Characteristics and Long-Term Outcome of Patients with Systemic Immunoglobulin Light-Chain Amyloidosis

2014 ◽  
Vol 133 (4) ◽  
pp. 336-346 ◽  
Author(s):  
Lærke Marie Nelson ◽  
Finn Gustafsson ◽  
Peter Gimsing
Keyword(s):  
Light Chain ◽  
Treatment Strategy ◽  
Cardiac Involvement ◽  
Al Amyloidosis ◽  
Single Center ◽  
Immunoglobulin Light Chain ◽  
Long Term Outcome ◽  
Cardiac Amyloid ◽  
Current Series

Background/Aims: Immunoglobulin light-chain (AL) amyloidosis is a systemic disorder that causes progressive organ dysfunction. The optimal treatment strategy requires accurate patient stratification with an emphasis on the extent of cardiac involvement. Reports on its prognosis are sparse and predominantly originate from highly selected centers. We aimed to evaluate patient characteristics and outcomes in a cohort treated at a single center. Methods: This is a single-center retrospective study of 63 consecutive patients diagnosed with AL amyloidosis between January 2000 and December 2012. Patients were evaluated by treatment strategy and cardiac involvement. Results: The mean age at diagnosis was 61.4 years (±8.9), and 39 patients (62%) were male. Thirty-two (51%) patients presented with cardiac amyloid involvement (CA) and the remaining 31 (49%) had noncardiac amyloidosis (NCA). The median follow-up time was 12.7 months (0.3-90.8), and 38 (60%) patients died during follow-up. The median overall survival (OS) was 29 months (95% CI 12.1-57.2) and the OS was not significantly lower for patients with CA compared to NCA (log-rank = 0.21). Conclusion: The prognosis in AL amyloidosis is grave, but the outcome with treatment in the current series was comparable to those in series from larger centers. CA did not significantly predict the OS.

scholarly journals Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Paolo Swuec ◽  
Francesca Lavatelli ◽  
Masayoshi Tasaki ◽  
Cristina Paissoni ◽  
Paola Rognoni ◽  
...  
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Cardiac Amyloid

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4525-4525 ◽  
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.

scholarly journals Solid state NMR assignments of a human λ-III immunoglobulin light chain amyloid fibril

2020 ◽  
Author(s):  
Tejaswini Pradhan ◽  
Karthikeyan Annamalai ◽  
Riddhiman Sarkar ◽  
Ute Hegenbart ◽  
Stefan Schönland ◽  
...  
Keyword(s):  
Solid State ◽  
Light Chain ◽  
Solid State Nmr ◽  
Cardiac Involvement ◽  
Gene Segment ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Fibril Structure ◽  
Amyloid Deposits ◽  
Complementarity Determining Regions

Abstract The aggregation of antibody light chains is linked to systemic light chain (AL) amyloidosis, a disease where amyloid deposits frequently affect the heart and the kidney. We here investigate fibrils from the λ-III FOR005 light chain (LC), which is derived from an AL-patient with severe cardiac involvement. In FOR005, five residues are mutated with respect to its closest germline gene segment IGLV3-19 and IGLJ3. All mutations are located close to the complementarity determining regions (CDRs). The sequence segments responsible for the fibril formation are not yet known. We use fibrils extracted from the heart of this particular amyloidosis patient as seeds to prepare fibrils for solid-state NMR. We show that the seeds induce the formation of a specific fibril structure from the biochemically produced protein. We have assigned the fibril core region of the FOR005-derived fibrils and characterized the secondary structure propensity of the observed amino acids. As the primary structure of the aggregated patient protein is different for every AL patient, it is important to study, analyze and report a greater number of light chain sequences associated with AL amyloidosis.

Abnormal NT-ProBNP in AL Amyloidosis Patients without Cardiac Involvement at Diagnosis - A Predictor of Subsequent Cardiac Involvement.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1500-1500
Author(s):  
Ashutosh D. Wechalekar ◽  
Helen J. Lachmann ◽  
Julian D. Gillmore ◽  
Philip N. Hawkins
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Myocardial Dysfunction ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
International Consensus ◽  
Cardiac Amyloid ◽  
Significant Difference

Abstract Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased treatment related morbidity and mortality, and regression of cardiac amyloid deposits is extraordinarily slow following chemotherapy that suppresses the underlying aberrant light chain production. Diagnosis of cardiac amyloidosis is normally made by echocardiography, by which time significant diastolic dysfunction has usually developed. Atrial natriuretic peptides (ANP, BNP and its N-terminal fragment NT-ProBNP) are useful in early diagnosis of myocardial dysfunction. Serum NT-ProBNP concentration has been reported to be a promising marker of cardiac dysfunction in AL amyloidosis, and patients with normal NT-ProBNP values at diagnosis have superior outcomes. We report here the outcome of patients attending the UK National Amyloidosis Centre (NAC) who had elevated NT-ProBNP at diagnosis of AL amyloidosis but who did not have accompanying evidence of cardiac involvement using conventional consensus criteria. To exclude the confounding effect of renal failure which is associated with substantial elevation of NT-ProBNP, we studied patients with serum creatinine <150 μmol/L and creatinine clearance of >50ml/min at diagnosis in whom there was less than 10% change in renal function after treatment. AL type amyloidosis was confirmed in all patients histologically with corroborating genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses/progression were defined according to recent international consensus criteria (Gertz et al 2005). 102 patients who had no evidence of cardiac involvement by these conventional parameters and who otherwise conformed with our study criteria were identified. Median creatinine was 87 μmol/L (44–128), albumin 33g/L (10–65), bilirubin 7 μmol/L (1–65) and alkaline phosphatase 89 units/L (36–2649). The median interventricular septal and left ventricular posterior wall thickness was 9 mm (7–11 mm). 62 (61%) patients had NT-ProBNP ≤ 35pMol/L at diagnosis while 40 (39%) had NT-ProBNP of >35 pMol/L. There was no significant difference in the baseline characteristics of either group. 5 patients in each group did not respond to the initial chemotherapy (p=0.46). With median follow-up of 60 months, 19/40 (47%) of patients with NT-ProBNP >35pMol/L at diagnosis developed evidence of cardiac involvement compared to only 6/62 (10%) of whose baseline NT-ProBNP was ≤ 35 pMol/L (p<0.001). The Kaplan-Meier estimated median overall survival has not been reached for either group but the estimated 7 year survival was significantly better in the group with NT-ProBNP of ≤35pMol/L compared to those with greater values (92% vs. 82%, p=0.03). In conclusion, these preliminary findings suggest that patients who have elevated NT-ProBNP concentration but no conventional evidence of cardiac involvement at diagnosis of AL amyloid appear to be at greater risk of developing cardiac amyloidosis during follow-up, and have a poorer prognosis. It reasonable to speculate that such patients have early cardiac involvement at diagnosis that cannot be identified by conventional non-invasive methods, and that their risk of subsequently developing clinically significant cardiac amyloidosis may be reduced by striving to achieve complete remission of their underling clonal plasma cell disease.

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

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2887-2887 ◽  
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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