Advancements and Updates in the Treatment Options for CLL - Episode 3

Data on Limited-Duration Therapy in CLL with MRD Testing

January 14, 2021

Oncology experts discuss emerging data looking at limited duration therapy based on minimal residual disease (MRD) testing, and potential implications.

Daniel Wojenski, PharmD, BCPS, BCOP: Katie, what are your thoughts in terms of MRD [minimal residual disease] testing? Talking about the therapies that I’m discussing, I would like to hear your thoughts on where you think MRD testing is looking at limited-duration therapy and selecting some of these options that I’ve discussed, like venetoclax. What are we going to be looking at with MRD testing there?

Katie Culos, PharmD, BCOP: This is a somewhat controversial issue. I know in a lot of our hematologic malignancies, the existence of MRD or not is something that is in vogue, and in years we’ll have a lot more information that supports using it or how it helps us guide therapy. However, in CLL [chronic lymphocytic leukemia], we’re talking about the patients who are going to select regimens, as you mentioned, that are fixed duration. And after therapy is complete, we can assess whether they’ve achieved an undetectable minimal residual disease. Typically, after their therapy is completed, around 3 months later, we’ll take peripheral blood as well as bone marrow samples and then assess for any presence of the leukemic cells.

Typically, the definition for MRD is going to be less than 1 CLL cell in around 10,000 leukocytes. Of the data that have been published so far in CLL, we clearly know that if you do achieve MRD-negative status that you will have better outcomes, longer progression-free survival [PFS] and disease-free intervals. There was a study you talked about for fixed duration with our chemoimmunotherapy and you mentioned FCR [fludarabine, cyclophosphamide, rituximab], specifically in those patients who had the mutated IGHV status.

When you looked at patients who achieve a CR [complete response] and then additionally had undetected minimal residual disease, we saw that 51-month progression-free survival. Compared with those who achieved a CR without with detectable MRD, that was shrunk down by half to 25 months. Clearly, there is an association with a much longer disease-free interval if you can get that deep response that’s defined by undetectable minimal or residual disease.

As far as venetoclax comes the CLL114 study, which was largely supporting the FDA approval of venetoclax with obinutuzumab. This study compared it with chemoimmunotherapy with chlorambucil and obinutuzumab. When we looked at the progression-free survival, we saw that this was significantly improved with the novel agent venetoclax. With a 40-month follow-up, we still hadn’t reached our progression-free survival for the venetoclax group, and it was around 35.6 months for the chemoimmunotherapy arm. However, if we then looked at their MRD status after the completion of their fixed-duration therapy, we saw a massive difference in how profound those CRs were. Around 76% of patients in the venetoclax arm did achieve undetectable minimal residual disease vs 35% in the chemoimmunotherapy arm.

As we get more follow-up—and I’ll discuss more data on CLL114 in a little bit—you are seeing different agents with different capability to induce deeper remissions. As you said, a lot of these advancements are over the last 2, 3, 4 years, and we need time to truly show us which agents are going to have different outcomes for our patients. Right now, MRD has a strong role as a prognostic indicator. It’s something for sure to present to your patients, to say we have studies that could be able to give you an idea of what your progression-free survival will be. Beyond that, I don’t know if it’s really guiding many therapeutic choices post-treatment.

As you mentioned, the iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria is going to drive most clinicians on recommended further treatment. Regardless of your status, I don’t think it’s going to jump anyone to start therapy, give you maintenance therapy. We’ll talk about that in a little bit. It can give your patient a window to expect. However, we’re going to wait until their symptoms that you previously talked about would drive somebody to start new therapies.

The other significance of MRD you’ll see is in clinical trial design. It’s a very enticing end point and impressive data to be able to show with your drug regimen. As some of the new studies that are ongoing are just briefly, and some of the interim analysis is published, we’re seeing that as an important secondary end point. Of course, what we love to do when anything works is add more together. We’re definitely doing that in CLL by combining now our novel agents.

There were some studies that are ongoing and starting to show their data combining, most commonly ibrutinib with venetoclax to see what effect we can get combining the novel agents. Those have shown good disease control and the ability to induce an MRD in about half those patients. Taking it the next step, there are some trials looking at throwing obinutuzumab in with the combination of those agents, so doing a doublet of novel therapy and adding an immunotherapy. However, our follow-up was short. It looks like the doublet therapy is as good as triplet, but we’re definitely going to need some longer data to show us the differences between combination therapy and consider the risk and benefits of that.