In:
Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2952-2952
Abstract:
Background: Immunoglobulin light chain-associated (AL) amyloidosis is associated with the deposition of fibrils in abdominothoracic organs, notably the heart, liver, spleen and kidneys, resulting in organ dysfunction and significant morbidity. The heterogeneous organ presentation of amyloid and the variable amounts of amyloid burden make accurate and rapid diagnosis challenging. At present, organ biopsy and inferences based on anatomic imaging or changes in serum and urine biomarkers are commonly used to assess organ involvement. Currently, there are no approved radiotracers in the US for the non-invasive detection of AL amyloid load in major organs. To address this, we have developed a synthetic peptide radiotracer, designated 124I-p5+14 (AT-01), suitable for PET/CT imaging. This peptide binds many forms of amyloid through multivalent electrostatic interactions with the amyloid-associated glycosaminoglycans and fibrils. Preclinical studies demonstrated the specific reactivity of the peptide with diverse forms of amyloid (Wall, J.S. et al. (2015) Molecules, 20, 7657). Based on these observations, peptide p5+14 was labeled with iodine-124 and evaluated in a Phase 1/2 PET/CT imaging trial of patients with systemic amyloidosis (NCT 03678259). Herein we describe 23 patients with systemic AL amyloidosis and 5 healthy subjects that have completed the study. Efficacy endpoints include patient- and organ-based sensitivity of 124I-p5+14 uptake in the heart, liver, spleen and kidney. Methods: Subjects, & gt;18 years of age, with a confirmed diagnosis of AL amyloidosis based on organ or abdominal fat pad biopsy findings, with organ-related biomarker changes. Patients taking heparin therapy were excluded. Subjects received an IV infusion of & lt;2 mg of 124I-p5+14 ( & lt;2 mCi) and images were acquired at 5-6 h post injection using a Biograph PET/CT with a low dose CT. Prior to imaging, the organ-based distribution of amyloid was determined based on review of the medical record. PET/CT images were evaluated for visual uptake of radiotracer by a reader blinded to patient-related clinical data. Patient and organ-specific sensitivity were determined based on comparison of visual interpretation of the images by a reader blinded to organ involvement and the organ involvement based on the clinical record. Results: Twenty-three patients with systemic amyloidosis and five healthy subjects completed the study. No subjects discontinued or were lost to follow-up. In healthy subjects, radioactivity was observed in the parotid, salivary and thyroid glands, saliva, stomach lumen and urine in the ureters and bladder, consistent with the biodistribution of free radioiodide. No uptake in abdominothoracic organs was observed. In contrast, patients with AL amyloidosis exhibited uptake in the heart (71% of patients), kidneys (61%), spleen (43%), liver (30%), pancreas, lung, bone marrow and other sites. The patient-based sensitivity (patients with visual uptake in at least one anatomic site) was 96% (22/23). The organ-based sensitivity (i.e., clinically positive heart, liver, spleen or kidney that exhibited visual uptake of 124I-p5+14) was 86% (13/14 heart; 3/3 liver; 1/1 spleen; 7/10 kidney). Of note, the one patient without cardiac uptake was 8 years post diagnosis and 7 years post successful stem cell transplant therapy. The percent of abdominothoracic organs detected by PET/CT imaging was 68% higher (47 vs 28) than was noted clinically (16/14 heart; 7/3 liver; 10/1 spleen; 14/10 kidney) Conclusion: PET/CT imaging of amyloidosis using 124I-p5+14 provides accurate detection of AL amyloid deposits in multiple organ systems. Clinically undetected amyloid was observed in numerous anatomic sites with amyloid visualized by 124I-p5+14 in 68% more abdominothoracic organs as compared to that documented in the clinical record. Non-invasive PET/CT imaging with 124I-p5+14 can improve detection of amyloid throughout the body providing a more comprehensive picture of the disease and may provide a method to monitor changes in disease progression. Acknowledgments: This study was supported in part by the National Heart Lung and Blood Institute, National Institutes of Health, through the Science Moving Towards Research Translation and Therapy (SMARTT) program and by contributions to the ACTP Gift Fund at the UTGSM. Disclosures Wall: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder, Research Funding. Martin: Attrlaus Inc: Current holder of stock options in a privately-held company. Stuckey: Attralus Inc: Current holder of stock options in a privately-held company. Guthrie: Attralus Inc: Current Employment, Current holder of stock options in a privately-held company. Kennel: Attralus Inc: Current holder of stock options in a privately-held company, Patents & Royalties: Inventor and patent holder.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2021-154327
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2021
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1468538-3
detail.hit.zdb_id:
80069-7
