The desire to detect minimal residual disease in patients with cancer as a way to predict prognosis or relapse risk became a reality in the past decade due to the development of technology sensitive enough to measure minute levels of cancerous cells in human tissue.
Since then, several questions surrounding the clinical utility of minimal residual disease (MRD) in hematologic malignancies — including its potential as a surrogate endpoint for survival, and the optimal method with which to detect it — have been the subject of extensive research and intense debate.
The evidence in some areas is robust, but much of it is retrospective. Many experts in the field have called for randomized trials, but simply defining study parameters has proved challenging because detection techniques, benchmarks to distinguish MRD-positive and MRD-negative status, and effective approaches to eradicate residual cells vary greatly by disease.
The FDA conducted a series of public hearings earlier this year to explore the value of MRD measurement in hematologic malignancies, and the discussions revealed there is some common ground. Use of MRD has been established as an accepted prognostic factor in certain pediatric cancers in the United States, and it has been shown to play a critical role in evaluation of patient response and treatment efficacy in multiple forms of leukemia.
As the scientific evidence mounts, an increasing number of advocates are calling on members of the research and clinical communities to come together to build further consensus.
Retrospective studies suggest minimal residual disease has clinical value in the treatment of hematologic malignancies, but prospective trials are needed to better define positive and negative status, said Timothy S. Pardee, MD, assistant professor of hematology and oncology at Wake Forest Baptist Medical Center.
Source: Photo courtesy of Wake Forest Baptist Medical Center
“The data are becoming increasingly difficult to ignore,” Timothy S. Pardee, MD, assistant professor of hematology and oncology at Wake Forest Baptist Medical Center, told HemOnc Today. “As more of these retrospective studies come out, it will become necessary for the clinical community to pay attention.”
Setting the stage
Two studies released this year related to multiple myeloma encapsulate the issues at hand but also highlight the potential utility of MRD detection.
Up to half of patients with myeloma demonstrate complete response to current treatments. However, the persistence of MRD causes most to relapse, highlighting the need for more sensitive techniques to define response, said Joaquin Martinez-Lopez, MD, PhD, of the hematology service at Hospital Universitario in Madrid.
Martinez-Lopez and colleagues conducted a study to compare the prognostic value of traditional response criteria and MRD measurements as determined by multiparameter flow cytometry (MFC) and genetic deep sequencing. The analysis included bone marrow samples collected from 68 patients.
Patients deemed MRD negative (MRD levels <10-5) demonstrated significantly improved median OS (not reached vs. 86 months; P=.026). Researchers reported 35 patients demonstrated conventional complete response. Of them, 24 were MRD positive and 11 were MRD negative. The MRD-negative patients demonstrated significantly improved median OS (not reached vs. 80.9 months; P=.041).
“For patients in complete response by traditional response criteria, the presence or absence of MRD by sequencing delineated two groups of patients with significantly different OS,” Martinez-Lopez and colleagues wrote. “MRD negativity by sequencing may be a better prognostic indicator than complete response by traditional complete response criteria.”
There may be barriers to widespread use, however.
“At the moment, identification of malignant cells by next-generation sequencing is limited by depth and coverage of sequencing,” John DiPersio, MD, PhD, deputy director of the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis School of Medicine, told HemOnc Today. “It will be necessary to sequence the patient and then look for the mutation, because each patient will have an array of mutations.”
Mutations can be grouped into one or more clones, and sequencing can identify those clonal populations, DiPersio said.
Although sequencing technology has — at least until now — been prohibitively expensive, documentation of mutations in certain malignancies, such as acute myelogenous leukemia, may make it more feasible, DiPersio said.