Ryan W. Jacobs, MD
There have been major breakthroughs in the treatment of patients with chronic lymphocytic leukemia (CLL), explained Ryan W. Jacobs, MD, such as the addition of the small molecule inhibitors ibrutinib (Imbruvica), venetoclax (Venclexta), and idelalisib (Zydelig).
However, Jacobs said that until physicians have head-to-head data, ongoing discussion of emerging and clinically pertinent findings and their effect on treatment decisions is critical.
With the FDA approval of frontline ibrutinib in March 2016, Jacobs says that single-agent ibrutinib seems to “level the playing field” for those higher-risk patients who are not going to see the same results with chemoimmunotherapy.
In the relapsed/refractory CLL setting, results from the phase III MURANO trial presented at the 2017 ASH Annual Meeting showed that combination therapy with venetoclax and rituximab (Rituxan) significantly lowered the risk of disease progression or death compared with bendamustine and rituximab (BR).
“I feel like this is a real ‘game changer’ in the treatment of relapsed patients with CLL. It's the first study that has a chemotherapy-free approach compared with chemotherapy,” said Jacobs.
In an interview during the 2018 OncLive®
State of the Science Summit™ on Hematologic Malignancies, Jacobs, a physician of Levine Cancer Institute, discussed the use of small molecule inhibitors in the treatment of patients with CLL.
OncLive: How have these inhibitors impacted the treatment paradigm?
In the frontline setting, ibrutinib is still the only small molecule inhibitor that is approved by the FDA. When you're talking about use of novel treatments in the frontline setting, you're specifically making decisions between chemoimmunotherapy that we have used for years and ibrutinib, which has been FDA approved in the frontline setting since 2016.
All indications have shown that when we do a workup and look at the genes of patients with high-risk prognosis using FISH analyses and IGHV
analyses, these patients do worse with chemoimmunotherapy. These are the patients with 17p deletion, 11q deletion, trisomy 12, and unmutated IGHV
; they have less return on historical treatments with chemoimmunotherapy but with all the same toxicities. In my practice, I am swayed to use a more novel approach like ibrutinib in these particular patients.
The data show us that ibrutinib seems to level the playing field for the large majority of patients with these high-risk prognostic findings. The patients with 11q deletion seem to do just as well as the patients without 11q deletion, and the patients with unmutated IGHV
seem to do just as well as the patients with an IGHV
mutation. In weighing the risks and benefits of treatment, there’s an argument to be made that these higher-risk patients who won’t see the same returns with chemoimmunotherapy are going to have more of a long-term benefit with ibrutinib.
In the relapsed setting, I focused on showing the available data that we have and looking at comparing and contrasting the 3 different agents that we have available. There is less debate between chemoimmunotherapy and novel agents in the relapsed setting because chemoimmunotherapy did not do well for patients once they had been exposed to prior treatments.
Thankfully, we have much better treatments now with ibrutinib, venetoclax, and idelalisib. I highlighted the data that are out there for these patients, specifically the most recent publication on venetoclax and its use in combination with rituximab. It was compared with bendamustine and rituximab, and venetoclax/rituximab significantly outperformed it, not surprisingly.
It's significant in that sense. It's also significant in the sense that it's the first treatment with a new small molecule inhibitor that involves defined treatment timelines. Patients on that study were only treated with venetoclax for 2 years and rituximab for 6 months toward the beginning of treatment. Therapy was stopped in responding patients after 2 years. There has been hope for a long time that we can get away from recommendations for indefinite treatment because small molecule inhibitors are expensive and have toxicities.
How has ibrutinib demonstrated success in treating chronic graft-versus-host disease (GVHD)?
At Levine Cancer Institute, rates of chronic GVHD are quite low with our approach of using posttransplant cyclophosphamide. For patients who ultimately develop chronic GVHD that is refractory to steroids, ibrutinib represents the first and only approval by the FDA for this population.