Introduction:
Venetoclax is an oral inhibitor of the anti-apoptotic protein BCL-2, and is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL). Dependence of CLL cells on alternative anti-apoptotic proteins may result in intrinsic resistance to BCL-2 inhibition. The predictive and prognostic role of the expression of BCL-2 alternative proteins in CLL patients treated with venetoclax has not been yet explored.
Methods:
Patients with CLL treated with single agent venetoclax at MD Anderson Cancer Center between 05/2012 and 01/2016, and with available pre-treatment bone marrow samples, were included in the study. All samples were analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1, and >1 positive CLL cells per high power field (40X) was considered positive.
Response was assessed according to 2008 iwCLL guidelines, using the clinical and imaging criteria.
Results:
Twenty-seven patients were included in the study: 74.1% were male, 50% aged > 65 years, and 63% had Rai stage III-IV; 26% had mutated IGHV, 48% had del17p/del11q by FISH, and 40% had a complex karyotype by metaphase cytogenetics; 96% had been previously treated, 37% with a BTK inhibitor.
Overall, 15% had pre-treatment bone marrow samples positive for BCL-W, and 7% for BCL-2A1 (Figure), while none of the samples was positive for BCL-XL or MCL-1.
Overall response rate was 93%, and 14 (52%) patients achieved CR. A higher CR rate was observed in patients with positive BCL-W (75% vs 48%, p=0.60), positive BCL-2A1 (100% vs 48%, p=0.60), and double positive patients (80% vs 45%, p=0.33), though not statistically significant
After a median follow-up of 50 months (95%CI, 46-54 months), 13 (48%) patients progressed, and median progression-free survival (PFS) was 51 months (95% CI, 27-75 months). A longer median PFS was observed for patients with positive BCL-W (not reached [NR] vs 36 months, p=0.46), positive BCL-2A1 (NR vs 35 months, p=0.29), and double positive patients (NR vs 36 months, p=0.20)(Figure 2), though not statistically significant.
At most recent follow-up, 9 (33%) patients died, all of progressive disease, and median overall survival (OS) was 65 months (range, 2-65 months). A longer median OS was observed for patients with positive BCL-W (NR vs 65 months, p=0.19), positive BCL-2A1 (NR vs 65 months, p=0.36), and double positive patients (NR vs 65 months, p=0.12) (Figure), though not statistically significant.
Conclusion:
Pre-treatment expression of BCL-2 alternative proteins by IHC does not predict response to venetoclax in patients with CLL. More sensitive techniques, such as gene expression profiling and BH3 profiling, are needed to explore the predictive role of alternative anti-apoptotic pathways in these patients. Dependence on alternative BCL-2 proteins may associate with a better outcome for CLL patients, and larger dataset are needed to confirm this finding.
Citation Format: Fateeha Furqan, Ellen J. Schlette, Francisco Vega, Ignacio I. Wistuba, Luisa M. Soto, Mario L. Piubelli, William G. Wierda, Alessandra Ferrajoli, Paolo Strati. Expression of BCL2 alternative proteins and association with outcome in CLL patients with venetoclax [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 801.
