ABT-199: Novel Bcl-2 specific inhibitor updated results confirm substantial activity and durable responses in high-risk CLL
Chronic Lymphocytic Leukaemia (CLL) is the most common leukemia in adults in the Western world and is diagnosed in approximately 5 persons per 100,000 population per year. Whereas many cancers are associated with rapid proliferation of tumor cells, in contrast CLL is largely a disease of gradual "accumulation", where the leukemic cells have a profoundly prolonged life-span. The mechanism underlying this is an escape from the normal process of physiologic programmed cell death, or apoptosis. The B-cell lymphoma-2 (BCL-2) gene and the derived protein, and related members of the larger family of BCL-2 proteins which share the common "BH3"-binding element in their structure are the regulators of this process of apoptosis and it has long been known that CLL cells overexpress this pro-survival BCL-2 protein.
An oral drug, ABT-199/GDC-0199 was designed to exclusively mimic the binding of this "BH3" structural element exclusively to the BCL-2 protein, hence the drug class designation of "BH3-mimetic". This action restores the regulatory process that tells cancer cells to self-destruct. The drug is jointly developed by AbbVie and Genentech and is being investigated in a repertoire of studies from phase-I single agent, combination with anti-CD20 monoclonal antibodies and standard chemotherapy, and is in phase-II and III studies in CLL.
The current presentation updates the results of the CLL arm of the ongoing phase-I single-agent study and establishes;
- The safety of the agent when delivered using a carefully monitored step-wise dose escalation schedule which has largely obviated the earlier risk of rapid tumor destruction with associated chemical imbalances (tumor lysis syndrome; TLS)
- An excellent long-term safety profile with few patients stopping drug due to toxicities beyond the first few weeks of dosing,
- The dose of 400 mg is currently selected for safety expansion, although no formal maximum tolerated dose (MTD) had been defined
- Remarkable efficacy in a patient population with multiply relapsed or refractory disease (overall response rate 77%), with high overall response rates (75 - 79%) and impressive complete remission rates (22 - 29%) and clearance of "minimal residual disease" (MRD) even in the high-risk subsets of patients with the adverse risk del(17p) chromosomal abnormality associated with p53 mutation / dysfunction, an un-mutated immunoglobulin heavy chain gene (IGHV) and those with disease refractory to fludarabine.
- Durable disease control with an actuarial progression free survival of 59% at 24 months for those patients treated at doses of ≥400 mg
Declaration: Prof Seymour has acted as a consultant and member of Advisory Boards to AbbVie, Genentech & Roche.Abstract S702 - EHA Annual Congress