Potential for Measurable Residual Disease as an End Point in Chronic Lymphocytic Leukemia Research

Talal Hilal, MD, Mayo Clinic Comprehensive Cancer Center, Phoenix, Arizona, discusses results from a meta-analysis that aimed to examine measurable residual disease (MRD) as an end point in chronic lymphocytic leukemia (CLL) clinical trial research.

“This study was conceived after multiple areas within the hematologic malignancy field have picked up steam with regards to measurable residual disease as an end point in clinical trials,” explained Dr Hilal.

Transcript:

My name is Talal Hilal. I'm a hematologist at [the] Mayo Clinic in Arizona. I treat patients with (chronic lymphocytic leukemia) CLL and lymphoma. I [also] do bone marrow transplant[s] and (chimeric antigen receptor) CAR-T therapy.

This study was conceived after multiple areas within the hematologic malignancy field have picked up steam with regards to measurable residual disease (MRD) as an end point in clinical trials. Some obviously have made a lot of headway in showing an association with outcomes in patients who achieve undetectable MRD in many malignancies, including [acute lymphocytic leukemia] (ALL) and more recently in myeloma, including policy implications. We sought to review and pull data from randomized trials and CLL to look at the association of MRD with outcomes in general.

The initial question was [progression-free survival] (PFS) and [overall survival] (OS), but we found quickly that overall survival was not often reported in association with MRD in many of these prospective studies, possibly due to lack of long-term follow up. We narrowed down the question to PFS only. So, can MRD be sort of an intermediate end point that can be a surrogate to progression-free survival in CLL? The idea is that if it is associated strongly with PFS, the next question is: Is that good enough for it to become an end point for accelerated approvals and trials?

We did this as a meta-analysis. We identified prospective single arm or randomized trials that assessed targeted agents, so BCL-2 inhibitors or (Bruton tyrosine kinase) BTK inhibitors and obinutuzumab-based treatments, because we do have some data from the chemoimmunotherapy era associating MRD with PFS.

This was a more modern look at the new era of therapy for CLL. We identified 11 prospective trials; 9 were randomized, and 2 were non-randomized. A total of about 2,700 patients were analyzed and we had to model [and] extract some of the survival curves from the papers, some of the manuscripts, and try [to] digitally get the information in terms of survival at various time points in association with MRD to be able to pull the data together. [In] a lot of these studies, MRD was an exploratory end point, maybe a secondary end point, but not a primary end point.

The stratification for these trials was not really including MRD as an important end point in the beginning of this study design. What we found is that in these prospective trials, there was a statistically significant difference in the pool survival estimates between groups. Those that achieved undetectable MRD versus those that had MRD at the end of treatment estimated [that] 2-year PFS was about 91% in those who achieve undetectable MRD versus about 75% in those with undetectable MRD. When you stratify based on [the] line of treatments, some of these trials were frontline, some of them were relapsed/refractory, and as well, looking at time-limited approaches versus continuous approaches, we found an association in pretty much every single line of therapy. The association was maybe not as significant in the relapsed/refractory BTK inhibitor continuous therapy, and this makes sense.

There was a lot of debate on whether continuous therapy BTK inhibitor really translates to better PFS, because you often don't achieve undetectable MRD in those patient populations yet. We did see some association there, and there could be some heterogeneity in the pooling, but it's a very clear stark difference in patients who are treated in the frontline setting with time-limited therapy and the relapsed setting with time limited therapy. If you exclude BTK inhibitors, you see a bigger difference as well. Of course, this is sort of a first step in moving the needle to evaluate MRD.

There are certain FDA requirements on how to perform some of these meta-analyses [for] this to become an intermediate end point that the FDA recognizes. Hopefully this will be one of the first studies moving in that direction. I think ultimately the question is going to be: Is this clinically significant enough for patients? We know CLL now is a lot easier to treat. Patients have very long durations of progression-free survival. So, do we really need to achieve undetectable MRD? Does having a prolonged PFS really matter to patients or are we still trying to pursue overall survival? Those are all critiques and criticisms that are going to come in association with this research question.

Source:

Rios-Olais F, McGary A, Tsang M, et al. Measurable residual disease and clinical outcomes in chronic lymphocytic leukemia. JAMA Onc. Published online July 11, 2024. doi:10.1001/jamaoncol.2024.2122