Clinical value of MRD detection in blood cancers ‘increasingly difficult to ignore’
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.
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.
A surrogate for OS
Rawstron and colleagues conducted a study to determine whether MRD assessment by MFC provides prognostic value in multiple myeloma. The investigators assessed MRD in 378 intensive-pathway patients after induction therapy and in 397 intensive-pathway patients at day 100 after autologous stem cell transplantation. They also assessed MRD in 245 nonintensive-pathway patients at the end of induction therapy.
Among intensive-pathway patients, the absence of MRD at the 100-day mark after transplantation was associated with improved PFS (P<.001) and OS (P=.0183). Researchers observed the PFS advantage in patients with both favorable (P=.014) and unfavorable (P<.001) cytogenetics, as well as in those who achieved immunofixation-negative complete response (P=.0068).
However, among nonintensive-pathway patients, MRD assessment after induction therapy failed to predict PFS (P=.1).
Transformations in myeloma therapy necessitated efforts to detect MRD and define its prognostic value on survival outcomes, Nikhil C. Munshi, MD, an associate professor of medicine at Harvard Medical School, and Kenneth C. Anderson, MD, director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute, wrote in an editorial that accompanied the Rawstron study.
Available methods include allele-specific oligonucleotide polymerase chain reaction (ASO-PCR), which can detect up to one clonal cell in 105 normal cells, and immunophenotypic assays, which can detect one clonal cell in 104 normal cells by use of MFC.
The findings by Rawstron and colleagues trigger an important discussion about whether MRD detection, regardless of method, can help predict survival and guide clinical practice.
“With available technologies and ease of MRD measurement, it is now time to carry out additional large prospective studies to define the clinical significance of MRD and its impact on patient outcome in myeloma,” Munshi and Anderson wrote. “It may be possible, as in chronic myeloid leukemia, to both assess and monitor MRD using standardized assays and thereby both inform therapy and improve patient outcome.”
MRD detection in AML
Two studies published in the Journal of Clinical Oncology in September examined the prognostic value of MFC-detected MRD in AML.
Sylvie Freeman, MBChB, MRCP, DPhil, FRCPath, clinical senior lecturer in immunohematology and a consultant hematologist at the University of Birmingham in the United Kingdom, and colleagues evaluated MRD by flow cytometric detection of leukemia-associated immunophenotypes in patients aged at least 60 years with AML.
The study prospectively assessed 892 patients who participated in the United Kingdom National Cancer Research Institute AML16 Trial. The analysis included 427 patients who entered complete remission after one or two courses of therapy.
Fifty-one percent of patients in complete remission from the first course achieved MRD-negative status, defined by flow cytometry, and 64% achieved MRD-negative status when in remission after the second course. Researchers observed significantly higher 3-year OS rates among patients who were MRD negative after the first course (42% vs. 26%) and the second course (38% vs. 18%) than those who were MRD positive (P<.001 for both).
Three-year relapse rates were lower for patients who were MRD negative after the first course (71% vs. 83%; P<.001) and the second course (79% vs. 91%; P<.001). The median time to relapse was 17.1 months among MRD-negative patients vs. 8.5 months among MRD-positive patients.
Multivariate analysis results indicated that MRD status after the first course independently predicted survival.
“MRD assessment by flow cytometry to define response to treatment can be applied to most AML patients and is clearly prognostic, differentiating patients with a higher risk of relapse,” Freeman told HemOnc Today. “Our study shows it can add important prognostic information following induction for older patients.”
Terwijn and colleagues conducted a multicenter trial to evaluate immunophenotypical MRD assessment in adults younger than 60 years with AML in complete remission.
The analysis included 164 bone marrow samples obtained after one induction cycle, 183 samples obtained after the second induction cycle and 124 obtained after consolidation therapy.
After all courses of treatment, low MRD values predicted favorable OS, relapse and adverse relapse-free survival rates.
MRD independently predicted outcomes in the entire cohort, as well as in those with intermediate-risk cytogenetics.
Multivariable analysis after the second cycle of treatment — the time when clinicians must make decisions about consolidation treatment — showed MRD values >0.1% of white blood cell counts were associated with increased relapse risk. The association persisted after adjustment for consolidation treatment time-dependent covariate risk score, as well as early or later complete remission, the researchers wrote.
Risk stratification in future studies should be based not only on risk estimation assessments at diagnosis but also on MRD as a therapy-dependent prognostic factor, Terwijn and colleagues concluded.
Although acceptance of flow cytometry is gaining ground, challenges remain, DiPersio said.
