PF625 VENETOCLAX FOR THE TREATMENT OF TRANSLOCATION (11; 14) AL AMYLOIDOSIS
Authors: M.H. Sidiqi, A.S. Al Saleh, N. Leung, M. Aljama, D. Jevremovic, W. Gonsalves, F. Buadi, T. Kourelis, R. Warsame, E. Muchtar, M. Hobbs, M. Lacy, D. Dingli, R. Go, S. Hayman, V. Rajkumar, S. Kumar, A. Dispenzieri, G. Morie, P. Kapoor
Journal: HemaSphere (2019)

Background: Venetoclax is a B cell lymphoma 2 (BCL-2) inhibitor that has shown activity as a single agent and in combination with other therapies in patients with multiple myeloma, particularly those harboring t(11;14) associated with high BCL-2 expression. Approximately 50% of patients with immunoglobulin light chain (AL) amyloidosis have t (11;14), making venetoclax a suitable agent to consider in treating patients with this rare disease. Data with venetoclax in AL remain sparse, with only 1 published case report in the literature to our knowledge. Aims: We aimed to identify the safety and efficacy of venetoclax in patients with AL amyloidosis. Methods: We conducted a retrospective review of all patients with AL amyloidosis treated with venetoclax between February of 2017 and February of 2019 at the Mayo Clinic. Results: We identified 7 patients treated with venetoclax for AL amyloidosis during the study period. Baseline characteristics for the cohort are listed in Table 1. Median age was 60 years (range 52–68) and 5/7 patients were male. Median number of prior lines of therapy was 2 (range 2–3). Previous therapies included proteasome inhibitors in 7/7, alkylators (cyclophosphamide or melphalan) in 7/7, daratumumab in 2/7, and lenalidomide in 2/7 patients. One patient had received a stem cell transplant. Most common organs involved were renal (5/7) followed by heart (3/7), nerve (2/7) and gastrointestinal (1/7). Light chain type was lambda in 5/7 patients. All patients had t (11;14) detected on fluorescence in situ hybridization (FISH) studies of the bone marrow. Venetoclax was used as a single agent in 3 patients and in combination with bortezomib and dexamethasone in 3 patients. One patient was commenced on venetoclax in combination with bortezomib, lenalidomide and dexamethasone, with the lenalidomide dropped after one cycle due to neutropenia. All but 1 patient underwent dose titration and escalation before stabilizing at a daily dose of 400 mg in 4/7 patients and 800 mg in 2/7 patients. One patient is currently going through dose titration aiming for a dose of 800 mg daily. Median duration of therapy was 6 months (range 0.5–24 months) and at last follow-up 5/7 patients remain on venetoclax. None of the patients experienced tumor lysis syndrome with initiation of venetoclax. Therapy was discontinued in 2 patients, due to dose limiting cytopenias and attainment of desired hematologic response respectively. Gastrointestinal side effects were reported in 4 patients (3 of whom received venetoclax in combination with bortezomib). Of 5 patients who were evaluable for a hematologic response, 2 achieved CR and 3 achieved a VGPR. Median time to best hematologic response was 3.7 months (range 3.4–8.4 months). At last follow up, one of 3 patients with cardiac involvement achieved a cardiac response 3 months after initiation of venetoclax. Two of 4 evaluable patients with renal involvement achieved a renal response at 10 and 16 months post initiation of venetoclax respectively. The other 2 patients have stable renal function. After a median follow-up of 13 months post initiation of venetoclax, none of the patients have progressed or died.Summary/Conclusion: Venetoclax is a safe and efficacious agent in patients with AL amyloidosis. It may be administered as a single agent or in combination with other plasma cell directed agents and has the ability to induce both hematologic and organ responses. Prospective trials are needed to further elucidate the role of this agent in patients with AL amyloidosis.