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Molecular minimal residual disease predicts poor outcomes for acute myeloid leukemia
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The detection of molecular minimal residual disease during complete remission appeared associated with higher relapse rates and shorter survival among patients with acute myeloid leukemia, according to findings published in The New England Journal of Medicine.
“Although the majority of patients with newly diagnosed AML have morphologic complete remission after they are treated with intensive induction chemotherapy, relapse rates remain high,” Mojca Jongen-Lavrencic, MD, PhD, of Erasmus University Medical Center in the Netherlands, and colleagues wrote. “Decisions about the choice of postremission therapy [among] patients with AML currently depend on the identification of a selected set of genetic markers at diagnosis and the detection of residual disease with multiparameter flow cytometry. Quantitative molecular evaluation during complete remission could further improve prognostication of outcomes [among] patients with AML.”
The analysis included 482 patients aged 18 to 65 years (median age at diagnosis, 51 years; 50% men) with newly diagnosed AML.
Jongen-Lavrencic and colleagues conducted targeted next-generation sequencing at the time of diagnosis and again following induction therapy, during complete remission.
Four-year OS, RFS and rates of relapse served as the main study outcomes.
The researchers detected at least one mutation among 89.2% of patients.
These mutations remained present among more than half (51.4%) of patients during complete remission and occurred at various allele frequencies (range, 0.02%-45%).
Persistent DTA mutations common among patients with age-related clonal hematopoiesis — such as mutations in DNMT3A, TET2 and ASXL1 — did not appear correlated with an increased rate of relapse.
After the researchers excluded DTA mutations, detection of molecular minimal residual disease appeared associated with a significantly higher 4-year relapse rate compared with no minimal residual disease (55.4% vs. 31.9%; HR = 2.14; 95% CI, 1.57-2.91).
Detection of molecular minimal residual disease also appeared linked with lower 4-year OS rates (41.9% vs. 66.1%; HR for death = 2.06; 95% CI, 1.52-2.79) and with lower rates of RFS (36.6% vs. 58.1%; HR for relapse or death = 1.92; 95% CI, 1.42-2.54).
Multivariate analysis showed non-DTA mutations that persisted during complete remission had significant independent prognostic value for relapse rates (HR = 1.89; 95% CI, 1.34-2.65), RFS (HR for relapse or death = 1.64; 95% CI, 1.22-2.2) and OS (HR = 1.64; 95% CI, 1.18-2.27).
Researchers also compared next-generation sequencing for detection of persistent non-DTA mutation with flow cytometry for the detection of residual disease in a subgroup of 340 patients with sufficient samples. Results showed concordant results among 69.1% of patients, whereas persistent non-DTA mutations were detected only with sequencing among 64 patients and only with flow cytometry among 41 patients. Researchers concluded sequencing had significant additive prognostic value for rates of relapse (P < .001), RFS (P < .001) and OS (P = .003).
“In gaining a further understanding of the genetics of minimal residual disease [among] patients with AML, we are given the opportunity to refine postremission therapy,” David P. Steensma, MD, and Benjamin L. Ebert, MD, PhD, both of the Dana-Farber Cancer Institute and Harvard Medical School, wrote in an accompanying editorial.
“Therapeutic targeting of specific mutations that are present during remission could delay or prevent relapse,” they added. “Although the concept of persistent minimal residual disease strikes fear in the hearts of oncologists because of its implications in acute lymphoblastic leukemia and other diseases, assessment for minimal residual disease in AML is more nuanced — one must take into account not only whether a mutation is present after initial therapy, but what that mutation is. In some cases, as Dante pointed out, the devil is not so black as he is painted.” – by Andy Polhamus
Disclosures: Jongen-Lavrencic reports no relevant financial disclosures. Please see the full study for all other authors’ relevant financial disclosures. Ebert reports grants from Celgene; personal fees from Genoptix outside the submitted work; and a pending patent related to identifying and treating patients with a predisposition to, or afflicted with, a cardiometabolic disease. Steensma reports grants from H3 Biosciences and Kura; personal fees from Celgene, Janssen, Onconova, Otsuka, Takeda and Tesaro; and personal and other fees from Acceleron.
