ABNORMAL LIGHT-CHAIN TESTING AND DIAGNOSIS OF TRANSTHYRETIN AMYLOID CARDIOMYOPATHY (ATTR-CM) AMONG PATIENTS REFERRED FOR TECHNETIUM-99M PYROPHOSPHATE IMAGING

Background: Amyloid cardiomyopathy progresses more rapidly and has different manifestations than more common cardiomyopathies. Nevertheless, survival of selected cardiac amyloid patients after orthotopic heart transplantation (OHT) followed by autologous stem cell transplant is similar to other restrictive cardiomyopathies. The importance of clinical presentation and pre-transplantation characteristics on outcome in patients with AL amyloid cardiomyopathy evaluated for heart transplantation is still not well defined. Methods: The impact of echocardiographic, hemodynamic, and clinical parameters on outcome in 46 patients evaluated for OHT and enrolled in the International Consortium for Cardiac Amyloid Transplant (iCCAT) database was studied. Cox proportional hazards models of time to death were used. End point was death after transplant evaluation censored at transplant. Results: The median age at the time of transplant evaluated was 57.6 (+/- 9.6) years, and the mean time from presentation to listing was 27 (+/- 26) days. 19 (41%) patients underwent OHT after an average wait time of 72 days. Univariate risk factors associated with death after initial evaluation were cardiac output (p=0.012), right ventricular stroke work index (p=0.033), left ventricular end diastolic dimension (p=0.024), left ventricular outflow tract velocity time integral (p=0.019), mean arterial pressures (p=0.005), NT pro-BNP (p=0.007), presence of pleural effusion (p=0.005), as well as elevated kappa and lambda serum free light chain concentrations (p=0.004). Whereas left ventricular ejection fraction did not correlate with death after evaluation, increased right ventricular wall thickness remained a strong mortality predictor in a multivariate model with light chain difference and cardiac output (HR 1.6 for every 1 mm increase in thickness, p=0.017). Conclusions: Pleural involvement, high light chain burden, and right ventricular infiltration predicted death while awaiting a donor organ and may be markers of more systemic disease. Ultimately, this could affect transplant candidate selection and allocation strategies.

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Rare Concomitance of Primary Systemic Amyloidosis with Immunoglobulin M Monoclonal Gammopathy or Waldenstrom Macroglobulinemia.

Blood ◽

10.1182/blood.v104.11.1502.1502 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1502-1502

Author(s):

Kathleen A. Hecksel ◽

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Morie A. Gertz

Keyword(s):

Median Survival ◽

Light Chain ◽

Mayo Clinic ◽

Plasma Cells ◽

Systemic Amyloidosis ◽

Lambda Light Chain ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Amyloid Cardiomyopathy ◽

Echocardiographic Evidence

Abstract Introduction: Primary systemic amyloidosis occurs when a clonal plasma cell population secretes light chains (or light chain fragments) that deposit in tissues as amyloid and cause organ failure and ultimately patient death. Primary systemic amyloidosis generally results from non-proliferative small populations of plasma cells. While it is known that IgG, IgA and light chain producing plasma cells can secrete amyloid in association with myeloma, fewer medical professionals recognize that IgM-secreting lymphoplasmacytic cells can produce amyloid proteins. When monoclonal IgM secreting marrow lymphocytes are present, amyloidosis can result with or without overt Waldenstrom Macroglobulinemia. Patients and Methods: All patients seen at the Mayo Clinic between January 1968 and August 2000 with both a serum IgM monoclonal protein and biopsy-proven amyloidosis were analyzed. The Mayo Clinic Dysproteinemia Database recognized 128 patients (42 female, 86 male) with a median age of 65 years. Results: Seventy-two percent (n=92) of the patients have died with a median survival of 1.72 years following biopsy proven amyloidosis (figure 1). Median serum IgM monoclonal spike was 1.38 g/dL. In addition, serum IgM kappa to lambda light chain ratios (1:3) were found to be reversed in patients with IgM gammopathy when amyloid was present (compared to the reverse ratio (3:1) in patients with Waldenstrom macroglobulinemia in the absence of amyloidosis). Subcutaneous fat, rectum and bone marrow revealed amyloid in 72%, 69% and 70%, respectively, providing non-invasive techniques for amyloidosis diagnosis without the risks of bleeding associated with renal or hepatic percutaneous biopsy. Variables not shown to affect survival included the following: age, gender, serum M spike, urine protein, alkaline phosphatase, creatinine, light chain isotype, ejection fraction, and percent marrow plasma cells. The presence of amyloid cardiomyopathy (defined as a cardiac interventricular septal thickness greater than 12 mm.) was the only variable to adversely affect survival. Of the patients with echocardiographic evidence of cardiomyopathy, the median survival was 10.8 months. In contrast, the patients without echocardiographic evidence of cardiomyopathy at diagnosis had a median survival of 39 months (figure 2). Conclusion: Amyloidosis is underappreciated and should be considered in the differential diagnosis of all patients presenting with IgM gammopathy. Patients found to have amyloidosis in this setting should be tested for amyloid cardiomyopathy, as its presence predicts poor outcome. Lambda light chain in serum IgM samples should increase the index of suspicion for the presence of amyloid since IgM lambda is present in only 25% of IgM MGUS or Macroglobulinemia patients but is seen in 75% of IgM amyloidosis patients. Figure Figure

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Autologous Stem Cell Transplant after Heart Transplant for Light Chain (AL) Amyloid Cardiomyopathy

The Journal of Heart and Lung Transplantation ◽

10.1016/j.healun.2008.05.016 ◽

2008 ◽

Vol 27 (8) ◽

pp. 823-829 ◽

Cited By ~ 83

Author(s):

Martha Q. Lacy ◽

Angela Dispenzieri ◽

Suzanne R. Hayman ◽

Shaji Kumar ◽

Robert A. Kyle ◽

...

