GADOLIN Trial: Relapsed/Refractory Follicular Lymphoma

John M. Burke, MD:A group has looked at MRD [minimal residual disease] testing in the GADOLIN trial and published their data in theJournal of Leukemia. I believe they presented it at the ASH [American Society of Hematology] Annual Meeting & Exposition last year. It’s very interesting. MRD first stands for either measurable or minimal residual disease. It’s a complex topic depending on how you test for it and where you test for it—whether it is blood or bone marrow. These investigators used a quantitative PCR [polymerase chain reaction] test for either a portion of the translocation t (14;18) or the immunoglobulin gene. That was the technique they used to find minimal residual disease in patients.

The GADOLIN trial was for those who had relapsed disease where patients were randomly assigned to bendamustine [BENDA] alone or bendamustine plus obinutuzumab [OBIN] with OBIN maintenance. The results showed improved outcomes, progression-free survival, and overall survival in the group that got the combination of obinutuzumab and bendamustine. These investigators then have gone back and looked at their MRD data. MRD was tested pretreatment and then after 3 cycles. It was tested again at the end of chemotherapy treatment and every 6 months thereafter.

They found that about 70% of patients were able to detect a product that could be followed with minimal residual disease, which leaves 30% not able to have a product detected. It’s not something that would be applied to every patient. They showed that patients who achieved a negative MRD state at the end of therapy had a better prognosis than those who did not achieve MRD negativity or positive MRD. So, it had prognostic implications.

Unlike what we’ve seen in CLL [chronic lymphocytic leukemia], MRD did not trump the treatment that they had received. Patients with MRD-negative disease who had been treated with the combination, BENDA plus OBIN, had better progression-free survival than patients with MRD-negative disease who were treated with only BENDA. It didn’t still matter what treatment the patient had received in terms of having an impact on their prognosis and their progression-free survival. MRD did not trump the treatment that they had received, so it’s not an independent prognosticator.

I would say that the authors of this article concluded that MRD is ready for routine clinical use, but they acknowledge that we don’t really know what to do with the results other than prognosticate. That is if the patient has MRD positivity, we don’t really know how to act to improve clinical outcomes that are important like progression-free survival. I’m not sure I agree that we in clinical practice should routinely be doing MRD testing. Honestly, my rationale is that we don’t really know what to do with the results. Yes, it has prognostic implications, but it’s also costly and I don’t know how to change my patients’ treatment if they have MRD positivity.

This is actually a very similar situation to what we face in patients with multiple myeloma where an MRD assay has been FDA approved, and it’s been shown very clearly that an MRD assay has prognostic implications. But those of us who treat myeloma know that we don’t know what to do if their MRD is positive and how to improve their outcome any more than we’re already doing. I think follicular lymphoma is in the same boat right now.

In the future, we would like to see 2 types of trials for MRD. One would be if we eliminate, if we use MRD to follow patients with lymphoma as opposed to using imaging studies that expose the patient to radiation such as CT [computed tomography] scans, PET [positron emission tomography] scans, and so forth. This is because it would be nice to be able to tell a patient that their disease is relapsing just by doing a blood test and knowing when that relapse is coming.

Second, it would be nice to know how to improve a patient’s outcome based on a positive MRD test result. That is, we could say, “We’ve given this patient 3 cycles of bendamustine and obinutuzumab, but their MRD is still positive. How can we do better? Should we take these patients who are MRD-positive and give them a different treatment?” Whereas, for the MRD-negative patients, we know they’re going to do really well. That would be a practical application of MRD testing. But, until we have data that tell us how to act on the results, I don’t plan to use MRD testing in my clinical practice.

Transcript edited for clarity.