Immunoglobulin Heavy Chain Amyloidosis: Patient Characteristics and Outcomes

Introduction Amyloidosis is a disorder caused by aggregation and deposition of misfolded proteins into highly ordered insoluble amyloid fibrils. The disorder can be caused by various proteins. Immunoglobulin (Ig)-related amyloidosis usually manifests as light chain amyloidosis (AL), but it may rarely manifest as heavy chain (AH) or heavy/light-chain (AHL) amyloidosis. Data regarding AH/AHL is limited in the literature. Methods We retrospectively reviewed the medical records of patients seen at Mayo Clinic Rochester with biopsy-proven MS-confirmed AH/AHL between 2003 to 2021. In patients who received treatment, hematologic and organ responses were assessed based on consensus criteria. Overall survival (OS) was calculated from time of diagnosis to death of any cause or last follow-up. Results We identified 28 patients with AH/AHL seen at Mayo Clinic, including two patients with localized amyloidosis. Baseline characteristics are presented in Table 1. Eleven patients had AH, with IgG being the most common subtype. The remaining 17 patients had AHL, most commonly with an underlying IgM monoclonal gammopathy. In patients with AHL, 9 (53%) had an associated kappa light chain and 8 (47%) had an associated lambda light chain. Patients were mostly diagnosed after routine testing showed increased serum creatinine or proteinuria (30%), or after presenting with generalized edema secondary to nephrotic range proteinuria (18%). Other presenting symptoms included peripheral neuropathy, chronic cough, palpitations, nausea and vomiting, and hematuria. No monoclonal protein was detected in the serum of 7 patients (26%); Another 7 patients (26%) had a monoclonal protein detected by IFE/Mass-Fix only. Of the remaining 13 patients with a measurable serum monoclonal protein, the median level was 1.7 g/dL (interquartile range 0.6 to 2.5). The median involved free light chain (iFLC) level was 3.29 (range 1.2 to 136) and median difference between iFLC and uninvolved FLC (dFLC) was 2 mg/dL (interquartile range 0.94 to 26). Amyloid was detected in the bone marrow biopsies of 10/27 patients (37%); 17 (63%) had an underlying plasma cell neoplasm (median bone marrow plasma cell burden 9%, range 4-70), 8 (30%) had underlying lymphoplasmacytic clone (median bone marrow burden 20%, range 5-80), and 2 (7%) had underlying chronic lymphocytic leukemia clone (median bone marrow burden 10%, range 5-15). One patient had both a plasma cell neoplasm and a CLL clone. Fat aspirate was positive for amyloid in only 2/19 (11%). Of the 20 patients with baseline data available for staging, per the Mayo 2012 classification criteria, 11 (55%) were in stage I, 6 (30%) were in stage II, 3 (15%) were in stage III and no patients had stage IV disease. Most patients (67%) had single organ involvement, with 19% having two organs involved and 11% with three organs involved. The kidneys were the most involved organ (56%), with the peripheral nervous system and heart being the next two most involved organs, 22% and 19% respectively. Other involved organs include lungs (localized), bladder (localized), lymph nodes, mesentery, ureters, and thyroid. Various treatments were used in 26 patients but response data was only available for 19 patients, with 6 (32%) achieving hematologic CR, 5 (26%) achieving VGPR, 6 (32%) achieving PR, and 2 (11%) having no response; 7 (37%) had at least 1 organ response after the first line of treatment, exclusively in patients who achieved CR or VGPR. After median follow up of 6.9 years, 9 patients died. The 1-year overall survival (OS) was 96% and 5-year OS was 66%. Conclusion AH/AHL is a rare disorder, mostly involving one organ (frequently renal), associated with underlying plasma cell neoplasms or lymphoproliferative disorders. When compared to a previously published cohort of patients with AL seen at Mayo Clinic, patients with AH/AHL had a similar median age, but more patients had underlying IgM monoclonal gammopathy, a lower iFLC and dFLC, less advanced disease and longer OS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal