of 3.6 (2.3, 5.7), 3.8 (2.5, 5.9), and 3.3 (2.2, .50). On multivariate analysis, our newly described alternate 3 level, hs-cTnT alone staging system is independent of other factors including period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models using NT-proBNP and cTnT were explored, but none performed better than the original staging system or the new hs-cTnT system. Conclusion: The direct numeric result from the hs-cTnT result cannot merely be substituted for a cTnT result in the Mayo amyloid staging system. Consideration could be made for AL staging systems using hs-cTnT alone and relegating the NT-proBNP for measuring cardiac response. Disclosures: Jaffe: Roche: Consultancy.

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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

Blood ◽

10.1182/blood-2018-99-118464 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 958-958 ◽

Cited By ~ 6

Author(s):

Divaya Bhutani ◽

Siyang Leng ◽

Andrew Eisenberger ◽

Mathew S. Maurer ◽

Sofia Shames ◽

...

Keyword(s):

Research Funding ◽

Cardiac Amyloidosis ◽

Longitudinal Strain ◽

Cardiac Involvement ◽

Pearson Correlation ◽

Global Longitudinal Strain ◽

Cardiac Response ◽

Al Amyloidosis ◽

Amyloid Deposits ◽

Phase 1B

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.

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Efficacy of Modified Vrd-Lite for Transplant Ineligible Multiple Myeloma

Blood ◽

10.1182/blood-2020-143459 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 4-4

Author(s):

Mizuki Ogura ◽

Tadao Ishida ◽

Moe Nomura ◽

Hirofumi Irita ◽

Junichiro Nashimoto ◽

...

Keyword(s):

Adverse Effect ◽

Multiple Myeloma ◽

Cardiac Amyloidosis ◽

Staging System ◽

Treatment Interruption ◽

Cardiac Complications ◽

High Dose ◽

Al Amyloidosis ◽

Newly Diagnosed ◽

The Impact

BACKGROUND: High dose chemotherapy followed by autologous peripheral blood stem cell transplantation is an effective treatment for multiple myeloma. However, many patients with newly diagnosed multiple myeloma are transplant-ineligible because of their age and complications, result in a poorer prognosis than transplant-eligible patients. Furthermore, many of them cannot complete normal chemotherapy because of low tolerability. Here, we investigated the efficacy and safety of modified bortezomib with lenalidomide and dexamethasone (mVRD-lite) for transplant-ineligible patients with newly diagnosed multiple myeloma. STUDY DESIGN: A retrospective observational analysis was performed on patients who received mVRd-lite for the first line chemotherapy between Jan. 2016 and Mar. 2020 in our hospital. Patients who received high dose dexamethasone to reduce tumor burden, and patients who received bortezomib with dexamethasone or lenalidomide with dexamethasone as a reduction regimen of mVRd-lite were also included. We evaluated ORR, OS, PFS and adverse effect. mVRD-lite at first was administered over a 28-day cycle. Bortezomib 1.3 mg/m2 weekly was administered subcutaneously on days 1, 8, 15 and 22. Lenalidomide 15 mg was given orally 18 days, omitted on days 1, 8, 15, which are the days of bortezomib administration. Dexamethasone 20 mg was given orally on days 1, 2, 8, 9, 15, 16, 22, which are the day of and day after bortezomib. We also reviewed patients background, especially complication of light-chain amyloidosis and considered the impact of cardiac amyloidosis on patient prognosis. This study was conducted with the permission of the Ethics Review Board in our hospital. RESULTS: The subjects analyzed totaled 40 transplant-ineligible patients. 11(27.5%) patients were AL amyloidosis associated with multiple myeloma and 8(20%) patients had cardiac amyloidosis. Median age at diagnosis was 73 (range 48-86) and Male:Female=1:1. Most of them were judged inadequate to transplantation due to their age, general condition, or complication. One patient was ruled unfit to transplantation, because of his refusion. The Revised International Staging System (R-ISS) were I in 5 (12.5%), II in 25 (62.5%) and III in 8 (20%). 5(25%) patients switched to maintenance therapy. 17(42.5%) patients discontinued treatment, because of adverse effect (cardiac failure 4 ; two of them combined with cardiac amyloidosis, rash 4, peripheral neuropathy 3, infection 3, etc). 2(5%) patients died during treatment by mVRd-lite, because of Grade 4 adverse effect, such as pneumonia. 11(27.5%) patients died during observation period and causes of death were primary disease and TRM. 1(2.5%) patient was died of heart failure associated with cardiac amyloidosis. The overall response rate(ORR) during treatment period of mVRd-lite was obtained in 34(85%), including sCR in 5 (12.5%), VGPR in 13 (32.5%) and PR in 14(30%). 2(5%) patients achieved MRD negative. SD were observed in 3(7.5%) patients. 3(7.5%) patients were not evaluated efficacy because of treatment interruption by adverse effect. Overall survival rate at two year is 64.3%, median OS was not reached, at a median follow-up of 20 months. CONCLUSIONS: Transplant-ineligible multiple myeloma patients are associated with poor prognosis. Modified RVD-lite is one of the appropriate therapeutic options, in the transplant-ineligible multiple myeloma patients. Twenty-five percent of patients with cardiac amyloidosis had treatment discontinued due to cardiac complications. Further study is needed for treatment of patients with multiple myeloma complicated with cardiac amyloidosis. Disclosures Ishida: Janssen: Speakers Bureau; Celgene: Speakers Bureau; Ono pharmaceutical co: Speakers Bureau; Takeda pharmaceutical co: Speakers Bureau. Nashimoto:Janssen: Speakers Bureau; Celgene: Speakers Bureau. Tsukada:Takeda pharmaceutical co: Speakers Bureau. Suzuki:Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria; Bristol-Myers Squibb, Celgene and Amgen: Research Funding.

