Michael Choi, MD

Question 1. In your opinion, what were the most clinically relevant CLL data presented at ASCO this year?

Answer
The results of the German CLL14 clinical trial were definitely practice-changing.¹ Accompanied by the FDA [US Food and Drug Administration] announcement of approval for venetoclax/obinutuzumab,² it is a new standard for patients with previously untreated CLL.

The results showed a clear difference in progression-free survival in patients who received 1 year of venetoclax/obinutuzumab compared with patients who got obinutuzumab and chlorambucil. A key part of the trial was that both regimens were given for a fixed, 1-year duration. We now have a new standard of care that patients can receive for a defined period of time before coming off therapy and enjoying treatment-free remission.

Question 2. Can you discuss the importance/significance of achieving a negative minimal residual disease (MRD) status after treatment for CLL?

Answer
Testing for MRD is one way of determining depth of response. Achieving undetectable MRD after treatment for CLL, in my mind, tells me that a patient has had the greatest depth of response that we can measure, or received the most potent treatment we could have administered. It also correlates with treatment-free remission in that a patient with an undetectable amount of CLL will likely have a longer duration before any cells [become] proliferative enough to become detectable and then further, to become clinically meaningful. Patients who stop therapy with some measurable disease will intuitively have a shorter remission.

For some treatments, like treatments that target the B-cell signaling pathway, achieving undetectable MRD status is not of as great importance because those treatments can be continued long term and provide continuous suppression of disease.

Question 3.What is your view on the recent developments in the field of chimeric antigen receptor T-cell (CAR-T) therapies in CLL?

Answer
CAR-T cell therapy is certainly an exciting area of research. To see that some patients who have highly refractory disease can still have long-term remission after CAR-T treatments is very encouraging.

There are trials going on now that primarily include patients who have failed multiple lines of therapy or have high-risk disease.

For example, at my center at UCSD, we are part of the JUNO JCAR17 trial. Interim results were reported at the 2019 ASCO Annual Meeting showing about an 80% response rate, including about a 67% rate of undetectable MRD among high-risk cases.³ I still tell patients that I hope most of them won’t need CAR-T cell treatment in their lifetime, and existing therapies like ibrutinib and venetoclax will continue to provide most of them with long remissions with high quality of life. But in those minority of cases where these therapies stop working or cause other problems, it is nice to know that CAR-T cell treatment is an option.

Question 4. Real-world data seem to suggest that use of tyrosine kinase inhibitors (TKIs) for CLL is associated with high discontinuation rates because of adverse events. What are your strategies for monitoring and addressing adverse events in patients being treated with TKIs?

Answer
This is one of the most challenging aspects of managing patients on kinase inhibitors. The management of adverse events starts during counseling, before treatment initiation. Now, patients are already quite knowledgeable that mild, but manageable, side effects are commonplace. I think it is a little bit easier to manage side effects when they are somewhat expected. That said, we still hope that patients will have minimal side effects or that the side effects get better over time. We emphasize that a lot of side effects, like joint aches or diarrhea, tend to get better over the first few months of treatment. If a patient can tolerate it, it is often unnecessary to reduce the dose or stop the medication.

However, there are some side effects that cause us to consider reducing the dose or stopping the medication. These are things like severe bleeding or cardiac toxicity. For those side effects, it is important to make sure that patients know about the symptoms of these problems, so that they can report issues promptly.

I often learn from my own patients about how to manage some of these symptoms. For some patients, things like heating pads or adjusting the time of drug administration to the evening have helped for some side effects. We don’t stop our patients from trying various remedies that they come across that may help. That said, we do try to be cognizant of drug-drug interactions.

Question 5. What impact does genome sequencing have on treatment selection, and how do you communicate with patients about genetic testing?

Answer
I find it almost ironic that genetic testing results have perhaps become less critical to take into account when deciding on treatment options for CLL mainly because our current therapies – ibrutinib, venetoclax, and other kinase inhibitors — are largely effective regardless of major genetic results. There is not a major cytogenetic result that predicts that any current therapies will be ineffective from the start. However, we do still send for these tests, and they have some prognostic importance as far as duration of remission.

As far as next-generation sequencing, I think it is still an area that we are learning about and figuring out how to best integrate into our patients’ care. For patients on ibrutinib, testing for point mutations in BTK or PLC-gamma can help identify patients at high risk for relapse or can explain the mechanism of resistance. Those tests have great utility in some clinical circumstances. I think with more time, we will find out if there are other specific point mutations that should impact how we decide on treatment or monitor our patients.