ORLANDO, Florida ― The investigational agent venetoclax (under development by AbbVie in partnership with Genentech/Roche) achieved high response rates in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), which is associated with a very poor prognosis.
In a pivotal phase 2 trial conducted in 107 CLL patients harboring the 17p deletion [del(17p)], who have the worst prognoses, the new drug achieved an overall response rate of 79.4%. A year later, response was maintained in most patients (84.7%). "This is a very special population with the most dismal outcome," said lead author Stephan Stilgenbauer, MD, of the University of Ulm, Germany. He was speaking here at a press briefing during the American Society of Hematology (ASH) 57th Annual Meeting, where the study was presented.
"These patients have not only relapsed on conventional treatment, but they were homogeneously defined by the presence of the 17p deletion, and they are resistant to conventional therapy," he said.
Among those responding were eight patients (7.5%) who achieved a complete response or a complete response with incomplete blood count recovery (determined by an independent review committee [IRC]).
Among 45 patients who were tested for minimal residual disease (MRD), 18 attained MRD-negative status in peripheral blood, and about half (n = 25) of 48 patients who were assessed also had no CLL in the bone marrow, as determined by immunohistochemistry.
"Based on these data, venetoclax may be an attractive component to incorporate into novel combinations or to sequence in patients with this very-high-risk disease characterized by 17p deletion," said Dr Stilgenbauer.
Venetoclax has already received breakthrough therapy designation from the US Food and Drug Administration (FDA) for patients with relapsed or refractory CLL who are harboring the 17p deletion. The manufacturers have now filed approval applications in the United States and the European Union for this in indication.
Approximately 3% to 10% of CLL patients have the 17p deletion at diagnosis, and it occurs in 30% to 50% of patients with relapsed/refractory CLL, according to the manufacturer. The median life expectancy for CLL patients with the 17p deletion is less than 2 to 3 years.
An Option Where None Existed
Venetoclax is an orally bioavailable, selective BCL-2 inhibitor that induces apoptosis in CLL cells independently of p53. As previously reported by Medscape Medical News, trial results presented earlier this year showed that combining venetoclax and rituximab (Rituxan, Genentech, Inc) produced encouraging results in CLL patients with relapsed or refractory disease.
In addition, results of a phase 1 dose-escalation study of venetoclax monotherapy in patients with relapsed/refractory CLL, of whom 89% had poor prognostic clinical or genetic features, were recently published in the New England Journal of Medicine to coincide with the ASH meeting. In this study, the overall response rate was also 79%. Complete remissions occurred in 20% of the patients, including 5% who had no MRD in evidence on flow cytometry. The 15-month progression-free survival estimate for the groups receiving the 400-mg dose was 69%.
"What we are seeing in the phase 2 study and the one just published in the New England Journal of Medicine is that about 80% of patients in these very refractory groups have had a good response, and for some of those patients, it's potentially a very durable response," commented Tait D. Shanafelt, MD, professor of medicine at the Mayo Clinic, in Rochester, Minnesota, who was not involved in the studies.
"Some patients can even get down to MRD-negative states, which in these refractory patients are depths of remission that we couldn't typically achieve with our traditional treatments," Dr Shanafelt told Medscape Medical News
"This is another medicine that really has the potential to add to our armamentarium for patients who previously didn't have good treatment options," Dr Shanafelt added.
Tumor Lysis Syndrome
One of the concerns with venetoclax is tumor lysis syndrome, a potentially life-threatening oncologic emergency that is caused by massive tumor cell lysis, which is associated with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation.
"This agent has been shown to induce very rapid and very deep remissions," said Dr Stilgenbauer. "There is a concern of tumor lysis syndrome, because the rapid destruction of these cells can potentially do harm."
Therefore, a step-wise, ramped-up dosing schedule was introduced in the phase 2 trial. "The starting dose was 20 mg, which is only 5% of the target dose of 400 mg," he explained. "And with this 5% dose, we were already seeing the destruction of tumor cells. This highlights the highly dramatic efficacy of this agent."
There are not many therapeutic agent that can achieve a tumor response at only 5% of the target dose, Dr Stilgenbauer added.
Despite the risk, Ephraim P. Hochberg, MD, assistant professor of medicine, Harvard Medical School, and instructor in hematology/oncology, Massachusetts General Hospital, Boston, does not think tumor lysis syndrome will be a major deterrent to using this new agent.
The outcomes are very exciting and promising in this difficult-to-treat population, he commented. "In this study, they titrated the dose up slowly.
"Tumor lysis syndrome occurs with the rapid killing of tumor cells," Dr Hochberg told Medscape Medical News. "It's too much of a good thing, so the goal is to slow it down."
Whenever this drug is given, it will have to be ramped up slowly, he explained. "My guess is that when it does come on the market, we will have a highly specific algorithm to use, so that it can be given safely out in the community setting."
The phase 2 trial that Dr Stilgenbauer and colleagues reported at the meeting was conducted in 107 patients with relapsed/refractory CLL who had the 17p deletion. Only one patient did not have del(17p); of 83 patients for whom data were available, 60 (72.3%) had mutated TP53 (investigator reported). The median age was 67 years.
Patients had received a median of two prior regimens, although this ranged from 1 to 10. These included fludarabine (72.9% of patients, of whom 37.4% were fludarabine refractory) and bendamustine (50.5%, of whom half [50%] were were bendamustine refractory).
In addition, 45 patients (42.1%) were deemed to be at high risk for tumor lysis syndrome, determined on the basis of the presence of lymph nodes measuring ≥10 cm (or nodes measuring ≥5 cm with ALC ≥ 25 x 109/L).
At data cutoff (April 30, 2015), the median time on study was 12.1 months (range, 0.03 - 21.5 months).
Responses were determined by both an IRC and investigators using iwCLL 2008 criteria.
The median time to first response was 0.8 months, and the median time to complete response was 8.2 months, determined by IRC. To date, overall median duration of response, progression-free survival, and overall survival have not yet been reached.
The actuarial 12-month progression-free and overall survival rates were 72.0% and 86.7%, respectively.
Toxicity was high but acceptable in this extremely high-risk patient population. Dr Stilgenbauer explained that neutropenia and infections were lower than would be expected for this cohort.
Virtually all of the 103 patients (96%) who were evaluable experienced a treatment-emergent adverse event of any grade, including 76% who experienced grade 3/4 events.
Grade 3/4 events that occurred in 10% or more of the patients included neutropenia (40%; 25 patients had grade 4), anemia (18%), and thrombocytopenia (15%). Infection of grade ≥3 occurred in 20% of patients, the most common being pneumonia (5%). Among 11 deaths that occurred, seven were due to progressive disease, and four to adverse events.
Laboratory-identified tumor lysis syndrome was reported in five patients, but all cases were manageable with minimal interruption to the treatment regimen, the researchers reported.
The trial was funded by AbbVie, developer of venetoclax. Dr Stilgenbauer has received honoraria from or is a member of the board or advisory committee of AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, and Hoffman La Roche. Several coauthors report relationships with industry, including the drug developers, and several were employees of AbbVie.
American Society of Hematology (ASH) 57th Annual Meeting. Abstract LBA-6. Presented December 8, 2015.