Outcomes of Venetoclax in Patients with Relapsed or Refractory AL Amyloidosis
Authors: Theodorakakou Foteini , Fotiou Despina , Spiliopoulou Vasiliki , Migkou Magdalini , Malandrakis Panagiotis , Ntanasis-Stathopoulos Ioannis , Roussou Maria , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Solia Irene , Papanikolaou Asimina , Gakiopoulou Charikleia , Gavriatopoulou Maria , Terpos Evangelos , Dimopoulos Meletios-Athanasios , Kastritis Efstathios 
Published: December 2024

Introduction: Almost 50% of patients (pts) with light chain (AL) amyloidosis, harbor translocation t(11;14) on their clonal plasma cells and as a result, these cells overexpress BCL-2. Venetoclax is a selective BCL-2 inhibitor that has been shown to induce high rates of deep hematologic responses in patients with plasma cell malignancies harboring t(11;14), including pts with AL. However, the efficacy of venetoclax has not been evaluated in AL in the context of prospective studies, and retrospective case-series remain the only source of data. Here we present our experience in patients with AL amyloidosis treated with venetoclax-based therapy.
Methods: We analyzed the data of 23 consecutive pts with relapsed and/or refractory AL, treated in the Department of Clinical Therapeutics, Athens, Greece, who received venetoclax-based therapies. All data were prospectively collected, following our institution's policy.
Results: Among these 23 pts, 21 (91%) were positive for t(11;14), 1 patient (4%) had t(11;14) in less that 10% of CD138+ plasma cells and 1 (4%) was negative but had an IgM secreting lymphoplasmacytic clone. At the time of diagnosis, 83% patients had cardiac involvement, 48% had renal, 17% had liver, 9% had nerve and 26% had soft-tissue involvement. The Mayo 2004/European stage distribution was 13%/39%/26%/22% for stages 1/2/3A/3B and renal stage distribution was 52%/38%/10% for stages 1/2/3. Median bone marrow infiltration at diagnosis was 20% (range 0-85%), 22% had kappa and 78% lambda LC clones and median baseline dFLC was 346.5 mg/L.
At the time of venetoclax initiation, 21 pts (91%) had been exposed to bortezomib and 13 pts (56.5%) to daratumumab. Median number of prior therapies was 1 (1-3). Six pts (26%) were in hematologic relapse, 13 (56.5%) had inadequate hematologic response (i.e PR or less on their previous line of therapy) and 4 (17%) had persistent organ dysfunction and less than a hemCR. At start of venetoclax therapy the median dFLC was 92.29 mg/L (1.33-2969.63 mg/L), NTproBNP was 4065 ng/L (30.1-30000 ng/L), hsTnT was 51 ng/L (4.28-249 ng/L), eGFR 51 ml/min/1.73m2 and proteinuria was 4446 mg/24h (418-3890 mg/24h); accordingly, 8 pts (35%) had developed cardiac progression and 12 (52%) renal progression, while 3 (13%) were on dialysis. Nine pts (39%) received venetoclax monotherapy, 8 (35%) received venetoclax with low dose dexamethasone and 6 (26%) received venetoclax with daratumumab and dexamethasone.
Median time from 1st line therapy to initiation of venetoclax was 6.8 months (1.9-109 months); median duration of venetoclax therapy was 5.6 months (0.3-29.5 months) and median dose was 400 mg (200-800 mg). Among evaluable pts (n=17), hematologic response rate was 76%, with hemCR in 7 (41%), hemVGPR in 5 (29%) and PR in 1 (6%); a dFLC&lt;10 mg/L was achieved by 8 pts (35%). Median time to response was 0.5 months (0.3-6 months). In all the 8 pts (35%) that MRD was evaluated with NGF, was undetectable. Two pts (9%) had hematologic relapse: 1 during treatment and 1 after treatment discontinuation. Among 13 evaluable pts with cardiac involvement, 3 (23%) achieved a cardiac response and among 7 evaluable pts with renal involvement, 1 (14%) achieved renal response.
Regarding toxicities considered as related to venetoclax, 9 pts (39%) developed infections (Gr1/2: 3, Gr3: 1 and Gr5: 4), 1 (4%) had diarrhea Gr2, 1 (4%) had anemia Gr3 and 2 pts (9%) had thrombocytopenia (Gr2 and Gr4). Dose was reduced in 1 patient (4%) and treatment was discontinued in 4 (17%); reasons for discontinuation was toxicity in 3 pts (13%) and disease progression in 1 (4%). Fourteen pts (61%) are still on therapy. Of the 2 pts that had hematologic progression/relapse, one received further therapy including daratumumab and the other re-started venetoclax.
Median follow up of the cohort is 12 months. Eight pts (35%) have died, 3 pts (37.5%) due to AL and 4 (50%) due to infections. Median OS has not been reached; one- and 2-year OS rate was 61%.
Conclusions: Treatment with venetoclax induces high rates of complete hematologic response and undetectable MRD, in patients with AL that have failed therapy with bortezomib and /or daratumumab. Low rates of organ responses are probably due to short follow-up time and pre-existing advanced organ dysfunction. Despite low risk of cardiac or renal complications, the risk of infections due to immunosuppression should not be underestimated and preventive measures are important to reduce this risk.