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High-Dose Melphalan and Stem Cell Transplantation for Patients with AL Amyloidosis and Cardiac Involvement

Blood ◽

10.1182/blood.v118.21.2043.2043 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2043-2043

Author(s):

Saulius Girnius ◽

David C Seldin ◽

Karen Quillen ◽

Nancy T Andrea ◽

John Mark Sloan ◽

...

Keyword(s):

Overall Survival ◽

Cardiac Involvement ◽

Troponin I ◽

Performance Status ◽

Stage I ◽

Stage Iii ◽

High Dose ◽

Al Amyloidosis ◽

Cardiac Biomarker ◽

High Dose Melphalan

Abstract Abstract 2043 Treatment of AL amyloidosis (AL) with high dose melphalan and autologous stem cell transplant (HDM/SCT) results in a high rate of durable complete hematologic responses associated with clinical responses and improvement in survival. However, patients with cardiac involvement are at increased risk of treatment-related mortality (TRM). Recently, cardiac biomarkers, B-type natriuretic peptide (BNP) and troponins, have been used to predict survival for AL amyloidosis patients, including those undergoing treatment with HDM/SCT. Here we report on treatment-related mortality (TRM), overall survival, and time to next treatment (progression) and hematologic responses in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarker stage, treated with HDM/SCT. Eligibility for HDM/SCT was based upon strict functional and clinical criteria rather than upon staging based upon biomarkers, and required a Zubrod performance status <2, NYHA heart failure class < III, left ventricular ejection fraction (LVEF) >40%, and adequate cardiopulmonary reserve at a stair climb. Cardiopulmonary exercise testing was also used for some patients. Cardiac involvement was determined by electrocardiographic and echocardiographic abnormalities, as defined by Consensus Opinion of the 10th Symposium on Amyloid and Amyloidosis. A cardiac risk assessment or “cardiac staging” system incorporating biomarkers was used, with patients assigned to stage I (normal biomarkers, BNP < 100 pg/mL and troponin I < 0.1 ng/mL), II (one elevated biomarker) or III (both biomarkers elevated). Between 1/2008 and 10/2010, 35 patients with AL amyloidosis and cardiac involvement were treated with HDM/SCT. The median age was 58 years (range, 41–72). There were 17 males (49%) and 29 (83%) with lambda clonal plasma cell dyscrasia. All but one patient had multi-organ involvement and 80% (n=28) had renal involvement. Eleven percent (n=4) patients had cardiac biomarker stage I disease, 31% (n=11) had stage II disease, and 57% (n=20) had stage III disease. The median troponin I level was 0.121 ng/mL (range, 0.006 – 0.523), and the median BNP was 224 pg/mL (range, 18–923). The median interventricular septal thickness was 13 mm (range, 9–18) and the median LVEF was 60% (range, 40–70). Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. The total dose of melphalan, administered over two consecutive days, depending on age, severity of cardiac disease and performance status. Forty % (n=14) received 200 mg/m2 HDM and 60% (n=21) received 140 mg/m2 HDM. TRM, defined as deaths within 100 days of SCT, occurred in 3 patients (9%), all cardiac stage III (3/20, 15% of the stage III patients); patients with cardiac stage I or II did not have any TRM. This compares to a TRM of 3% (n=1/30) in patients without cardiac involvement who were treated with HDM/SCT during the same time period (Fisher's exact test, p=0.6177). There were two additional deaths during the first year after HDM/SCT, one with cardiac stage II disease and one with stage III disease. Three-year overall survival for combined Stage I and II disease was 93%, for Stage III it was 76%, and for the cohort without cardiac involvement it was 96% (p=0.08). Three-year progression free survival for combined Stage I and II disease was 69%, for Stage III it was 45%, and without cardiac involvement it was 69% (p=0.0424). Median overall survival and progression free survivals have not been reached, with a median follow-up for 21 months. By intention-to-treat analysis, 23% (n=8) of patients achieved a hematologic complete response (CR) and 46% (n=16) a partial response (PR) at 1 year following HDM/SCT. Thirty % (n=11) required additional treatment by one year following HDM/SCT. While the cardiac biomarker stage III group clearly encompasses patients at high risk of early mortality from disease and complications of treatment, for patients that meet functional criteria for HDM/SCT, this therapeutic modality may offer the potential for effective treatment for selected stage III patients. Disclosures: No relevant conflicts of interest to declare.

