Zanubrutinib in AL amyloidosis associated with Waldenström Macroglobulinemia and other B-cell Non-Hodgkin Lymphoma
Approximately 5-7% of immunoglobulin amyloid light-chain (AL) amyloidosis cases are associated with IgM M-proteinemia and/or an underlying B-cell clone (B-NHL), such as IgM monoclonal gammopathy of undetermined significance (MGUS) or Waldenström Macroglobulinemia (WM). Intensive immunochemotherapy is considered the preferred treatment option, but it is often not feasible due to age and/or amyloid-related morbidities or may not lead to the required deep response. Bruton tyrosine kinase inhibitors (BTKi) are highly effective in WM. However, in a small case series with ibrutinib in IgM amyloidosis, serious (cardiac) side effects were observed, translating into poor tolerability. Zanubrutinib, a BTKi associated with less (cardio)toxicity and a trend towards deeper responses, could potentially be a more feasible approach.
Between November 2020 and December 2024, data of all consecutive AL amyloidosis patients with underlying WM or other B-NHL that took at least 1 dose of zanubrutinib were retrospectively collected across 11 (inter)national hospitals. All patients signed informed consent. Hematologic and organ response parameters were collected every 3 and 6 months, respectively, and assessed according to consensus criteria for AL amyloidosis. AEs were graded in accordance with CTCAE v5.0.
Twenty-one patients with AL amyloidosis associated with WM or other B-NHL were included (Figure 1). Median follow-up was 14.2 months (range 2.5-43.1) and median time on zanubrutinib was 7.9 (range 1.6-24.4) and in 9 (43%) patients, therapy was still ongoing. At best response, responses were observed in 8 of 19 (42%) patients, of which 4 (21%) achieved a very good partial response (VGPR).
Three (14%) patients died while on therapy due to progression of AL amyloidosis, of which 2 related to heart failure in patients with Mayo stage II & IIIb cardiac involvement. It is unknown to what extent these were related to the cardiac amyloid and/or the zanubrutinib. Two (10%) patients died after discontinuation of zanubrutinib, 1 from infection and 1 due to pancreatic carcinoma. Median overall survival (OS) and event-free survival (EFS) were not reached (Figure 2). OS at 12 months was 90% (95% CI, 78-100%). Grade ≥3 AEs were reported in 12 (57%) patients, mostly concerning neutropenia/infections and bleeding diathesis.
Zanubrutinib resulted in a 42% overall hematologic response rate and a 1 year OS of 90% in this subgroup of mostly pretreated patients. Cardiac events remain a concern particularly with high grade cardiac amyloid involvement, and deep responses are still achieved in only a minority, indicating there is still an unmet need for effective treatment. However, these data suggest that zanubrutinib might represent a feasible treatment option for patients with AL amyloidosis with underlying WM or other B-NHL, especially for patients unfit for or refractory to intensive immunochemotherapy.