Chronic Lymphocytic Leukemia
Chronic Lymphocytic Leukemia: Mechanisms of Resistance to Treatment
Acquired resistance to the small-molecule inhibitors that are used in the treatment of chronic lymphocytic leukemia (CLL) is a significant clinical challenge. The development of rational drug combinations and novel molecular entities to address drug resistance in CLL is an important part of ongoing research.
Associate Professor of Medicine
“Although we are beginning to understand the mechanisms of resistance to novel agent monotherapy, we really do not know much about resistance to the combinations.”
We see very different patterns of resistance that develop in response to the frontline treatment regimens for CLL. Starting with chemoimmunotherapy, we would typically see resistance occur through the selection of more aggressive clones with TP53 mutations or an evolution to Richter’s syndrome via broad-based genomic mechanisms of resistance. In contrast, resistance to Bruton tyrosine kinase (BTK) inhibitors, which has been studied most extensively with ibrutinib, is generally associated with a much more focused array of mutations. And then, BCL-2 inhibition with venetoclax may result in resistance involving multiple pathways and antiapoptotic mechanisms, and this is another major area of research interest.
Several studies have highlighted the importance of mutations in BTK and its immediate downstream kinase, PLCG2, in ibrutinib resistance. Of these mutations, the point mutations in the C481 binding site in BTK are the most common. The same mutations are expected to occur with the use of second-generation irreversible BTK inhibitors. This is where noncovalent BTK inhibitors such as pirtobrutinib (LOXO-305) may have a role. A recent phase 1/2 study in those with relapsed/refractory CLL found that patients respond similarly to pirtobrutinib whether or not they had the BTK resistance mutation. This is a drug that is likely to have an immediate impact on the field once it is approved by the US Food and Drug Administration, particularly in the population of patients progressing on BTK inhibitors. It also appears to be well tolerated based on preliminary safety data.
With regard to resistance to venetoclax, there are many other mechanisms in play, with most resistant cases not explained by known genetic mechanisms. Several groups, including our own, are working in this area, and we have identified a role for MCL-1, an alternative antiapoptotic protein in the BCL-2 pathway that seems to be important in the setting of venetoclax-resistant CLL. Previously, it had been shown that increased phosphorylation of BCL-2 family members (eg, BCL-2 at serine-70 or MCL-1 at threonine-163) was associated with stabilization of the level of the antiapoptotic protein MCL-1. We presented preclinical data at the 62nd American Society of Hematology Annual Meeting and Exposition showing that these phosphorylation events can potentially be overcome with agents such as fingolimod (FTY720) to resensitize malignant lymphoid cells to venetoclax-induced apoptosis. We are also working on a trial of an oral cyclin-dependent kinase inhibitor called voruciclib that can indirectly inhibit MCL-1, and there is interest in eventually combining it with venetoclax.
Although we are beginning to understand the mechanisms of resistance to novel agent monotherapy, we really do not know much about resistance to the combinations. For example, we do not know whether we will see BTK mutations or BCL-2 mutations in patients who receive ibrutinib/venetoclax combination regimens.
Aslan B, Kismali G, Chen LS, et al. Development and characterization of prototypes for in vitro and in vivo mouse models of ibrutinib-resistant CLL. Blood Adv. 2021;5(16):3134-3146. doi:10.1182/bloodadvances.2020003821
Chong SJF, Collins MC, Hackett L, Davids MS. Re-wiring BCL-2 family anti-apoptotic protein dependencies through modulating phosphorylation to re-sensitive venetoclax-resistant lymphomas malignancies to BCL-2 inhibition [abstract 1890]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Lin VS, Lew TE, Handunnetti SM, et al. BTK inhibitor therapy is effective in patients with CLL resistant to venetoclax. Blood. 2020;135(25):2266-2270. doi:10.1182/blood.2020004782
Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901. doi:10.1016/S0140-6736(21)00224-5
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Skånland SS, Mato AR. Overcoming resistance to targeted therapies in chronic lymphocytic leukemia. Blood Adv. 2021;5(1):334-343. doi:10.1182/bloodadvances.2020003423
Yue XY, Chen Q, He JS. Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies. Cancer Cell Int. 2020;20(1):524. doi:10.1186/s12935-020-01613-z