Challenging the Value of Minimal Residual Disease in Predicting Outcome of Patients With Chronic Lymphocytic Leukemia
Year: 2023
Type: editorial
Abstract: Improvements in treatments for patients with chronic lymphocytic leukemia (CLL) can allow therapeutic eradication of any detectable disease by even the most sensitive methods.Intuition dictates that patients who do not have any detectable minimal residual disease (MRD) after treatment should have a longer progression-free survival (PFS) than those who have residual disease after therapy.Clinical studies evaluating for MRD after therapy and assessing its relationship with PFS provided evidence that clearance of MRD may supplant other metrics for assessing the response to therapy.For example, patients who have undetectable MRD (uMRD) after chemoimmunotherapy (CIT), but who achieved only a partial response by International Workshop on Chronic Lymphocytic Leukemia criteria, 1 had a longer PFS than patients who had achieved a complete response, but had detectable MRD after therapy. 2 Similar observations subsequently were made for patients treated with venetoclax and anti-CD20 monoclonal antibodies (mAb).3,4 Moreover, the relative level of MRD detected after therapy appeared to correlate inversely with the length of disease remission.This has led to the assumption that clearance of detectable MRD may be among the most consequential surrogate markers for a prolonged PFS after fixed-duration (FD) therapy.For this reason, work has focused on defining practical means for detecting MRD (Fig 1).Many clinical pathology laboratories can certify that a sample contains fewer than 1 CLL cell in 10,000 cells (ie, <10 24 or MDR4) using flow cytometry to analyze cells stained with a panel of fluorochrome-conjugated antibodies, each specific for any one of the six cell surface proteins (eg, CD19, CD20, CD5, CD43, CD79b, and CD81).Flow cytometry actually can determine with confidence that there are fewer than 1 in 100,000 CLL cells in any given sample (ie, <10 25 or MRD5), 5 but this understandably requires high-level expertise and attention to collecting data on millions of cells and not just a few hundred thousand.There generally is good concordance between flow cytometry and molecular sequencing analysis for the immunoglobulin heavy (IGH) complementarity determining region 3 (ie, the variable, diversity, and joining genes [VDJ] rearrangement) that is idiosyncratic for the leukemia cell population.However, sequencing analysis for the VDJ rearrangement generally is more sensitive than flow cytometry and can determine whether there are fewer than one in a million CLL cells in a sample (ie, <10 26 or MRD6).However, such sequencing methods require molecular characterization of the VDJ rearrangement in pretreatment CLL cells; moreover, some VDJ rearrangements are difficult to sequence for a variety of reasons (eg, high guanine-cytosine content).Both techniques are limited by the numbers of cells available for analysis and can be affected by uneven distribution of residual disease in sampled tissue compartments; for example, sampling the blood for MRD within 3-6 months after having had anti-CD20 mAb therapy typically lowers the sensitivity for detecting MRD in the blood compared with the marrow.Assessing the cell-free DNA (cfDNA) in plasma for CLL-associated VDJ rearrangements is a newer method that has the advantage of being able to analyze for residual disease across multiple compartments and, in theory, could assess the total body MRD after therapy with a sensitivity that appears at least similar, if not greater, than that of flow cytometry.6 However, some of the limitations noted for detecting clonal VDJ rearrangements in DNA extracted from leukocytes also apply to assays for MRD in cfDNA; moreover, for unexplained reasons, detection of MRD in some patients (eg, those with del(11q)) appeared more readily achieved using flow cytometry than through analysis of cfDNA for idiosyncratic clonal VDJ rearrangements; this did not appear to be the case for patients lacking del(11q), suggesting that the sensitivity of this approach for monitoring MRD may be influenced by factors associated with the leukemia cell's cytogenetics.
Source: Journal of Clinical Oncology
DOI: 10.1200/jco.23.00619
Author: Thomas J. Kipps
Institutions: University of California San Diego, Moores Cancer Center
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4379512751