Stephan Stilgenbauer, MD, discusses the significance of a clinical trial and the impact venetoclax could have on patients with CLL who harbor a 17p deletion.
Stephan Stilgenbauer, MD
Patients with chronic lymphocytic leukemia (CLL) who harbor a 17p deletion present a treatment challenge, says Stephan Stilgenbauer, MD.
“17p deletion disrupts the very important tumor suppressor gene TP53,” says Stilgenbauer, associate professor at the Department of Haematology, Oncology, Rheumatology and Infectious Diseases of the University of Ulm, Germany. “These patients are characterized by a very poor outcome and they are usually refractory to chemoimmunotherapy. New treatments are urgently needed for this population.”
One treatment that shows promise for this difficult-to-treat patient population is the Bcl-2 inhibitor venetoclax (GDC-0199/ABT-199).
In a phase phase II clinical trial lead by Stilgenbauer, 79.4% of the 107 patients evaluated responded to venetoclax monotherapy. This included 8 patients (7.5%) who experienced a complete response (CR) or a CR with incomplete marrow recovery (CRi). The median time to first response was 0.8 months (range, 0.1-8.1 months) and the median time to CR/CRi was 8.2 months (3.0-16.3 months.)
These results have been submitted as part of new drug applications to the FDA and the European Medicines Agency, according to the pharmaceutical companies developing the drug. In May 2015, the FDA designated venetoclax as a breakthrough therapy for patients with del17p CLL.
In an interview with OncLive, Stilgenbauer discusses the significance of this trial and the impact venetoclax could have on patients with CLL who harbor a 17p deletion.Stilgenbauer: This was a single-arm, phase II pivotal trial that used venetoclax as monotherapy. This was a dose ramp-up study, starting with 20 mg and going up to the target dose of 400 mg. This was done to mitigate the tumor lysis syndrome risk because of the dramatic activity of this drug. It has to be handled with care so as to not result in too brisk tumor cell reduction, which could cause harm.
In this trial, we observed tumor lysis syndrome only on the laboratory level in very few patients and the mitigation schedule put in place was very effective. No patient had clinically relevant tumor lysis syndrome.The primary endpoint of this study was overall response rate (ORR) as determined by an independent review committee. The ORR was 79.4%. There was quite a portion, over 10%, of patients receiving a CR, CRi, or nodular partial response (nPR); therefore, these were very deep responses.
Furthermore, more than 20% of patients that responded achieved MRD-negativity in their blood, which means there was no detectable disease anymore. Progression-free survival and overall survival endpoints were very favorable for this population. Importantly, this was combined with a good tolerability of the drug. In essence, this data provides evidence that venetoclax is another very tolerable treatment option for these patients and has possibilities for combination with other novel agents in development.What was really very surprising and a very positive finding over and over again, was the repeatability of the onset of response. The median time to normalization of the lymphocytosis in the blood of these patients was less than 3 weeks. The reduction in the lymph node volume, the median time to first response, also occurred in less than 1 month. It is very important for these patients to see that they can rapidly achieve a response, their symptoms improve, and disease is reduced. This is a very, very important thing.The other drugs that have really revolutionized the treatment of CLL, so far, are ibrutinib (Imbruvica) and idelalisib (Zydelig), which are B-cell receptor signaling antagonists that are already licensed for this population. However, this population is still at high risk with these drugs to relapse, and therefore, new developments are needed. The next steps with clinical trials will obviously be to combine these novel agents together, and find out the best combination or sequential schedule to achieve the best outcome for these patients.
Venetoclax is also being investigated in combination with monoclonal antibodies or anti-CD20 antibodies, such as rituximab (Rituxan) or obinutuzumab (Gazyva). In preliminary data, it was indicated that the responses of venetoclax could increase by combining with a monoclonal antibody, which is obviously a very attractive combination regimen.The leading toxicity of venetoclax is tumor lysis syndrome. When you get over the initial ramp-up, and make sure that tumor cell reduction occurs at a well-tolerated rate, I have found the drug to be very well tolerated. Indeed, the adverse events profile in the large studies is very favorable. The risk of infection that these patients are at is very, very high due to their prior therapy. However, infection rate were actually favorable compared to frontline chemoimmunotherapy regimens such as FCR. Overall, from a patient perceptive, this is an oral therapy, it is very well tolerated, and infections are not the leading problem. Therefore, it is very good step forward.In the general practice when we treat CLL patients, these results mean in the global perspective that we are living in an era where, fortunately, in addition to chemotherapy or chemoimmunotherapy, we now have more agents available, such as ibrutinib, idelalisib, and now, potentially a licensing perspective for venetoclax. This provides a whole new set of options to treat these patients and these treatments are very well tolerated and very efficacious. The outlook for our patients is very bright.