Programmed Cell Death as a Therapeutic Target in Chronic Lymphocytic Leukemia

Regulation of Apoptosis and Cancer

The main mechanism of cell death in both physiological and malignant cells is apoptosis. There are two main pathways leading to the initiation of this programmed cell death – the external pathway, activated by so-called death receptors (e.g. TNF), and the internal pathway, usually activated by cellular stress. The induction of these pathways activates caspases, enzymes that then cleave key cellular components, leading to cell death.

One of the key processes in the internal pathway is strictly regulated by proteins from the BCL-2 family, which includes both pro-apoptotic factors and anti-apoptotic survival proteins, such as Bcl-2, Bcl-XL, and Mcl-1. These are often overexpressed in tumor tissues, allowing malignant cells to better survive and increase their resistance to anticancer treatment. It is known that overexpression of Bcl-2 leads to resistance to radio- and chemotherapy and genotoxic stress in many types of tumors. On the other hand, this phenomenon can also be exploited for selective targeting of therapy directly at these cells.

Bcl-2 Inhibitors and Their Therapeutic Potential

A very effective approach to targeting anti-apoptotic factors from the BCL-2 family focused on designing molecules that bind with high affinity to the hydrophobic grooves of these proteins. The first of the inhibitors selective directly for the Bcl-2 protein was venetoclax, which showed significant activity with a rapid onset of effect in many tumor disease models during research.

During pilot studies of venetoclax in the treatment of chronic lymphocytic leukemia (CLL), it was found that most patients with poor prognosis achieved clinical response to treatment, and 69% of patients with refractory CLL treated with 400 mg venetoclax monotherapy once daily achieved 15-month progression-free survival.

Venetoclax in the Treatment Algorithm for Hematologic Malignancies

In the Czech Republic, venetoclax is now reimbursed in combination with rituximab for adult patients with relapsed or refractory CLL who are refractory to the last treatment or who relapsed within 24 months after the end of previous treatment, are not suitable for chemoimmunotherapy after relapse, or have a proven TP53 mutation or del17p.

1st Line Treatment of CLL

Since August 1, 2021, venetoclax in combination with obinutuzumab can be prescribed with full reimbursement in the 1st line treatment of CLL for patients with comorbidities that prevent them from undergoing full-dose fludarabine-based treatment. For these patients, the current standard reimbursed treatment is a combination of chlorambucil with obinutuzumab or rituximab, or a regimen of bendamustine + rituximab.

Venetoclax in combination with obinutuzumab was highly effective in the phase III clinical trial in patients with CLL and comorbidities precluding fludarabine treatment in the 1st line of treatment − 88.2% of patients achieved 2-year progression-free survival compared to 64.1% in the chlorambucil + obinutuzumab group.

Conclusion

The Bcl-2 protein inhibitor venetoclax demonstrated high efficacy in combination with obinutuzumab, an anti-CD20 antibody, in previously untreated CLL patients whose comorbidities prevent them from receiving full-dose fludarabine treatment. Therefore, it will now also be reimbursed for this indication in the Czech Republic, with treatment reimbursement continuing until the exhaustion of 12 therapy cycles or until disease progression or unacceptable toxicity occurs.

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Sources:
1. Hafezi S., Rahmani M. Targeting BCL-2 in cancer: advances, challenges, and perspectives. Cancers (Basel) 2021; 13 (6): 1292, doi: 10.3390/cancers13061292.
2. Summary of the 3rd Evaluation Report on Venclyxto. SÚKL, June 3, 2021. Available at: www.sukl.cz/file/96155_1_1