Mrd emerging as a biomarker in acute leukemia h2 database download

Propelled by strong results in clinical trials, minimal residual disease (MRD) has emerged as a biomarker for directing treatment and as a predictor for outcomes in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).

In results published in April in the New England Journal of Medicine, corresponding author Peter J. M. Valk, PhD, of the Department of Hematology, Erasmus University Medical Center, and colleagues found that MRD positivity was associated with a higher rate of relapse and a lower rate of relapse-free survival (RFS) and overall survival (OS) for patients with newly diagnosed AML. 1

Researchers obtained samples of bone marrow or peripheral blood from 482 patients with previously untreated AML (n = 428) or refractory anemia with excess of blasts collected from 2001 to 2013.

Patients had to be in either complete remission (CR) or CR with incomplete hematologic recovery (CRi), with less than 5% blast cells in the bone marrow, after receiving 2 cycles of induction chemotherapy.

The investigators used multiparameter flow cytometry (MFC) and targeted next-generation sequencing (NGS) at diagnosis to detect mutations that could serve as a marker of residual disease. They detected mutations in 54 genes commonly found in patients with hematologic cancers. Overall, 430 patients (89.2%) were positive for at least 1 such mutation.

Compared with no detection, the detection of molecular MRD positivty was associated with a significantly higher relapse rate (55.4% vs 31.9%; HR, 2.14; P 0.1%. The primary efficacy endpoint of BLAST was complete MRD response, defined as absence of detectable MRD using an assay with a sensitivity 0.1%, including 61 in first CR, 25 in second CR, and 1 in third CR. Sixty-nine patients (79.3%; 95% CI, 70.4- 87.6) achieved a complete MRD response within the first cycle.

The full analysis set from BLAST included 113 patients who were determined to be MRD-positive, based on a measurement of ≥0.1% from an assay with a minimum sensitivity of 0.01% after ≥2 weeks from their last chemotherapy treatment. Among the evaluable patients in this group, 77.9% (95% CI, 69.1%-85.1%) achieved MRD CR within the first cycle. Two additional patients achieved MRD CR after the second cycle.

Using the 87-patient FDA efficacy analysis set, the 18-month RFS rate was 56% and the estimated median RFS was 22.3 months. The estimated median RFS time in first CR at the time of treatment with blinatumomab was 24.6 months (95% CI, 18.7-not applicable), and the median RFS time in the second or third CR was 11.0 months (95% CI, 6.8-15.4) (TABLE 2). RFS was numerically longer for patients in first CR than for those in the second or third CR.

A propensity score analysis for the patients in first remission, with or without hematopoietic recovery, in BLAST and in Study 20120148 demonstrated that the RFS for patients treated with blinatumomab was significantly greater than in historical controls. Study 20120148 was a retrospective cohort study investigating the hematological RFS and OS in adult patients with Philadelphia chromosome–negative BCP ALL in hematological CR with MRD.

As noted by Roland B. Walter, MD, PhD, MS, an associate member in the Clinical Research Division, Fred Hutchinson Cancer Research Center, in an editorial accompanying the findings from Freeman et al, results from MRD tests are not perfectly predictive. Even without subsequent therapy, not every patient who is MRD-positive will relapse and not every patient who is MRD-negative will be cured, even with standard therapy. 4

“The prognostic significance of any MRD test result critically depends on the assay characteristics,” he wrote. “Current assays are neither standardized nor harmonized, which is perceived as [an] important hurdle for the embracement of MRD-based response definitions. Even though work toward correcting this deficiency is ongoing, methodologies continue to evolve rapidly, and it will take time before mature assays become available with reproducible operating characteristics when implemented across laboratories or institutions.”

Although Freeman et al observed distinct prognostic groups for 5-year OS after incorporating MFC-MRD with established response criteria of PR and RD, Valk et al concluded that the detection of residual leukemia using both methods was associated with an excessively high probability (approximately 75%) of relapse. Furthermore, the absence of detection of residual disease with both methods correlated with a relatively low probability of relapse (approximately 25%).

“In this study, gene sequencing and multiparameter flow cytometry each had independent and additive prognostic value with respect to rates of relapse and survival in patients with AML,” Valk and colleagues wrote. “Thus, the combined use of sequencing and flow cytometry during complete remission warrants further development and evaluation in clinical practice.”