Complete morphologic remission is considered the first requirement for achieving long-term, leukemia-free survival and a potential cure in patients with acute leukemia, including acute myeloid leukemia (AML), and is the goal of all therapeutic strategies to date. Recognizing that the majority of patients with AML continue to experience disease relapse and succumb to complications of the disease, consolidation courses of chemotherapy or allogeneic stem cell transplant have been administered routinely to patients who are able to tolerate these treatments. With solid tumors, it has long been recognized that cancer is a systemic disease, and adjuvant chemotherapy after surgical resection of the tumor is now a well-established protocol. Both transplant and chemotherapy are efforts to tackle the persistent residual disease that is believed to be responsible for relapse and treatment failure for AML, and they work on the premise that such residual disease is sensitive to traditional chemotherapeutic agents.
Farhad Ravandi, MD
With significant improvement in the sensitivity of available assays to detect minute amounts of leukemia cells, the assessment of measurable residual disease (formerly referred to as minimal residual disease; MRD) is being used more extensively in patients who are undergoing therapy for acute leukemias, including AML.1 Detection of submicroscopic levels of leukemia left behind after achieving morphologic remission is now used routinely in most academic centers and is increasingly being used in assisting further management of AML. Of course, there are significant remaining limitations and shortcomings to this strategy.
Limitations of MRD Assessment
Commonly available MRD assessment assays include multiparameter flow cytometry to detect leukemia cells that express aberrant antigens, by comparing the antigen expression to normal cells, detecting aberrant leukemia-associated immunophenotypes, or a combination of the two.2 Although this assay can be used almost universally, it requires adequate fresh specimens, and significant expertise is necessary for the interpretation of its results, thereby limiting its utility to centers where such expertise is available.3
Molecularly based assays that detect aberrant fusion products of recurrent chromosomal translocations or recurrently mutated genes have the advantage of being more widely available and less dependent on individual user interpretation.3 These molecular aberrations have become established in some subsets of AML, such as acute promyelocytic leukemia, as the surrogate endpoint for achieving long-term cure, as well as being markers for monitoring disease response and for preemptive therapy.4
The major limitation of detecting molecular aberrations is that they are not universal, and the AML subsets carrying these mutations and fusion transcripts are less common in the older AML population, which accounts for the majority of patients with AML.1 With the increased availability of next-generation sequencing techniques, a few studies have examined the potential utility of mutation clearance, comparing pre- and post-treatment mutation profiles as a means of detecting MRD and thereby allowing potential expansion of the candidate population for such molecular assays.5
Utility of MRD Negativity:
The Debate Continues
Although multiple studies published in the literature have determined that achieving a negative MRD state is associated with better outcomes, there is still considerable debate among leukemia experts about the utility of an MRD-negative state in therapeutic decision-making. This is partly because of the lack of availability of a uniformly effective treatment to eradicate MRD, which would be associated with significant improvement in survival.
Furthermore, despite the availability of highly sensitive assays for detecting MRD, these assays are not absolute. Even in the most established settings, some individuals with MRD negativity have disease relapse, and some patients with MRD positivity have long-term, disease-free survival.
Clearly, with the establishment of increasingly sensitive assays and perhaps with the application of several assays in the same patient (for example, multiparameter flow cytometry and next-generation sequencing to determine mutation clearance), one could be more confident about a negative result indicating no residual leukemia and hence no risk of relapse. In a study by Jongen-Lavrencic et al, a subset of patients had both flow cytometry and mutation data; patients with negative results for MRD by both assays had the least likelihood of relapse, and those who tested positive for MRD with both assays had an approximately 73% risk of relapse at 4 years.5 However, it is important to note that, even now, the multitude of published studies using different assays with different sensitivities to detect MRD have shown a benefit to MRD-negative over MRD-persistent status.6
Therapeutic Strategies to Eradicate MRD
How to treat MRD in the setting of AML should be the subject of research and new drug development. It is intuitive to believe that residual cells, after initial induction and consolidation chemotherapy, are likely to be resistant to the standard cytotoxic agents used to achieve the response; therefore, strategies and drugs with different mechanisms of action should be used to eradicate them.
This is also likely true of MRD that persists after the use of the recent novel, nonintensive regimens that include venetoclax in the first-line setting. Intuitively, MRD eradication is likely to be more effective if one uses therapeutic strategies that differ from those treatments initially used to achieve the response. However, one should also consider other possible mechanisms of resistance to therapy, particularly the role of the microenvironment and the presence of leukemia stem cells surviving in the protective niche of bone marrow stromal cells.
We have long relied on the graft-vs-leukemia effect of allogeneic stem cell transplant performed in first remission to increase the depth of response and improve long-term survival in patients with higher-risk AML. Several reports have demonstrated that outcomes for patients with AML who undergo allogeneic stem cell transplant in remission are worse when their pretransplant assessment indicated the presence of MRD.7 However, by no means should this be taken as an indication that patients with MRD should not undergo transplant when it is indicated and possible. Currently, transplant remains the most effective established means of treating MRD, and a recent study suggested the
superiority of myeloablative transplant over
reduced-intensity conditioning regimens.8
Debates persist on whether one should try to convert a patient who is MRD-positive to one who is MRD-negative prior to proceeding with transplant. Clearly, this would also depend on the limits of detection by the assay employed. However, with the lack of an established and proven modality for this purpose, such a conversion should be considered only in the setting of an appropriate clinical trial.
Treatments on the Horizon
Potentially novel strategies that remain to be evaluated include the use of other agents that can harness the immune system of the host, such as bispecific T-cell–engaging antibodies, chimeric antigen receptor T cells, and leukemia antigen–targeted vaccines. Other molecularly targeted agents such as FLT3 kinase inhibitors, IDH inhibitors, and venetoclax-based combinations will also likely be evaluated. Many of these agents will also be investigated in the maintenance setting, and it will be important to examine their effect on MRD to gain further insights into how residual leukemia cells and their interaction with the immune microenvironment contribute to the development of disease relapse, sometimes many years later.9 The successful development and approval of blinatumomab for the eradication of MRD in patients with acute lymphocytic leukemia have provided a roadmap for successful drug development in the setting of MRD in AML.10
Dr. Ravandi is Professor of Medicine and Chief of the Section of Acute Myeloid Leukemia, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views
of ASCO or The ASCO Post.
DISCLOSURE: Dr. Ravandi has received honoraria from AbbVie/Genentech, Agios, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Orsenix, Pfizer, and Takeda; has served as a consultant or advisor to AbbVie/Genentech, Agios, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Celgene, Certara, Jazz Pharmaceuticals, Novartis, Orsenix, Syros, and Taiho Oncology; and has received research funding from Amgen, Astex Pharmaceuticals, Bristol Myers Squibb, Cellerant Therapeutics, MacroGenics, Prelude, Selvita, Taiho, and Xencor.
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