“Just because you can identify a cytogenetic abnormality indicating poor risk does not mean you can intervene and get a better outcome,” he said. “They are not easily exportable, reproducible or validated. The phenotype of the malignant cells are different in each patient, so it is necessary to identify a unique flow-based phenotype and then follow those cells.”
Roland B. Walter, MD, PhD, assistant member of the clinical research division at Fred Hutchinson Cancer Research Center and assistant professor of medicine in the division of hematology at the University of Washington School of Medicine, agreed.
“The evidence is overwhelming that MRD denotes a subset of patients at high risk of poor outcome and increased relapse risk,” Walter told HemOnc Today. “What is much less clear is whether MRD-directed therapy — ie, the goal to revert an MRD-positive state into an MRD-negative state — changes the ultimate outcome of the patient. There is some evidence in acute lymphoblastic leukemia, in particular with bispecific T-cell–engaging antibodies, that this might be the case, but most studies have not addressed this.”
Another obstacle associated with flow cytometry involves the reality of false-positive and false-negative tests.
“They can be highly sensitive and highly predictive of relapse, but there is room for improvement,” DiPersio said.
It may be difficult to examine this approach in a multicenter setting, said Gerrit Schuurhuis, PhD, of the department of hematology at VU University Medical Center in Amsterdam.
“If large studies are planned, our suggestion would be to perform the assays in a few already specialized core centers,” Schuurhuis said. “The misleading thing is that, even if MRD would be carried out in a multicenter way, it may still be possible to define patients groups with different outcomes. This is simply due to the fact that MRD is such a strong prognostic factor. However, such a multicenter approach will likely lead to a certain percentage of false-positive or false-negative patients who could have been diagnosed for MRD status more properly.”
Many institutions use quantitative PCR assay to measure levels of WT-1 expression, DiPersio said.
“This can be standardized because WT-1 is a shared antigen, a normal gene but overexpressed,” DiPersio said. “It is a nearly perfect test but, unfortunately, has not been widely accepted, validated and standardized.”
The use of PCR in AML and ALL also may present challenges, DiPersio said.
“It depends on known fusions associated with specific AML malignancies,” he said. “The problem with those diseases is that they’re all low risk. It may be more useful to use PCR in intermediate-risk diseases where we can intervene with more aggressive treatment.”
In ALL, PCR is only reproducible in BCR-ABL and Philadelphia chromosome-positive disease, according to DiPersio.
Optimism in Ph+ALL
Farhad Ravandi, MD, professor of medicine in the department of leukemia at The University of Texas MD Anderson Cancer Center, and colleagues found that combined use of MFC and real-time PCR predicted outcomes in Ph+ALL.
The final analysis included 76 patients (median age, 54 years) who achieved complete remission after one course of induction chemotherapy plus a tyrosine kinase inhibitor; subsequent TKI treatment with either imatinib (Gleevec, Novartis) or dasatinib (Sprycel, Bristol-Myers Squibb) in addition to chemotherapy; and 2 years of TKI maintenance therapy.
Clinicians performed MFC and quantitative PCR monitoring of MRD after induction therapy, and again after approximately 3-month intervals.
Major molecular response was defined as BCR-ABL/ABL <0.1% corrected to the international scale devised for monitoring chronic myeloid leukemia.
Researchers reported no survival differences based on achievement of major molecular response at complete remission (P=.22). However, they reported significantly improved survival among patients who achieved a major molecular response at 3 months (P=.02), 6 months (P=.04), 9 months (P=.05) and 12 months (P=.01).
Negative flow cytometry results at complete remission failed to predict extended survival (P=.02). Negative MRD results by flow cytometry at 3 months (P=.04) and 12 months (P=.001) were associated with improved survival.
The results show use of PCR and flow cytometry to monitor MRD identifies patients who benefit from intensified therapy at first complete remission.
“While our results aligned with our observed outcome in this study and the MFC and real-time PCR technologies are very sensitive, these tools do not yet provide absolute results,” Ravandi said. “We advise that each treatment decision be made on a patient-to-patient basis and to take into account each patient’s unique situation. The next step is to refine and standardize our approach to better define which patients are truly disease-free and who should be recommended for more aggressive treatment.”
No common standards
A critical area of disagreement in the United States revolves around the definition of MRD.
“If I say a patient has a level of 10-5, and if that patient goes to another institution that can only detect to 10-3, they’ll be negative in one institution and positive in our institution,” Ravandi told HemOnc Today. “Different institutions have different definitions and capabilities.”
MD Anderson Cancer Center and a limited number of other comprehensive cancer centers and academic institutions in the United States have the necessary techniques and expertise to measure and monitor MRD. Consequently, the country overall is behind countries such as Germany and the UK, where this is done systemically for most patients, Ravandi said.
