A significant number of MRD-negative patients still relapse.… This is why we still mainly use pretherapy factors like genetics, white blood cell count, and age to make clinical decisions.— Richard M. Stone, MD
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Although a majority of major cancer centers may test for minimal residual disease (MRD), a recent survey conducted by researchers at Moffitt Cancer Center, Tampa, Florida, suggests most oncologists remain uncertain about what to do with the results. At the National Comprehensive Cancer Network® (NCCN®) 12th Annual Congress: Hematologic Malignancies™, Richard M. Stone, MD, outlined potential uses of MRD monitoring in acute myeloid leukemia (AML) in first complete remission but cautioned that basing therapeutic decisions on the technology may still be a few years away.1
Prospective Monitoring to Predict Relapse
According to Dr. Stone, Chief of Staff and Program Director of Adult Leukemia at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston, one potential use for MRD is prospective monitoring of patients after chemotherapy or allogeneic stem cell transplant to predict relapse and intervene with preemptive therapy. A trial conducted nearly 10 years ago in acute promyelocytic leukemia, a subtype of AML, used real-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts.2 Of the 30 patients who had positive transcripts, 16 received preemptive arsenic trioxide (Trisenox) therapy, and only 6 of these 16 patients experienced overt relapse—a lower rate of relapse compared with that of historical controls. Nevertheless, said Dr. Stone, the treatment is prohibitively expensive.
“The overall cost was $5,400 per patient, but it was $25,600 in non–high-risk patients,” said Dr. Stone. “We give all-trans retinoic acid and arsenic to everybody now anyway, so providers should stop trying to find transcript in every patient with acute promyelocytic leukemia.”
MRD Assessment Informs Prognosis
A more important use of MRD assessment, said Dr. Stone, is to inform prognosis within subgroups of AML. Patients who harbor an FMS-like tyrosine kinase 3 (FLT3) mutation with internal tandem duplications (ITD), for example, almost always receive a transplant due to poor prognosis, whereas those with core-binding factor (CBF)-mutated AML typically do not.
As Dr. Stone reported, however, MRD monitoring may offer the ability to fine-tune the selection process within these genetic subtypes. A study of 143 adult AML patients assessed for MRD by flow cytometry showed that those with FLT3 wild-type disease achieving an MRD-negative status had a better outcome than those who remained MRD-positive (4-year relapse-free survival of 54% vs 17%; P < .001).3
“MRD-positive patients performed almost as poorly as FLT3-ITD mutation,” said Dr. Stone, “so we can clearly refine prognosis within a genetic subgroup.”
MRD Monitoring in AML
- MRD should be included in any major clinical trial, but guidance regarding an appropriate intervention for MRD-positive patients is needed.
- The use of MRD as a surrogate marker for drug development is intriguing.
According to Dr. Stone, MRD status in CBF-AML might also make a difference in treatment selection. A separate study of patients with CBF-AML found that those with an MRD level of at least 1% at one point following induction therapy experienced relapse 90% of the time, with a median remission duration of 10 months (P < .001).4 “This is one group of patients we could justify transplanting,” Dr. Stone observed, “but that doesn’t mean it’s going to make a difference.”
MRD test results have also been shown to improve outcome prediction,5 albeit modestly, when included with more typical clinical data (ie, age, gender, performance status, white blood cell count, platelet count, bone marrow blast percentage, cytogenetic risk, and NPM1/FLT3-ITD status). Because predictive outcome was only improved by 3%, however, MRD testing is not worth the effort for that reason alone, according to Dr. Stone.
Testing Limitations
Whether performed with multiparameter flow cytometry or next-generation sequencing, MRD testing also has several technical and practical limitations. With multiparameter flow cytometry, for example, not all leukemic cells have an abnormal phenotype and an immunophenotypic antigen shift between diagnosis and relapse. There is also a lack of standardization on measurement and reporting as well as variations in fluorescent intensities and instrument performance. With next-generation sequencing molecular MRD monitoring, on the other hand, error rates allow for only low-sensitivity detection of mutated sequencing, and somatic mutations (eg, DNMT3A) can be found in healthy individuals.
“A significant number of MRD-negative patients still relapse,” said Dr. Stone. “Could it be MRD is responsible for the relapse? This is why we still mainly use pretherapy factors like genetics, white blood cell count, and age to make clinical decisions.”
Risk Stratification
Despite these limitations, however, MRD test results may refine risk stratification for patients in morphologic remission. According to Dr. Stone, a positive MRD test is associated with a higher relapse risk and/or shorter survival at the cohort level: on day 15 of the first cycle of chemotherapy; after the first or second cycle of chemotherapy; during or after postremission chemotherapy; before autologous or allogeneic transplantation; and after transplantation.
“MRD status is often the most important adverse factor in univariate analyses and often the only prognostic factor in multivariable analyses,” Dr. Stone added. “The major question, though, is how to deal with the results.”
A retrospective analysis of 99 patients receiving myeloablative hematopoietic cell transplantation for AML in first morphologic remission suggests that MRD status prior to transplant is associated with an increased risk of relapse and death after transplant, even after controlling for other risk factors.6 In this study, the rate of 2-year overall survival for MRD-positive patients was 24%, compared with 75% for those with MRD-negative disease. Although the presence of MRD usually predicts for worse outcomes with more aggressive measures, said Dr. Stone, these measures are largely ineffective. A separate study showed that intensification of bone marrow transplant conditioning failed to reduce the risk of relapse in the MRD-positive setting.7
“Given the lack of proven therapeutic interventions, knowledge of MRD may impose a psychological burden on patients if we can’t do anything about it,” said Dr. Stone. “More randomized trials are needed to guide appropriate intervention.”
Future Use of MRD
In the meantime, investigators are searching for a reliable “MRD eraser” in AML. Although SL-401, a novel targeted therapy directed to the interleukin 3 receptor, decreased MRD in a single patient, it’s still too early for it to be used in the routine setting, but there are other potential MRD erasers. They include anti-CD33 and anti-CD123 agents as well as a dendritic cell vaccine. According to Dr. Stone, MRD could also be used as a surrogate endpoint of controlled, clinical trials to expedite drug approval.
MRD assessment of common and rare NPM1 mutations should be widely available soon, but it is currently only available in research settings.— Jessica K. Altman, MD
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“We in the leukemia community are eagerly awaiting guidelines from the NCCN and other groups,” said Jessica K. Altman, MD, of the -Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “MRD assessment of common and rare NPM1 mutations should be widely available soon, but it is currently only available in research settings. In the meantime, providers may consider using flow cytometry on a patient to evaluate MRD, but a therapy that will improve MRD if detected may not exist.” ■
DISCLOSURE: Drs. Stone and Altman reported no conflicts of interest.
REFERENCES
2. Grimwade D, Jovanovic JV, Hills RK, et al: Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol 27:3650-3658, 2009.
3. Buccisano F, Maurillo L, Spagnoli A, et al: Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia. Blood 116:2295-2303, 2010.
4. Krauter J, Gorlich K, Ottmann O, et al: Prognostic value of minimal residual disease quantification by real-time reverse transcriptase polymerase chain reaction in patients with core binding factor leukemias. J Clin Oncol 21:4413-4422, 2003.
5. Othus M, Wood BL, Stirewalt DL, et al: Effect of measurable (‘minimal’) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia. Leukemia 30:2080-2083, 2016.
6. Walter RB, Gooley TA, Wood BL, et al: Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 29:1190-1197, 2011.
7. Walter RB, Gyurkocza B, Storer BE, et al: Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 29:137-144, 2015.
