SAN FRANCISCO – Novel targeted agents offer more options for treating chronic lymphocytic leukemia (CLL), and if properly leveraged, may be able to shorten the time on treatment, improving acceptability to patients and possibly reducing treatment costs, according to Dr. William G. Wierda.
BTK inhibitors
Agents that inhibit Bruton tyrosine kinase (BTK) block signaling through the B-cell receptor in CLL, triggering apoptosis, said Dr. Wierda, professor and medical director, department of leukemia, division of cancer medicine, at the University of Texas MD Anderson Cancer Center in Houston. One such agent, ibrutinib (Imbruvica), is approved by the Food and Drug Administration for treatment of relapsed CLL and for treatment of newly diagnosed CLL having 17p deletion, a high-risk factor.
Dr. William G. Wierda
Results from RESONATE-2, a randomized trial comparing ibrutinib with chlorambucil as frontline therapy in older adults with CLL or small lymphocytic lymphoma, will be reported later this year. “We don’t know the details of that publicly yet, but we do know from a press release that it is a positive trial and showed improvement in outcomes for ibrutinib-treated patients. With that data, we will likely have an expanded label for ibrutinib into the frontline setting, at least for the elderly population,” he said at the NCCN Annual Congress: Hematologic Malignancies.
Longer-term data, collected 3 years after patients started ibrutinib monotherapy, have been very good, with overall response rates of 90% in those with relapsed or refractory disease and 87% in those with treatment-naive disease (ASCO 2014. Abstract 7014). “The last time I saw these data updated, the complete remission portions have increased. So as patients remain on the treatment, responses do improve,” Dr. Wierda noted. Complete remission rates now are about 14% and 24%, respectively. Median progression-free survival has not been reached in either group.
Data from the randomized RESONATE trial, which led to ibrutinib’s approval in relapsed CLL, showed benefit relative to ofatumumab across subgroups, including patients who had disease that was refractory to purine analogs, who had the 17p deletion and who had received at least three prior regimens (ASCO 2014. Abstract LBA7008).
The main grade 3 or 4 toxicity of ibrutinib in patients with CLL is infections, but atrial fibrillation and bleeding/hemorrhage are each seen in about 5% of patients. “The trials all excluded patients on warfarin, so we do not recommend treating patients with ibrutinib who are on warfarin,” Dr. Wierda commented. “If patients are anticoagulated on warfarin and we want to put them on ibrutinib, I will usually switch them over to something like Xarelto [rivaroxaban],” he said. Toxicity generally declines with longer treatment.
Discontinuations because of toxicity or Richter transformation usually occur within the first 18 months (JAMA Oncol. 2015;1[1]:80-7). “The concerning [point] for me though is the patients who develop refractory disease. … The incidence starts to go up significantly as you go out beyond 30 or 36 months,” he said. “We are reviewing our data right now to see if we make a similar observation. But that suggests to me that the longer the patients stay on treatment, the more at risk they are for progressing and developing refractory disease.”
The HELIOS trial tested addition of ibrutinib to bendamustine (Treanda) and rituximab (Rituxan) (ASCO 2015. Abstract LBA7005). Results showed superior progression-free survival with the three-drug combination. “But the question that always comes up when this data is presented is, well, how would it compare with ibrutinib monotherapy? Until that question for me is adequately addressed … I would probably be inclined to give patients ibrutinib monotherapy over the combination,” Dr. Wierda said.
Trials are testing a wide range of other combinations. “To me, this suggests that we really don’t have a direction or a rational strategy for combinations with these agents. … Right now, I’m excited about combining ibrutinib with venetoclax. … They seem clinically complementary, and there is some laboratory data that suggests as well that there will be a complementary mechanism of action.”
PI3 kinase inhibitors
Inhibitors of PI3 kinase also block signaling through the B-cell receptor. In this drug class, idelalisib (Zydelig) is approved for treating relapsed CLL in combination with rituximab.
The phase III trial establishing efficacy of this combination showed that it improved both progression-free and overall survival over rituximab alone (ASH 2014. Abstract 330). Median progression-free survival was 19.4 months. There was similar benefit across various subgroups, including patients with 17p deletion or an unmutated IGHV gene, another high-risk factor.
One of the main toxicities of idelalisib, elevation of liver function test results, typically occurs early and is usually not treatment limiting. Colitis occurs with two predominant patterns: early onset and late onset. “The early colitis in my experience hasn’t necessarily been treatment limiting. We can usually get those patients through their diarrhea [by] withholding the drug; sometimes we’ll give budesonide, and can restart the drug at a lower dose,” Dr. Wierda said. “It’s the late colitis that we have difficulty with – colitis that occurs after patients have been on 3 months, 6 months. And in my experience, those patients have had more severe colitis, and it’s been more treatment limiting.”