Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group

Abstract

We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.

Graphical abstract

Figure 1.

Relapse risk and outcome for patients in CR according to MRD status at EOT. CIR (A) and OS (B) in BM (negative vs any positive RUNX1-RUNX1-T1 TL value). CIR (C) and OS (D) in PB.

Figure 2.

Impact of KIT mutation status on BM MRD kinetics. Log₁₀ RUNX1-RUNX1T1 TLs (A) and the reduction of RUNX1-RUNX1T1 TLs (B) are shown during the course of treatment.

Figure 3.

CIR during follow-up, according to MRD conversion (from MRD⁻to MRD⁺) and defined MRD cutoffs in BM and PB. (A) CIR of 25 patients with MRD conversion in BM. (B) CIR of 64 patients according to the MRD cutoff exceeding 150 RUNX1-RUNX1T1 TL/10⁶ B2M copies in at least 1 BM follow-up sample obtained in the posttreatment period. (C) CIR of 25 patients with MRD conversion in PB. (D) CIR of 39 patients according to MRD cutoff exceeding 50 RUNX1-RUNX1T1 TL/10⁶ B2M copies in at least 1 PB follow-up sample obtained in the posttreatment period. Time to relapse is calculated from the first sample, with a RUNX1-RUNX1T1 TL >150 (BM) or >50 (PB) RUNX1-RUNX1T1 TL/10⁶ B2M copies up to relapse and, in cases not exceeding these thresholds, from the first sample with increasing MRD level.

Figure 4.

Analysis of paired BM and PB samples in 125 patients. (A) Histogram plot of paired BM and PB RUNX1-RUNX1T1 TLs during therapy and the posttreatment period of the 125 patients, illustrating sample acquisition, interindividual RUNX1-RUNX1T1 TLs, intraindividual correlation of BM and PB TLs, and the MRD course of each patient. Color-coded histograms represent paired RUNX1-RUNX1T1 TLs in BM and PB (y-axis) at the indicated time points (x-axis) for each patient (z-axis). Missing samples are denoted by a corresponding blank area. (B) RUNX1-RUNX1T1 TL kinetics of paired BM and PB samples during therapy and follow-up. (C) Spearman rank correlation of RUNX1-RUNX1T1 TLs of all 680 paired BM and PB samples obtained during therapy and in the posttreatment period. (D) Distribution of paired samples according to their qRT-PCR status (positive/negative) in BM and PB.

Figure 5.

Proposed refined recommendation based on MRD at EOT and during follow-up. Assessment was conducted in patients with RUNX1-RUNX1T1⁺ AML, according to the ELN MRD Working Party, taking into account MRD status at EOT and during follow-up. Ind, induction therapy; Cons, consolidation therapy.