“The Europeans have been more organized in standardizing techniques,” he said. “They were able to do it because most testing is done in centralized labs. That may also be possible in the United States.
“We don’t have strong standardization of the way we use MRD and the way we measure it,” Ravandi added. “Without those standards, we cannot move forward nationally.”
The heterogeneity of malignancies also is a factor, said Meir Wetzler, MD, chief of the leukemia section and professor of medicine at Roswell Park Cancer Institute.
“Standards must be developed disease by disease,” he said. “This presents difficulties.”
Efforts to decide what should be standardized also have proved challenging.
“We have explored the possibility to standardize or harmonize the three most important aspects of MRD assessment,” Schuurhuis said. “One is the choice of monoclonal antibodies, instrument settings, etc. The second is defining immunophenotypic aberrancies at diagnosis that can be used to monitor MRD. The third is gating strategies for the usually very low numbers of bone marrow MRD cells to quantify MRD.”
Most patients with AML in the United Kingdom are treated within National Cancer Research Institute studies.
“Within these trials, MRD assays have been integrated in a standardized central approach in order to generate comparable data for the important questions of whether the resources needed for MRD testing translate to better patient outcome and, if not for all patients, for which subgroups and with which treatments,” Freeman said. “This strategy will be strengthened by European initiatives to harmonize MRD results in AML, particularly for flow cytometric assays.”
Pardee called on the US research community to pursue a similar goal.
“This is why we need a prospective trial — to define what is MRD positive and what is MRD negative,” he said. “We are waiting for this, but it’s slow to come.”
Even if detection methods and MRD measurements are standardized, the debate about the extent to which MRD can serve as a prognostic factor — and the benefits of identifying such a predictor — likely will continue.
“Depending on the malignancy, MRD can be an excellent surrogate for outcomes,” Ravandi said. “Of course, it is necessary to pay attention to other factors such as age, performance status and underlying disease biology, but MRD can have a role.”
Relapse also is related to treatment.
“In many malignancies, we don’t have ways to eradicate disease,” Ravandi said. “Of course it is useful to identify MRD to help predict which patients are likely to relapse, but unless you have a strategy to eradicate it, it is more of an intellectual concept than clinically relevant practice.”
“What is still uncertain is whether the outcome of both younger and older patients in any or all of the known genetic risk groups is improved when MRD results are used to direct treatment post-induction,” Freeman said. “This is a critical question, which is being addressed by ongoing and planned trials using both molecular and flow cytometric MRD assays.”
Regardless of the scientific evidence, another significant barrier must be overcome, Wetzler said.
“This is being driven by academics rather than industry,” Wetzler said. “There is no pharmaceutical stakeholder pushing the agenda forward. The industry is more interested in pushing specific drugs than something like MRD.”
DiPersio echoed Wetzler’s sentiment.
“People have been talking about this forever, but funding is very difficult right now,” DiPersio said.
Still, the difficulties go beyond money.
“You have to compare different platforms, but first you have to agree on which platforms to compare, and in which patient populations,” DiPersio said. “You have to compare the sensitivity and specificity of different platforms.”
The clinical community also must come to a consensus on how and when to follow patients, and which assays will be validated.
“All of this is going to require a great deal of agreement,” DiPersio said. “Unfortunately, the clinical community does not agree on much anymore, particularly with regard to something as complicated as MRD.” – by Rob Volansky
Freeman SD. J Clin Oncol. 2013;doi:10.1200/JCO.2013.49.1753.
Martinez-Lopez J. Abstract #8511. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.
Munshi NC. J Clin Oncol. 2013;31:2523-25266.
Ravandi F. Blood. 2013;doi:10.1182/blood-2012-11-466482.
Rawstron AC. J Clin Oncol. 2013;31:2540-2547.
Terwijn M. J Clin Oncol. 2013;doi:10.1200/JCO.2012.45.9628.
Walter RB. Blood. 2013;doi:10.1182/blood-2013-06-506725.
For more information:
John DiPersio, MD, PhD, can be reached at Division of Oncology, Campus Box 8007, Washington University Medical School, 660 S. Euclid Ave., St. Louis, MO 63110; email: email@example.com.
Sylvie Freeman, MBChB, MRCP, DPhil, FRCPath, can be reached at Department of Clinical Immunology, School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston Birmingham B15 2TT UK; email: firstname.lastname@example.org.
Timothy S. Pardee, MD, can be reached at Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157; email: email@example.com.
Farhad Ravandi, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd., Houston, TX 77030; email: firstname.lastname@example.org.