Keyword(s):

Stem Cell ◽

Heart Transplant ◽

Light Chain ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Amyloid Cardiomyopathy ◽

Al Amyloid

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Free Light-Chain Levels in Patients with Transthyretin Amyloid Cardiomyopathy in Attr-ACT

Blood ◽

10.1182/blood-2021-148691 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3787-3787

Author(s):

James E Hoffman ◽

Marla B. Sultan ◽

Balarama Gundapaneni ◽

Ronald Witteles

Keyword(s):

Plasma Cell ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Publicly Traded ◽

Monoclonal Gammopathies ◽

Plasma Cell Disorder ◽

The Mean ◽

Amyloid Cardiomyopathy ◽

Cell Disorder

Abstract Introduction: In cardiac amyloidosis (CA), immunoglobulin-derived light chains (AL) and transthyretin (TTR) are the most common amyloidogenic proteins infiltrating the heart. 1 Identification of the specific precursor protein leading to amyloid deposition is needed to establish the correct therapeutic approach. 2 In both AL- and TTR-related CA, an early and accurate diagnosis is critical to achieving the best treatment outcomes. TTR amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as other causes of heart failure (HF), including AL CA. 3 While almost all patients with AL amyloidosis have elevated serum free light-chain (sFLC) levels and abnormal free kappa:lambda (κ:λ) ratios, 4 patients with ATTR-CM can also have abnormal sFLC levels due to either an unrelated monoclonal gammopathy or relative κ-predominance in renal dysfunction. 2,5 Because ATTR-CM most often occurs in elderly adults and is commonly accompanied by renal comorbidity, we theorized that patients with ATTR-CM may have κ:λ ratios that approach, or exceed, the upper limit of the normal reference range (0.26-1.65 6). High light-chain ratios in these patients have the potential to increase the likelihood of misdiagnosis of a monoclonal plasma cell disorder and may lead to unnecessary referrals to hematologists and/or inappropriate treatments. To explore this theory, we evaluated κ:λ ratios in patients with biopsy-proven ATTR-CM who were enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). 7 Methods: In ATTR-ACT, a double-blind, placebo-controlled, randomized study, patients with biopsy-proven ATTR-CM, and without light-chain amyloidosis, received tafamidis or placebo for 30 months. In the current analysis, sFLC levels and κ:λ ratios were assessed in the intent-to-treat population (N=441), excluding patients with a prior diagnosis of monoclonal gammopathies (n=13; defined by MedDRA preferred terms: 'monoclonal gammopathy', 'plasma cell myeloma', 'plasma cell disorder', and 'hypergammaglobulinemia benign monoclonal'). Subgroup analyses were performed by estimated glomerular filtration rate (eGFR) category (≥60 vs ≥40 to <60 vs <40 mL/min/1.73 m 2). Findings were summarized using descriptive statistics (min/max, mean, median, and interquartile range [IQR]). Results: In 422 patients with ATTR-CM and available sFLC data, and without a prior diagnosis of monoclonal gammopathies, the mean κ:λ ratio was 1.45 (median, 1.20 [IQR, 0.98, 1.47]) (Figure). The ratio increased with declining renal function: eGFR ≥60 mL/min/1.73 m 2, mean, 1.25 (median [IQR], 1.11 [0.94, 1.38]); ≥40 to <60 mL/min/1.73 m 2, 1.52 (1.22 [0.99, 1.49]); and <40 mL/min/1.73 m 2, 1.62 (1.30 [1.05, 1.68)]. Conclusions: In patients with biopsy-proven ATTR-CM without known monoclonal gammopathies who were enrolled in ATTR-ACT, the mean κ:λ ratio showed a κ-predominance, often exceeding the upper range of normal in patients with more advanced kidney dysfunction. The findings suggest that individuals with ATTR-CM can have higher sFLC levels than those normally seen in the general population, and such elevations do not necessarily indicate the presence of monoclonal gammopathy of undetermined significance or AL CA. In an era when most patients with ATTR-CM and without monoclonal gammopathies are diagnosed noninvasively using bone scintigraphy, age- and renal-function-based sFLC norms are critical to ensure appropriate use of diagnostic testing modalities. References: 1. Maleszewski JJ. Cardiovasc Pathol. 2015;24:343-50. 2. Donnelly JP, et al. Cleve Clin J Med. 2017;84:12-26. 3. Witteles RM, et al. JACC Heart Fail. 2019;7:709-716. 4. Falk RH, et al. J Am Coll Cardiol. 2016;68:1323-41. 5. Geller HI, et al. Mayo Clin Proc. 2017;92:1800-5. 6. Katzmann JA, et al. Clin Chem. 2002;48:1437-44. 7. Maurer MS, et al. N Engl J Med. 2018;379:1007-16. Figure 1 Figure 1. Disclosures Hoffman: BMS, Celgene: Honoraria. Sultan: Pfizer: Current Employment, Current equity holder in publicly-traded company. Gundapaneni: Pfizer: Current Employment, Current equity holder in publicly-traded company. Witteles: Pfizer: Honoraria, Research Funding; Alnylam: Honoraria, Research Funding; Eidos: Research Funding.

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