Perspective
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Despite significant advances in the diagnosis and treatment of AML, relapse rates are high. The relapse is generally thought to arise as a result of residual leukemic cells not successfully eradicated by induction chemotherapy and subsequent postremission treatment, which consists of high-dose chemotherapy and allogeneic stem cell transplant. We urgently need better prognostication strategies to more accurately predict for relapse in AML and allow for improved individualization of postremission therapy.
The study by Jongen-Lavrencic and colleagues reported the results of targeted sequencing of the 54-gene panel based assessment for minimal residual disease (MRD) among patients with AML at remission-induction therapy. The study reported MRD as a strong predictor of relapse, a valuable prognostic marker in deciding the postremission treatment.
In this study, targeted gene sequencing and multiparameter flow cytometry each had independent and additive prognostic value with respect to rates of relapse and survival among patients with AML. MRD remained a significant predictor of relapse after adjustment for age, white blood cell count, cytogenetic and/or molecular risk, and whether one or two induction cycles were required to enter complete remission or complete remission with incomplete hematologic recovery. This study cements the role of gene sequencing-based MRD assay as a risk-stratification tool for patients with AML at the time of remission.
Although this is a pivotal study, there are still some challenges and open questions.
First, the 54-gene panel failed to capture approximately 10% of AML cases. So, standardization in testing mutations for measuring MRD is lacking. Further methodological advancements might increase the sensitivity of MRD testing.
Second, approximately one-third of patients in the study who were MRD negative still experienced disease recurrence shortly after achieving remission, and we do not have predictive factors for these patients.
Third, the study excluded patients with core-binding factor (CBF) leukemias, which represent a significant subset of AML. It is particularly relevant considering that the degree of response to initial chemotherapy, assessed through MRD testing, might be a decisive factor for the choice of allogeneic stem cell transplant as part of therapy for patients with CBF leukemias.
AML is a very heterogeneous disease and the overall prognosis remains poor. Genetic abnormalities detected at diagnosis are considered the strongest predictive factor for outcomes. They have been used to direct postremission consolidation therapy specifically, but not limited to, selection of candidates for allogeneic hematopoietic stem cell transplant.
Evaluation of minimal residual disease after achievement of complete remission has been used to direct and monitor therapy for patients with acute promyelocytic leukemia and chronic myeloid leukemia, but there’s limited utility for AML, and most prior studies focus on only a few leukemia-specific genetic aberrations.
The Dutch-Belgian Cooperative Trial Group for Hematology-Oncology, or HOVON, and the Swiss Group for Clinical Cancer Research, or SAKK, conducted this study and showed the detection of persistent DTA mutations (ie, mutations in DNMT3A, TET2 and ASXL1) — which are often present in persons with age-related clonal hematopoiesis — did not correlate with an increased relapse rate. After the exclusion of persistent DTA mutations, the detection of molecular minimal residual disease was associated with a significantly higher relapse rate and lower OS. In addition, multiparameter flow cytometry add to the prognostic value. The detection of residual leukemia with both next-generation sequencing and flow cytometry is associated with an excessively high relapse rate — approximately 75%.
Next-generation sequencing is becoming a new tool to predict outcomes for patients with AML and possibly directing post-complete remission consolidation in the future. However, cytogenetic at diagnosis, total white blood cell count at diagnosis, age and number of cycles to achieve complete remission remain important prognostic factors. More importantly, molecular minimal residual disease is only a prognostic factor, as some patients did not relapse despite detection of persistent mutations, and some relapsed despite achievement of molecular minimal residual disease-negative state.
It also is unclear whether treatment intensification can alter the natural history of the disease for patients who has molecular minimal residual disease after induction. Identifying a problem does not mean we have a solution.
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