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Interview with Dr. Andrew W. Roberts - EHA 2014
Bone Marrow Transplant Physician & Clinical Haematologist, Royal Melbourne Hospital, and Walter and Eliza Hall Institute of Medical Research, Victoria, Australia
Interview with Dr. Andrew W. Roberts, Bone Marrow Transplant Physician & Clinical Haematologist, Royal Melbourne Hospital, and Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Dr. Andrew W. Roberts has just presented a phase Ib study in patients with relapsed or refractory chronic lymphoid leukemia (CLL) combining the Bcl-2 inhibitor ABT-199 with rituximab, at the European Hematology Association (EHA) 2014 conference. Despite targeting a difficult patient group, some exciting results were obtained. The preliminary data provide hope and confidence for the formal safety and efficacy studies to come. The results lead to the start of a randomized phase III study, comparing the ABT-199 / rituximab combination with a combination of bendamustine and rituximab.
ABT-199 is a selective small molecule Bcl-2 inhibitor that can be taken orally. Bcl-2 is known as one of the key proteins that keep cancer cells alive, which is particularly the case in CLL. In CLL every cell in every patient has a high level of Bcl-2, leading to inappropriately long survival of these cells. Furthermore, Bcl-2 attributes to resistance to standard chemotherapy and monoclonal antibody therapy. Therefore, the idea was that Bcl-2 inhibition would cause CLL cells to die, and this might overcome resistance to other drugs.
Today the results of a phase I study using ABT-199 as monotherapy were presented by Dr. John F Seymour (Peter MacCallum Cancer Institute, University of Melbourne, Victoria, Australia), and Dr. Roberts presented the phase Ib study data on the combination therapy. In both studies, all patients were heavily pre-treated and several had poor prognostics, such as deletion 17. Many also had bulky disease, especially in the phase I study. As monotherapy the drug showed an overall response rate in the high 70%, independent of presence of poor prognostics. Also a 22% complete response rate was seen. Combined with rituximab, we see an even more rapid clearance of disease, 36% complete remission, and 84% overall response.
One of the downsides of a drug that works rapidly against a bulky disease like CLL, is something called tumor lysis. Early-on, this was a serious problem for ABT-199. In a few patient this caused tumor lysis syndrome, and this lead to two deads; one due to renal failure attributable to ABT-199 induced tumor lysis. The good news is that, since we have adjusted the regimen, slowly building up the dose, these problems have not been seen. Patients still respond, although now in weeks instead of in days, but the effect is still remarkable.