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European Collaborative Study of Treatment Outcomes in 347 Patients with Systemic AL Amyloidosis with Mayo Stage III Disease

Blood ◽

10.1182/blood.v118.21.995.995 ◽

2011 ◽

Vol 118 (21) ◽

pp. 995-995 ◽

Cited By ~ 1

Author(s):

Ashutosh Wechalekar ◽

Stefan O Schonland ◽

Efstathios Kastritis ◽

Philip N Hawkins ◽

Meletios A. Dimopoulos ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Clinical Trials ◽

High Risk ◽

Cardiac Involvement ◽

Staging System ◽

Stage Iii ◽

Al Amyloidosis ◽

High Risk Factors ◽

Intent To Treat

Abstract Abstract 995 N-terminal fragment of BNP (NT-proBNP) and cardiac troponin –T (TnT) or I (TnI) form a useful staging system in AL amyloidosis and poor outcomes have been reported in stage III patients treated before routine use of novel agents. These patients are routinely excluded from clinical trials and prospective outcome data is limited but recent studies suggest that some such patients may have better outcomes. We report the outcomes of 347 patients with Mayo stage III AL amyloidosis seen at the amyloid centres in London (UK), Pavia (Italy), Heidelberg (Germany) and Athens (Greece). Organ involvement and responses are defined according to 2005 amyloidosis consensus criteria. Presenting features were [n (%)/median (range)]: cardiac, renal and liver involvement in 338 (97%), 216 (62%) and 77 (22%) respectively, NT-proBNP 9106 ng/L (379–216187); TnI – 0.18 ng/ml (0.1–12); TnT −0.09 ng/ml (0.04–8.2) and IVS 15 mm (7–24). Treatments given were: Bortezomib combinations - 23 (7%), MDex - 150 (43%), thalidomide combinations - 96 (28%), lenalidomide combinations - 13 (4%). 30 (8%) were deemed too ill for treatment or died prior to treatment initiation. Only 37% completed the planned treatment course. The haematological responses on an intention to treat basis were seen in (Overall response rate/complete response (CR)/partial response (PR))(n(%)): MDex – 63(42%)/24 (16%)/39 (26%); Thalidomide combinations 31(32%)/11(12%)/20(21%), bortezomib combinations 10(43%)/6 (23%)/4 (17%), lenalidomide combination 5(38%)/0(0%)/5(38%). The median overall survival (OS) was 7.1 mos. The overall survival at 12 months from response evaluation was 74% for CR, 52% for PR and 18% for NR and from diagnosis was (median): CR – 59 mo, PR 28 mo, NR 10 mo and not assessable for response 2.9 mos. Stage III patients without echocardiographic evidence of cardiac involvement had excellent outcomes with 80% estimated 2 year OS. Using best fit cut-off, in multivariate model (including NT-proBNP., systolic blood pressure (SBP), ejection fraction, NYHA, ECOG, dFLC, LV wall thickness), NT-proBNP > 8000 ng/L (HR 2.3; p <0.0001) and SBP < 100 mm of Hg (HR 1.6; p<0.0001) were the only independent predictors of poor outcome. Using NT-proBNP >8000 ng/L and SPB <100 mm of Hg as high risk criteria, stage III patients can be further subdivided based on presence of none, one or two criteria with OS of 25 mo, 6 mo and 3 mo respectively. Using these criteria, on intent to treat basis, OS by CR/PR/NR was: no high risk factors – median not reached/69 mo/7 mo and one high risk factor - 59 mo/23 mo/4 mos respectively and too few patients for patients with two high risk factors making comparison unreliable. In conclusion, outcomes amyloidosis patients with stage III disease remain poor. However, stage III patients are heterogeneous and combination of NT-proBNP and SBP can usefully sub-classify these patients. Patients with abnormal biomarkers just due to renal failure in absence of cardiac involvement should be excluded from the current Mayo staging system. Although, treatment responses of stage III patients, on intent to treat basis, are poor with all regimes, it is encouraging that haematological responses improve outcomes and patients who achieve a CR have best outcomes. Clinical trials are urgently needed in patients with stage III disease to confirm these findings and define optimal treatment options. Disclosures: No relevant conflicts of interest to declare.

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