Clinical Characteristics and Therapeutic Response of Patients with Heavy Chain (AH) and Heavy and Light Chain (AHL) Amyloidosis

Background

Heavy chain (AH) and heavy and light chain (AHL) amyloidosis are rare subtypes of immunoglobulin-associated amyloidosis. They involve the accumulation of fibrils composed of fragments from the variable and constant domains of the heavy chain alone (AH) or both the heavy and light chains (AHL). Data on the clinical characteristics and treatment responses for these subtypes are limited.

Aim

To improve the understanding of AH and AHL amyloidosis, we report on the clinical characteristics and therapeutic outcomes of patients with AH and AHL amyloidosis who were evaluated at the Boston University Amyloidosis Center.

Methods

We conducted a retrospective review of patients seen at our institution between 2002 and 2024. Inclusion criteria was a biopsy-proven diagnosis of either AH or AHL amyloidosis by mass spectrometry (MS) or immunohistochemistry (IHC). Medical records were examined for demographics, clinical features, treatments administered, and organ response to treatment. This study was approved by the Boston University Institutional Review Board, and all patients provided written consent as per the Declaration of Helsinki.

Results

Of 2468 patients evaluated for amyloidosis between 2002 and 2024, 28 patients were diagnosed with AH (n=7) or AHL (n=21) amyloidosis. The cohort included 19 females (68%) with a median age of 73 years (range 54-86). The racial/ethnic distribution was 21 White, 4 Black, 2 non-Black Hispanics, and 1 Asian. Renal involvement was present in 20 patients (71%), with a median initial creatinine level of 1.5 mg/dL (IQR 0.88-1.89) and median 24-hour proteinuria level of 6.1 g/day (IQR 2.3-9.5), 17 of 20 patients (80%) had microscopic hematuria on presentation. Renal disease stages were stage I in 4 patients, stage II in 13 patients, and stage III in 3 patients. Cardiac, lung, hepatic, and gastrointestinal involvement was seen in 5 (18%), 4 (14%), 2 (7.1%), and 1(3.6%) patients respectively. Among AH patients, 5 of 7(71 %) had single-organ involvement including renal (n=2), lung (n=1), bladder (n=1) and skin (n=1). In AHL patients, 14 of 21 (66%) had single-organ involvement including renal (n=9), lung (n=3), palate (n=1), and cardiac (n=1).

Diagnosis was primarily established through kidney (n=20, 72%) or lung/endobronchial biopsy (n=4, 14%). Heavy chains were detected via IHC in 16 patients (57%) and MS in 12 patients (43%). The gamma chain was the most common heavy chain subtype identified (n=17, 61%), followed by mu (n=3, 11%). In AHL, the light chain isotype was lambda in 14 of 21 patients (66%). 6 of 28 patients had no detectable circulating monoclonal immunoglobulin in serum or urine. Bone marrow biopsy revealed plasma cell proliferation in 15 patients (54%) and lymphoplasmacytic proliferation or lymphoma in 5 patients(18%). Cytogenetic studies were available for 20 patients, with t(11;14) translocation detected in 3 patients(15%).

Treatment was administered in 20 of 28 patients, including high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) in 7 patients (35%), bortezomib-based regimens in 6 patients(30%), daratumumab-based chemotherapy in 4 patients (20%), and other regimens in 3 patients(15%). The median overall survival was 8.4 years. Due to the absence of standardized criteria for assessing hematologic response in AH or AHL amyloidosis, we used AL amyloidosis criteria for patients with a baseline dFLC > 50 mg/L only, 7 of 9 patients achieved Very Good Partial Response or better. Among 10 patients with available follow-up proteinuria data, 7 had a >50% reduction in 24-hour proteinuria at 12 months.

Conclusion

AH and AHL amyloidosis are exceedingly rare, accounting for only 1.1% of amyloidosis patients seen at our institution during the study period. In this series of 28 patients, AH and AHL amyloidosis were more frequently diagnosed in elderly White women. Renal involvement is the most common (75%) with a high rate of microscopic hematuria (81%) followed by cardiac (18%) and pulmonary (14%), suggesting a different organ tropism when compared to AL amyloidosis. Notably, 21% of patients had no detectable circulating monoclonal immunoglobulin. The median overall survival and organ response rates suggest a generally favorable prognosis, which might in part be explained by the high proportion of patients (68%) with single-organ disease but further studies are needed to confirm these findings.

Sanchorawala:Proclara, Caelum, Abbvie, Janssen, Regeneron, Protego, Pharmatrace, Telix, Prothena, AstraZeneca, Nexcella: Membership on an entity's Board of Directors or advisory committees; Pfizer, Janssen, Attralus, GateBio, Abbvie, BridgeBio: Consultancy; Celgene, Millennium-Takeda, Janssen, Prothena, Sorrento, Karyopharm, Oncopeptide, Caelum, Alexion: Research Funding.