Minimal residual disease a ‘powerful’ predictor for AML relapse, survival

ATLANTA — Detection of molecular minimal residual disease by next-generation sequencing remained highly prognostic for relapse and survival among patients with newly diagnosed acute myeloid leukemia, according to a prospective analysis presented during the late-breaking abstract session of the ASH Annual Meeting and Exposition.

“In our large prospective study including training and validation cohorts, targeted next-generation sequencing minimal residual disease [MRD] detection was established as a powerful and independent predictor for relapse and survival,” Tim Grob, MD, of the department of hematology at Erasmus University Medical Center in Rotterdam, Netherlands, said during his presentation. “In sensitivity analysis with time-dependent correction for allogeneic stem cell transplantation, next-generation sequencing MRD was applicable in virtually all newly diagnosed adults with AML.”

Most patients with AML achieve complete morphological remission after induction therapy. However, relapse rates remain high.

Molecular MRD detection by polymerase chain reaction-based technologies improves relapse prediction, but only for certain genetically defined subsets of AML. Further, there is little knowledge regarding the association between persisting somatic mutations after induction therapy and AML relapse.

“Next-generation sequencing has an advantage,” Grob said. “It allows for the assessment of a broad range of disease-related gene mutations in a single assay. Residual leukemia-specific mutations in bone marrow in morphological complete remission after induction therapy are supposed to represent the source of relapse. However, persistent mutations may also represent clonal hematopoiesis, analogous to age-related clonal hematopoiesis of indeterminate potential present in healthy individuals.”

Grob and colleagues conducted a large comprehensive study detailing the value of molecular MRD detection by next-generation sequencing among 482 patients with newly diagnosed AML aged 65 years or younger. Patients received two cycles of standard induction chemotherapy followed by consolidation in HOVON-SAKK clinical trials.

Next-generation sequencing (Illumina) evaluated a panel of 54 genes frequently mutated in myeloid malignancies at diagnosis and in bone marrow in morphological complete remission after completion of induction therapy.

Relapse served as the primary endpoint. OS served as the secondary endpoint.

To establish and subsequently test next-generation sequencing MRD, researching split the cohort into two cohorts — representative training (n = 283) and validation (n = 147) cohorts.

Overall, 89.2% (n = 430) of patients had somatic driver mutations present at diagnosis.

In 51.4% of patients, researchers detected persisting mutations in bone marrow during morphological complete remission at highly variable variant allele frequencies (range, 0.0002-0.47). Persisting mutation predominantly comprised DNMT3A (78.7%), TET2 (54.2%) and ASXL1 (51.6%).

However, these persistent mutations were not associated with the incidence of relapse at any variant allele frequency cutoff in the training cohort, indicating a stage of clonal hematopoiesis rather than a condition of impending relapse.

Conversely, in the subset of AML patients with persisting DNMT3A, TET2 and ASXL1 mutations, researchers observed a significant correlation with relapse when they considered any other persistent non-DNMT3A, TET2 and ASXL1 mutations (training cohort 5-year cumulative incidence of relapse, 76.4% vs. 39.4%; P = .002).

Further, MRD defined by persistent non-DNMT3A, TET2 and ASXL1 mutations was highly associated with risk for relapse (subdistribution HR = 1.85; 95% CI, 1.27-2.7). Researchers confirmed this association in the validation set (subdistribution HR = 2.81; 95% CI, 1.64-4.79).

MRD also was significantly associated with the 5-year cumulative incidence of relapse in the combined training and validation cohorts (58.3% vs. 33.9%; P < .001).

Presence of next-generation sequencing MRD predicted risk for reduced survival in the training cohort (HR = 1.64; 95% CI, 1.12-2.42) and validation cohort (HR = 3.08; 95% CI, 1.87-5.08).

In a multivariable analysis — adjusted for age, white blood cells, ELN 2017 risk classification and number of induction cycles needed to achieve complete remission — conducted among all 430 patients with somatic driver mutations at diagnosis, MRD expressed profound independent prognostic significance for relapse (subdistribution HR: 1.89; 95% CI, 1.34-2.65) and OS (HR = 1.64; 95% CI, 1.18-2.27). – by Chuck Gormley

Reference:

Jongen-Lavrencic M, et al. LBA-5. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.

Disclosures: Grob reports no relevant financial disclosures. One author reports consultant roles with, or research funding or honoraria from Celgene, Karyopharm, Johnson & Johnson, Novartis and Roche.