CLL: Post-Ibrutinib or Chemoimmunotherapy Approaches
Insights From: Michael Choi, MD, UC San Diego Medical Center; Matthew S. Davids, MD, Dana-Farber Cancer Institute; William Wierda, MD, PhD, MD Anderson Cancer Center
William Wierda, MD, PhD: Relapsed CLL is a difficult area to have a succinct discussion about, because it’s very complicated. It’s complicated because it’s driven by what patients received in the first-line setting. It’s driven by what agents are available at the time and what data are available at the time for the treatment for a particular patient. So, the choice of treatment for a relapsed patient will depend on several factors. It’ll depend on what they received previously, whether it was in the frontline setting or in the salvage setting, because patients can go from first-line treatment to get treatment for their first relapse, then they can relapse multiple times and there are many different treatments they can be exposed to. They can develop resistance to various treatments that they received previously.
Prior treatment, whether it was the first treatment or subsequent treatments, and whether or not patients are resistant or refractory to those treatments will dictate what you give a patient next if their disease is growing and progressive. We’ll take a couple of scenarios. If a patient received chemoimmunotherapy in the frontline setting—which is more common right now, because we’ve had chemoimmunotherapy whereas the integration of frontline ibrutinib has been a later event, so there are fewer patients who received ibrutinib frontline today than those who have received chemoimmunotherapy—the treatment options are retreatment with chemoimmunotherapy; going to a BTK [Bruton’s tyrosine kinase] inhibitor; or going to venetoclax plus rituximab, because we heard about the MURANO data at ASH [American Society of Hematology]. And clearly outcomes were better for patients who received venetoclax plus rituximab over bendamustine/rituximab in the relapsed setting.
Regarding frontline chemoimmunotherapy with a reasonably long remission, it’s reasonable to think about chemoimmunotherapy again. That would probably be less common these days than moving to one of the small molecule inhibitors. If a patient has had chemoimmunotherapy before and did not have deletion 17p but has acquired deletion 17p when they need retreatment, they need to go to a BTK inhibitor or to venetoclax-based therapy.
If they don’t have deletion 17p and they’ve had a long remission after first chemoimmunotherapy, it’s not unreasonable to think of and have a discussion about chemoimmunotherapy. But I think right now, the preference would be to move them to a BTK inhibitor like ibrutinib. More recently, the MURANO data would also support using venetoclax plus rituximab in that setting for relapsed disease.
In the relapsed setting, we talked about prior chemoimmunotherapy, but we can talk about prior ibrutinib therapy. If a patient has been on ibrutinib as their first treatment and their disease is progressing, or if they come off of treatment because they have some toxicity, the next treatment would be a good discussion. You could have a discussion about chemoimmunotherapy. There are less data about how well chemoimmunotherapy works in that setting, in patients who have failed ibrutinib. There are some data that support the use of venetoclax in that setting. Venetoclax plus rituximab would be a reasonable option in that setting and would probably be my preference as next therapy. I think as we get more data and as time goes on, we’re moving more away from using chemoimmunotherapy in favor of using the small molecule inhibitors.
Moving from chemoimmunotherapy to an ibrutinib-based therapy or to a venetoclax-based therapy, and then moving to a third-line PI3 kinase inhibitor-based therapy, would be the sequence of what we see today. That’s going to change because, as I mentioned, more patients are getting ibrutinib upfront. We might see ibrutinib first followed by venetoclax-based therapy followed by PI3 kinase inhibitors. Chemoimmunotherapy is somewhere, more likely prior to transplant if a patient has progressive disease and they’ve failed several prior lines of therapy.