Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial

Abstract

In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558).

Figure 1.

Patient flow chart.

Figure 2.

Peripheral blood (PB) and (BM) bone marrow MRD in 525 paired samples.

Figure 3.

Outcome according to PB- or BM-MRD at the end of consolidation therapy (MRD4). Cumulative incidence of relapse and overall survival are shown according to BM-MRD4 (A and B, respectively) or to PB-MRD4 (C and D, respectively). A MRD >0.001% was considered as positive.

Figure 4.

PB- and BM-MRD in 8 patients with persistent BM-MRD up to two years after end of treatment.

Figure 5.

Impact of CMR achievement on patient outcome. Peripheral Blood CMR was evaluated as a time-dependent variable and Simon-Makuch representations are shown for cumulative incidence of relapse (A) and overall survival (B). Time to PB CMR was split into 4 quartiles (Q1–4) to evaluate its impact on cumulative incidence of relapse (C).

Figure 6.

Impact of molecular relapse in patients with complete molecular remission. Simon-Makuch representations are shown for cumulative incidence of relapse (A) and overall survival (B) in patients who remain in CMR (CMR) or who experienced a molecular relapse (MRD+). Simon-Makuch representations are shown for cumulative incidence of relapse (C) and overall survival (D) in patients who experienced a molecular relapse confirmed (2 consecutive time-points, 2TP) or not confirmed (1 time-point, 1TP) on a subsequent sample.