Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol

Abstract

Purpose: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide).

Materials and methods: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4).

Results: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9).

Conclusion: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.

Trial registration: ClinicalTrials.gov NCT00550992.

Figures

FIG 1.

Prognostic impact of minimal residual disease (MRD) levels at the end of induction (EOI), as shown by Kaplan-Meier estimates of disease-free survival (DFS), for all patients (A), patients treated with protocol IB (B), and patients treated with araC, daunorubicin, etoposide (ADE)/mitoxantrone, araC, etoposide (MAE) (C). Outcome by treatment given of patients according to MRD at EOI, negative (D), intermediate (E), and high (F). Neg, MRD-negative; Interm, MRD-intermediate (−4); High, MRD-high (≥ 5 × 10−4). CR1, first complete remission.

FIG 2.

Prognostic impact of minimal residual disease (MRD) levels at the end of consolidation (EOC) (A-D) and after MARMA (E), as shown by Kaplan-Meier estimates of disease-free survival (DFS): EOC MRD for all patients (A), patients treated with protocol IB (B), patients treated with araC, daunorubicin, etoposide (ADE)/mitoxantrone, araC, etoposide (MAE) (C), and for all patients with MRD at EOI and EOC (D) and MRD after MARMA for all patients (E). Neg, MRD-negative; Interm, MRD-intermediate (−4); High, MRD-high (≥ 5 × 10−4). (D): Neg, MRD-negative at EOI and EOC; New Neg, MRD-positive at EOI and MRD-negative at EOC. For (A-D), One MRD-negative patient treated with ADE/MAE was excluded from these analyses due to missing data on first complete remission (CR1). For (E), One MRD-intermediate patient was excluded from this analysis due to missing data on CR1.

FIG 3.

CONSORT diagram. ADE, araC, daunorubicin, etoposide; CR1, first complete remission; KMT2Ar, KMT2A-rearranged; MAE, mitoxantrone, araC, etoposide; MRD, minimal residual disease.