Gerrit Schuurhuis, PhD, can be reached at VU University Medical Center, Department of Hematology, CCA-4.28, PO Box 7057, 1007 MB, Amsterdam, Netherlands; email: email@example.com.
Roland B. Walter, MD, PhD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, D2-190, Seattle, WA 98109-1024; email: firstname.lastname@example.org.
Meir Wetzler, MD, can be reached at Roswell Park Cancer Institute, Elm and Carlton streets, Buffalo, NY 14263; email: email@example.com.
Disclosure: DiPersio, Freeman, Pardee, Ravandi, Schuurhuis, Walter and Wetzler report no relevant financial disclosures.
Is MRD detection valuable for the treatment of myeloma?
MRD can help guide myeloma treatment.
The evolution of response criteria in myeloma is one that has occurred as our treatments have further improved. Although the current definition requires absence of any paraprotein in the blood or urine in combination with absence of clonal plasma cells in the marrow and a normal freelight chain ratio, it is clear that the use of more sensitive testing — such as multi-parameter flow cytometry (MPF) or polymerase chain reaction (PCR) testing for specific immunoglobulin gene rearrangements — are able to detect low levels of persistent disease, even among these patients who have met the current criteria for complete remission (CR).
It is also clear that patients who are able to achieve even lower levels of disease burden with negative testing by MPF or PCR have improved outcomes compared with those who do not achieve MRD negativity. Thus, among all patients in a complete remission, achieving MRD negativity results in improved outcomes compared with CR patients who are MRD positive.
However, this MRD testing is dependent upon sampling in the marrow, and even using the high sensitivity of MPF, it is possible that disease may be present that is missed using this testing. This raises the question of the role of imaging in myeloma. Although skeletal surveys continue to remain the standard, it is also becoming increasingly clear that — among patients in CR — those with a normal PET scan have an improved outcome compared with patients in CR who remain PET positive. However, the sensitivity of imaging alone as a modality to assess MRD may miss low-level disease present in the marrow. For this reason, I propose a new definition of CR that encompasses both MRD assessments using MPF, as well as imaging using PET/CT imaging.
It should be noted that, even if this is adopted, it remains unclear what the best time point is for assessing MRD by any method. Additional clinical trial testing is going to be required to fully define how and when to assess MRD, as well as to determine if or when treatment should be changed based on MRD assessment.
The ability to detect true CR patients using this new definition is very important, and is a function of our improved ability to eliminate the malignant clone using new and improved treatments for patients with myeloma. Further validation will be required to identify how this testing should modify which treatment, and duration of maintenance for all patients.
Sagar Lonial, MD, is professor and vice chair of clinical affairs in the department of hematology and medical oncology at Winship Cancer Institute at Emory University School of Medicine. He can be reached at firstname.lastname@example.org. Disclosure: Lonial reports no relevant financial disclosures.
MRD testing in myeloma is not yet ready for prime time.
A variety of new strategies to measure MRD in patients with multiple myeloma are being studied and have garnered substantial attention. These include more established radiographic approaches, such as MRI and PET; studies of myeloma markers, including the serum free light and free heavy chain levels; and newer measurements of myeloma cells themselves utilizing multiparameter flow cytometry, allele-specific oligonucleotide polymerase chain reaction, and even whole-genome sequencing.
All of these techniques are likely to be valuable additions to our monitoring armamentarium for myeloma. In addition, it is likely that patients who achieve and maintain a remission by each respective assay will have an excellent prognosis, especially in comparison to those who achieve and then rapidly lose that remission.
However, we first need to sufficiently standardize these assays so that comparisons of their value can be made not just within each study, but across different trials. We also need to determine which of these single assays, or which combination of assays, provides the greatest prognostic value for patients and their caregivers. Ideally, these assays should be broadly applicable to all myeloma patients, easy to administer and interpret, and performed at a moderate or low cost. Finally, prospective studies are needed to demonstrate that these data do not just predict prognosis, but that they can also change our clinical management. For example, is there a substantial survival benefit, and with an acceptable quality of life, to treating patients who do not achieve a complete remission by these MRD measures with additional chemotherapy to attain a remission? Also, is there a benefit to treating patients who convert from MRD negative to MRD positive earlier, rather than waiting until there are clinical signs of progression?
Ongoing and planned studies of these MRD measures will hopefully bring us answers to these crucial questions, at which point these assays can become part of our standard of care.
Robert Z. Orlowski, MD, PhD, is a professor in the department of lymphoma/myeloma at The University of Texas MD Anderson Cancer Center. He can be reached at email@example.com. Disclosure: Orlowski reports no relevant financial disclosures.