Achievement of MRD Negativity Predicts Favorable Prognosis in RUNX1-RUNX1T1+ AML

In patients with acute myeloid leukemia (AML) with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1+ fusion, serial assessment of measurable residual disease (MRD) can identify people at a high risk for relapse during treatment and follow-up, according to findings published in Blood. The authors also were able to define cutoff values for RUNX1-RUNX1T1+ transcript levels (TLs) detectable after induction chemotherapy that predicted relapse.

“Translocation t(8;21) leading to the formation of the RUNX1-RUNX1T1 gene fusion is considered to be a favorable AML subset in the 2017 risk stratification by the European LeukemiaNet,” lead study author Frank G. Rücker, MD, from Ulm University in Germany, and co-authors explained. While monitoring MRD is known to help determine likelihood of relapse, “standardizing MRD assays and choosing the right time points to inform treatment remains challenging.”

In this study, Dr. Rücker and researchers evaluated the prognostic impact of quantitative RT-PCR–based MRD monitoring in bone marrow and peripheral blood samples of 155 patients (median age = 48 years; range = 18-76 years) with RUNX1-RUNX1T1+ AML. All patients had a sample obtained at diagnosis and at least 2 subsequent time points during their treatment.

Overall, 2,297 samples were analyzed: 1,182 bone marrow samples and 1,115 peripheral blood samples.

All patients received standard-dose induction therapy with an anthracycline- or cytarabine-based regimen. After the first cycle of chemotherapy, 77% of patients achieved a complete response (CR) using conventional clinical and pathological criteria, which increased to 98% after the second cycle. The 4-year overall survival (OS) rate was 75% and the 4-year relapse-free survival (RFS) rate was 64%. At end of treatment, MRD-negativity was achieved in the bone marrow of 51 of 99 patients (52%) and in the peripheral blood of 64 of 86 patients (74%).

The researchers found that, compared with patients who remained positive for MRD, achieving MRD-negativity in either the bone marrow or peripheral blood was a favorable predictive factor of cumulative incidence of relapse (CIR) and OS:

  • 4-year CIR: 17% vs. 36% (p=0.021) in the bone marrow and 23% vs. 55% (p=0.001) in peripheral blood
  • 4-year OS: 70% vs. 93% (p=0.007) in the bone marrow and 47% vs. 87% (p<0.0001) in peripheral blood

Achieving reductions of RUNX1-RUNX1T1 TLs and MRD-negativity at defined time points also appeared to be of significant prognostic importance, the investigators noted. Patients who achieved MR2.5, or a >2.5-log reduction in RUNX1-RUNX1T1 TLs after the first chemotherapy cycle versus a ≤2.5-log reduction, had a significantly lower 4-year CIR in the bone marrow (22% vs. 43%; p=0.034) and peripheral blood (19% vs. 51%; p=0.008) analyses. In addition, those who achieved MR3.0, or a >3-log reduction in RUNX1-RUNX1T1 TLs after 2 cycles versus a ≤3-log reduction, had a lower 4-year CIR in bone marrow (28% vs. 51%; p=0.028) and peripheral blood (29% vs. 54%; p=0.036). Multivariate analysis found MR3.0 to be consistently significant for CIR in bone marrow (hazard ratio [HR] = 0.48; 95% CI 0.24-0.98; p=0.043) and peripheral blood (HR=0.35; 95% CI 0.14-0.85; p=0.021).

Patients with a KIT mutation had a lower CR rate (odds ratio = 0.34; p=0.014) and inferior OS (HR for death = 2.21; p=0.022) compared with those without the mutation. However, despite the predictive potential of a KIT mutation, RUNX1-RUNX1T1 TLs outweighed the prognostic impact of KIT mutation during therapy.

“Standardizing MRD assays and choosing the right time points to inform treatment remains challenging.”

—Frank G. Rücker, MD

During follow-up, almost all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, the authors reported. Based on these findings, “for an earlier and more precise prediction of relapse, MRD assessment should be performed in short (e.g., monthly) intervals in the early follow-up period of patients with RUNX1-RUNX1T1+ AML.” Taking the other findings into consideration, they recommended the following adjustments to guidelines for assessing MRD in this patient group: bone marrow and peripheral blood should be analyzed after each treatment cycle and at monthly intervals in the first year after end of therapy, with particular attention paid to patients with TLs exceeding the identified cutoff values.

The authors noted that these findings will need to be validated in larger cohorts, and findings are limited by the variation in sampling intervals during follow-up.

The authors report no relevant conflicts of interest.

Reference

Rücker FG, Agrawal M, Corbacioglu A, et al. Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group. Blood. 2019;134:1608-18.

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