We are very grateful to Weiss et al. for their confirmatory finding of acquired BCL2 mutations in patients with chronic lymphocytic leukemia (CLL) who became resistant to venetoclax treatment.1
We had identified mutations in BCL2 as a resistance mechanism characterizing patients with slowly outgrowing, refractory CLL after at least 3 years of continuous therapy with venetoclax.2 Correspondingly, Blomberry et al. had previously identified BCL2 variants up to 25 months before progressive disease in patients with CLL on long-term treatment with venetoclax.3
In contrast, the patient cohort studied by Herling et al. progressed after 4-22 months with CLL characterized by genomic features of Richter transformation.4 Indeed, half of their patients had histologically confirmed Richter syndrome and it was not reported if diagnostic attempts were made to exclude this in the remaining cases. The resistance mechanism of this aggressive phenotype may be different and the genomic characterization showed mainly variants known from aggressive lymphoma (e.g. tetraploidy, CDKN2A/B deletion, 8q gain). Such aggressive clones may outperform and abolish the slow outgrowth of BCL2 variants, which at this early time point remain subclonal (see Figure). We can confirm the absence of BCL2 mutations in cases with accelerated CLL and Richter syndrome after venetoclax treatment from analyses at our center, but these events should be the exception and not the rule deduced from current clinical trials with venetoclax in earlier treatment lines.
Moreover, the pattern of resistance with late occurring, specific mutations in CLL progression but not in early progression with transformed disease is analogous to what was observed in the context of ibrutinib treatment in CLL.65 Also in this scenario, early progressions were mostly Richter transformations devoid of BTK/PLCg2 mutations while late CLL progressions are characterized by such mutations in the vast majority of cases.
- Weiss J, Peifer M, Herling CD, Frenzel LP, Hallek M. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia Commentary. Haematologica. 2019; 104(11):e540. https://doi.org/10.3324/haematol.2019.232835Google Scholar
- Tausch E, Close W, Dolnik A. Venetoclax resistance and acquired BCL2 mutations in chronic lymphocytic leukemia. Haematologica. 2019. Google Scholar
- Blombery P, Anderson MA, Gong JN. Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia. Cancer Discov. 2019; 9(3):342-353. PubMedhttps://doi.org/10.1158/2159-8290.CD-18-1119Google Scholar
- Herling CD, Abedpour N, Weiss J. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018; 9(1):727. Google Scholar
- Woyach JA, Furman RR, Liu TM. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014; 370(24):2286-2294. PubMedhttps://doi.org/10.1056/NEJMoa1400029Google Scholar
- Ahn IE, Underbayev C, Albitar A. Clonal evolution leadingto ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017; 129(11):1469-1479. PubMedhttps://doi.org/10.1182/blood-2016-06-719294Google Scholar