Case 2: MRD Testing in CLL

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Anthony Mato, MD, MSCE:You touched on MRD [minimal residual disease]. I think that’s really important in practice. Can we talk a little about methodology? What methods are the best? What’s the sensitivity cutoff? Which compartment? I have lots of questions about MRD. What do you do in your own center?

Nupam A. Patel, MD:MRD in CLL [chronic lymphocytic leukemia] is an emerging, evolving topic. It’s not quite there as it is in acute leukemia. As previously mentioned, the basic modalities that we use are flow cytometry or by PCR [polymerase chain reaction], which will get to you that 1-in-10,000 level.

Anthony Mato, MD, MSCE:What about even deeper? My general impression is that flow cytometry generally can do 1 to 10^-4. ASO-PCR [allele-specific oligonucleotide PCR] or NGS [next-generation sequencing], maybe 10^-5or even 10^-6. The question is, do we need to go that deep? Does anyone have a feeling?

Sameer A. Parikh, MBBS:I don’t think there are any data yet that support that going that deep at 10^-5or 10^-6is associated with outcomes.

Obviously there will be data that show that a smaller proportion of patients will reach that threshold at 10^-5or 10^-6. I think we need more data with longer follow-up to actually make clinical decisions based on those technologies. The other thing, as you pointed out, is that it’s important to understand that there are at least 3 different compartments in CLL where the disease can be measured: the peripheral blood, the lymph nodes, and the bone marrow. All we are able to do now is the peripheral blood and the bone marrow. And a lot of disease may be present or may be residual in the lymph nodes. That also needs to be taken into account as we interpret the data that come out from MRD testing.

Anthony Mato, MD, MSCE:You said it perfectly. The depth of the response is a justification for why we could stop at 12 months. Does anyone think we need to actually check it in practice given that we’re going to stop everybody at 12 months based on the way this drug has been labeled?

Shuo Ma, MD, PhD:If you look at the progression-free survival based on the MRD status—remember, on the study everybody stopped after 12 months of treatment. About 57% of patients achieve an MRD-negative status in the bone marrow, whereas the rest of the patients did not. When you look at their progression-free survival, those who have MRD-negative response have a significantly prolonged progression-free survival. While it may not be practical for the community practice yet, I think in all of the clinical trials nowadays when you’re using venetoclax-based therapy, MRD is a very important end point because it seemed to be a really good surrogate marker to predict the long-term clinical outcome.

Sameer A. Parikh, MBBS:You’re right that in clinical practice, if you have finished 12 cycles of therapy with venetoclax and obinutuzumab in the frontline setting, regardless of what your MRD level is at that point, you’re not going to make any changes to your treatment plan. It will be important from a prognosis standpoint, where you could counsel patients as to how quickly is it likely that their disease is going to come back versus someone who’s MRD-negative at the end of 12 months of fixed duration therapy.

Shuo Ma, MD, PhD:That also is becoming the next clinical trial question. Maybe we should design studies that the end point is not a fixed duration, but rather your goal is to achieve MRD-negative status, so tailor your treatment based on MRD. That will be 1 of the future directions for a clinical trial.

Anthony Mato, MD, MSCE:At the ASH [American Society of Hematology Annual Meeting & Exposition] this year, the CAPTIVATE trial was presented in its earliest form in terms of the data available. Do you want to highlight that study and how decisions could be made based on MRD?

Sameer A. Parikh, MBBS:The CAPTIVATE study is a study that uses 2 of our best agents for CLL up front, a combination of ibrutinib and venetoclax. This study was done where they enrolled 164 patients. Similar to the CLL14 study, there was a phase in the first 3 months where single-agent ibrutinib actually in this study was used to “debulk” the patients to prevent the risk of tumor lysis syndrome that can happen with venetoclax ramp-up. Then patients received venetoclax starting in month No. 4.

This was a fixed-duration therapy for 12 months, and then patients were randomly allocated depending on what their MRD status was. If they were MRD negative at the end of 12 months, they could get randomized to either placebo or continuing ibrutinib for the next 12 months. If they did not have any detectable MRD—if it was not confirmed, meaning they were MRD positive—they would get randomized to the ibrutinib or the combination of ibrutinib and venetoclax. Early results from this study suggest that patients who continue with this therapy for the combination for a year have an MRD-negative rate of anywhere from 70% to 75%, both in the peripheral blood and the bone marrow, which interestingly is very similar to venetoclax and obinutuzumab in the frontline setting. I think longer data for the randomization that occurs after the 1-year time point are still not available, and those would be interesting results to follow up on.

Transcript edited for clarity.