Long-term follow-up of venetoclax therapy in AL amyloidosis

Abstract Background: The t(11;14) translocation occurs in 50–60% of patients with systemic AL amyloidosis. Venetoclax, an oral BCL-2 inhibitor, has shown promising efficacy across t(11;14)-positive plasma cell disorders, including AL amyloidosis. Previous studies have demonstrated high overall response rates with the use of venetoclax, especially in patients with t(11;14); however, long-term data on the durability of these responses are lacking. Methods: We conducted a multicenter, retrospective review of patients with AL amyloidosis treated with venetoclax. Eligible patients included those with biopsy-proven AL amyloidosis who had received venetoclax as part of their therapy. Baseline characteristics—including demographics, disease stage and organ involvement, treatment history, and response to therapy—were collected for all patients. Hematologic and organ responses were assessed according to standard response criteria for AL amyloidosis. Progression on venetoclax was defined as a ≥50% increase in the involved light chain to 10 mg/dL or initiation of a new therapy. Results: A total of 22 patients were identified. The median age at diagnosis was 64 years (range: 55–92), with 86% male and 82% lambda subtype. Revised Mayo stage at diagnosis was: Stage I in 20%, Stage III in 40%, and Stage IV in 40%. The median number of organs involved was 2 (range: 1–4), with cardiac involvement in 90% and renal involvement in 50% of patients. The t(11;14) translocation was present at diagnosis in 18 (81%) patients. All patients had received prior therapy before starting venetoclax, with a median of 1 prior line of therapy (range: 1–3). The most common frontline regimen was Dara-CyBorD, used in 68% of patients. Autologous stem cell transplantation (ASCT) was performed in 22% of patients as part of frontline therapy. Responses to frontline therapy were: complete response (CR) in 18%, very good partial response (VGPR) in 18%, partial response (PR) in 55%, and stable disease (SD) in 9%. Venetoclax was initiated due to suboptimal response in 55% of patients and progressive disease in 45%. The median time between first-line therapy and initiation of venetoclax was 10 months (range: 0.6–88 months). The majority of patients (63%) received venetoclax as a single agent, while 37% received it in combination with daratumumab. At the start of venetoclax therapy, disease characteristics included: Median albumin: 3.7 g/dL (range: 1.6–4.4), eGFR: 52 mL/min (range: 5–86), Median 24-hour urine protein: 2,604 mg/24h (range: 450–9,300) among patients with renal involvement, NT-proBNP: 1,388 (range: 105–68,000), High-sensitivity troponin: 55 (range: 6–4,043), Median difference in free light chains (dFLC): 7.7 mg/dL (range: 0.4–47). Hematologic response was observed in 95% of patients, including all patients with t(11;14) and 3 out of 4 patients without the translocation. Responses included CR in 54%, VGPR in 32%, and PR in 9%; a dFLC 1 mg/dL was achieved in 68% of patients. Organ responses were observed in 36% of patients. The median duration of venetoclax use was 15 months (range: 1–43). Over a median follow-up of 30 months (range: 1.5–56), 9 out of 22 patients (41%) required a subsequent line of therapy due to rising dFLC levels. Four patients progressed while on venetoclax, while progression occurred after discontinuation in 5/9 patients. Among these, 7 had previously achieved a CR or VGPR. The median time to next therapy following venetoclax was 13 months (range: 1–44). Three patients died during the follow-up period, including two due to progressive AL amyloidosis and one from metastatic hepatocellular carcinoma. Conclusion: Venetoclax is a highly effective therapy for patients with relapsed/refractory AL amyloidosis, particularly those with t(11;14). While a significant proportion of patients achieve deep hematologic responses, relapse occurs in a substantial number over time. Exploration of novel combination strategies in prospective trials is needed to achieve durable remissions with venetoclax in AL amyloidosis.