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Dr Danilov Talks Clonal Dynamics and Venetoclax Resistance in CLL
Alexey Danilov, MD, PhD, City of Hope National Medical Center, California, provided an informational presentation on clonal dynamics with CLL14 and venetoclax resistance in patients with chronic lymphocytic leukemia (CLL) at the 2021 virtual Leukemia, Lymphoma & Myeloma Congress.
“Clonal evolution is something we have talked about for decades. It occurs during natural progression of disease, with therapy, and impacts resistance. Clonal evolution may affect non-lymphoid hematopoietic compartments following cytotoxic therapy,” explained Dr Danilov.
Clinical data show that patients with CLL have distinct growth dynamic patterns. Growth varies from being exponential to moderate, particularly in untreated patients.
Multiple studies have shown that chemotherapy demonstrates a high risk of therapy-related myeloid neoplasms (tMN) following treatment in CLL. Research from Carney et al, 2010, show that tMN post-fludarabine reaches 10.5% at 5 years.
“We need to understand if clonal evolution occurs in venetoclax, thus conferring broad therapeutic resistance. Is there a risk of carcinogenesis with continuous venetoclax therapy? What are the clonal changes that underlie venetoclax resistance?” continued Dr Danilov.
The phase 3 CLL14 trial, an analysis of genetic markers and outcomes with front line obinutuzumab plus either chlorambucil (GClb) or venetoclax, explored the incidence of aberrations, mutations, and IgVH status in patients with CLL.
During the trial, patients with TP53 mutations experienced progression-free survival (PFS) and variant allele frequency (VAF) changes over time. Most patients under venetoclax had a decrease in VAF frequency, whereas those who received GClb had an increase in VAF frequency.
Similar changes were observed in patients with BIRC3 mutations. Substantial increases in VAF frequency were apparent in patients who received GClb, as nearly all patients underwent aberration expansion. In contrast, stable reactions were found with venetoclax.
“It doesn’t seem that venetoclax is an extension of noxious clonal expansion. This is important for future implications of therapies in CLL. Real-world clinical data show that patient responses are achievable with Bruton tyrosine kinase inhibitors (BTKis) post-venetoclax with a median PFS rate of 34 months,” explained Dr Danilov.
Continuous venetoclax is associated with persistent cytopenias, estimated at about 25% for those under treatment. A recent study from Blombery et al, 2021 investigated venetoclax for cytotoxic expression in myeloid cells to show the 5-year cumulative incidence of tMN was 8.8%.
Notably, all cases of tMN occurred in the context of prior fludarabine plus cyclophosphamide (FC) exposure (median of 9 years post-exposure). There were no cases of myeloid disease among patients who had no history of FC.
Further, BAX mutations are associated with reduced mitochondrial outer membrane (MOM) translocations and venetoclax resistance in myeloid cells. Dr Danilov inferred that this can be explained as a survival mechanism led by myeloid cells that resist continuous venetoclax expression.
“Back to the CLL14 study, evidence indicates that there is not an increased rate of second primary malignancies in patients who received venetoclax-obinutuzumab,” noted Dr Danilov.
The prevalence of having a BAX mutation in the trial was 32%, occurring independently of prior FC exposure. Additional research from Blombery found that BCL2 mutations present in CLL patients experience venetoclax resistance as well. TP53 and BAX networks confer resistance to BH3-mimetics across all hematologic malignancies, including acute myeloid leukemia (AML).
Other venetoclax resistant mutations include BTG1, CDKN2A/B, PD-L1, and BRAF.
“In summary, time-limited venetoclax treatment does not appear to induce clonal evolution in CLL and is not associated with secondary malignancies. Continous venetoclax is associated with BAX mutations, however tMNs occur mostly in setting of prior FC therapy,” concluded Dr Danilov.—Alexa Stoia
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