New Data Confirms Role of Residual Disease in AML Relapse

A study published yesterday in the New England Journal of Medicine concludes that, among patients with acute myeloid leukemia (AML), the detection of molecular minimal residual disease during complete remission had significant independent prognostic value with respect to relapse and survival rates.¹

The article, titled “Molecular Minimal Residual Disease in Acute Myeloid Leukemia,” notes, however, that the detection of persistent mutations that are associated with clonal hematopoiesis did not have such prognostic value within a 4-year time frame.

Despite relapse rates in AML patients remaining high, complete remission is frequently reached. Next-generation sequencing permits for the detection of molecular minimal residual disease in essentially every patient, but its clinical value for the prediction of relapse has yet to be established. The study — led by Mojca Jongen-Lavrencic, M.D., Ph.D.; and Tim Grob, M.D., of the Erasmus University Medical Center; Bart J. Biemond, M.D., Ph.D., of the Academic Medical Center Hematology Amsterdam, Netherlands; and Carlos Graux, M.D., Ph.D., Professor at the UCL Mont-Godinne – evaluated a large cohort of patients who were newly diagnosed with AML.

Samples of bone marrow or peripheral blood was collected were collected between 2001 and 2013 and evaluated to investigate whether targeted molecular monitoring with next-generation sequencing could add clinical value for predicting the recurrence of leukemia.

Four-year rates of relapse, relapse-free survival, and overall survival served as endpoints for the study.

Samples from 482 patients between the ages of 18 and 65 years were studied, and each had a confirmed diagnosis of previously untreated AML (428 patients) or refractory anemia with excess of blasts, with a score on the Revised International Prognostic Scoring System of more than 4.5 (54 patients). In 430 out of 482 evaluated patients (89.2%), at least one mutation was detected, and mutations persisted in 221 (51.4%) patients during complete remission and were present at various allele frequencies (range, 0.02 to 47%). The detection of persistent DTA mutations (i.e., mutations in DNMT3A, TET2, and ASXL1), which commonly exist in persons with age-related clonal hematopoiesis, was not correlated with an increased relapse rate.

“Because DTA mutations have been established as the most common gene mutations in persons with age-related clonal hematopoiesis, the persistent DTA mutations might have represented nonleukemic clones that repopulated the bone marrow after induction therapy,” it was noted in the study.

After persistent DTA mutations were excluded, molecular minimal residual disease associated with a significantly higher relapse rate than no detection was identified (55.4% vs. 31.9%; hazard ratio, 2.14; P<0.001). Lower rates of relapse-free survival and overall survival were also detected.

It was also confirmed that the persistence of non-DTA mutations during complete remission conferred significant independent prognostic value with respect to rates of relapse, relapse-free survival, and overall survival. A comparison of sequencing with flow cytometry for the detection of residual disease confirmed that sequencing had meaningful additive prognostic value.

The findings confirm that detection of residual leukemia with both gene sequencing and multiparameter flow cytometry is associated with an excessively high probability of relapse, and the absence of detection of residual disease is correlated with a relatively low probability of relapse.

“Targeted sequencing-based detection of molecular minimal residual disease during complete remission was associated with an increased risk of relapse or death in patients with AML,” the authors concluded. “However, over a 4-year follow-up period, the risk of relapse or death was not influenced by the persistence of genetic lesions that are associated with age-related clonal hematopoiesis.”

References:

Steensma David P., Ebert Benjamin L.. (2018) Clonal Hematopoiesis after Induction Chemotherapy for Acute Myeloid Leukemia. N Engl J Med 378:13, 1244-1245.