BCL2 D103Y

To evaluate if combination treatment of AZD0466 with BTK inhibitors would improve efficacy, we transplanted murine Eµ-TCL1 tumors into syngeneic recipient mice and randomized them for treatment with vehicle, ibrutinib (30mg/kg in drinking water), acalabrutinib (25mg/kg, p.o. QD), AZD0466 (70mg/kg, i.v., QW) and combination of AZD0466 with ibrutinib or acalabrutinib. Moreover, AZD4320 was highly efficacious in MAVER-1 and MINO cell line models where resistance to venetoclax mediated by BCL-XL upregulation was modelled by an in vitro dose escalation method. In summary, our pre-clinical study shows that the dual BCL2/BCL-XL inhibitor could represent an important treatment option for venetoclax resistance mediated by specific BCL2 mutations or BCL-XL upregulation and that its efficacy could be further improved upon combination treatment with BTKi.

After the first induction cycle with the 7+3 scheme (cytarabine + idarubicin), refractoriness was observed, in addition to the appearance of 6% of nuclei with BCL2 amplification by FISH, while maintaining the TP53 variant (confirmed by PCR). A new therapeutic scheme was initiated with decitabine 10- venetoclax... Clonal evolution of the leukemia was evidenced by the acquisition of BCL2 amplification alongside changes in the karyotype after antineoplastic treatment, and particularly following venetoclax administration, while maintaining the primary TP53 pathogenic variant.The increasing use of targeted therapies is improving remission and survival rates in most hematologic neoplasms, but it is also leading to the emergence of therapy-related clonal selections, as seen in this case, which could cause resistant relapses or even refractoriness. Understanding the mechanisms responsible for these phenomena would help to understand their relevance in the evolution of these patients.

To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax-rituximab combination therapy. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.

Methods Peripheral blood samples from 71 patients treated with venetoclax-rituximab or first line venetoclax-obinutuzumab combination were collected from 11 Hungarian oncohematological centres. In patients harboring multiple BCL2 mutations, convergent evolution of the CLL subclones may contribute to the driver mechanisms of resistance, justifying the comprehensive approach for the detection of these variants. In secondary venetoclax resistant cases displaying wild type BCL2 , further molecular screening methods are required to reveal alternative genetic or non-genetic reasons for disease progression.