Limited-Duration Therapy Based on MRD Testing

Experts in the field of chronic lymphocytic management (CLL) consider how MRD (minimum residual disease) testing affects the use of limited duration therapy.

Alison Duffy, PharmD, BCOP: What are your thoughts on the limited duration of therapy based on some of the emerging MRD [minimum residual disease] testing data?

Cody Steeves, PharmD, BCOP: MRD testing is certainly a valuable tool, especially in diseases where you use the heavy hitters out there. ALL [acute lymphocytic leukemia], for example, where we have definitive data that will tell us that negativity in MRD testing corresponds to longer response rates and better outcomes. CLL [chronic lymphocytic leukemia] MRD is a little bit more unique, and it has promise now for prediction, for sure.

There's some data dating back to about 2012, a re-analysis of CLL8 trial, which told us that obtaining a very low MRD or negative MRD, which they measured as less than 1 in 10,000, did correspond to significantly increased progression-free survival [PFS] times compared to medium or high levels of MRD, which is about 2 years per category in improvement.

Overall survival data also trended in the right direction there, too. However, the question really arises now within the more current setting of using these oral agents, especially these single-agent BTK [Bruton’s tyrosine kinase] inhibition, maybe single-agent BTK with a CD20 inhibitor combined with it, is that we're not really going to expect our patients to achieve MRD in this case.

The way the drugs work is, they kind of suppress the disease and keep them in a long-term partial response, but that could be good enough for long-term disease control, very high progression-free survival, very high overall survival [OS], and toxicity data that's usually very acceptable for all these oral agents.

So even though we're not seeing those deep remissions with MRD negativity, undetectable MRD, we certainly are still seeing a large benefit of using these agents without that. It does become a little more interesting as we get to that fixed duration, such as venetoclax and obinutuzumab.

There's some data now with venetoclax plus ibrutinib to get those more deep remissions, including MRD negativity. Then we potentially see these patients stop the drug. They're not committing to that lifelong therapy of taking a pill or several pills every day, and lifelong toxicities that may be associated.

The question that we really need answered at this time is, if these MRD negativities are resulting in withholdings or stoppings of the agent, will it lead to long-term response? And how long will that response be? Another question that we'll need to see the literature answer is if and when the disease were to come back, would we challenge with the same agent that got us to that MRD in the first place? Or is it like other diseases where we tend to shift therapies after a certain treatment failure?

One of the goals of MRD is certainly reducing the time on therapy for a patient. I have many patients who will be on maybe 1 or 2 other drugs. CLL is not very discriminatory with how healthy the patients are when they get it.

So they'll ask me the first question: how fast can I get off this drug? I don't want to take this drug forever, I want to be done in 3 months, 6 months, 12 months; as soon as possible. And I have other patients who might have 10-12, 15-20 other medications, and adding 1 more pill is really not a big deal to them. They're going to treat this like a chronic disease. The data tells they can take ibrutinib for a really long time and probably do very well.

So again, it's into more of that patient-specific treatment plan. If we're going to have a goal for an aggressive MRD-negativity treatment, or if we're going to keep this as a chronic disease and possibly use monotherapy for long-term disease control. What are your thoughts on that?

Alison Duffy, PharmD, BCOP: I definitely agree. It's the data, especially, as you mentioned, with venetoclax, in the relapsed/refractory setting as well, from the MURANO trial. It looks promising, but you're right, it's very patient-specific in terms of that being a goal, but also if that patient's willing to be on therapy for a long period of time. So it might be more of a win for some patients if this pans out as an approach to stopping therapy. I think we'll definitely see, as the data matures, and perhaps look to the chronic myeloid leukemia—the CML literature that's evolving, and recommendations in the NCCN [National Comprehensive Cancer Center] guidelines on therapy discontinuation.

For those patients, I would imagine some of those general principals looking the same in terms of when to stop, and potentially when to consider resuming. So it'll be interesting to see as the data evolves. I definitely agree.