MRD and KMT2A Fusion Partners in Predicting Outcomes of Childhood KMT2A-Rearranged Acute Myeloid Leukemia

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In a retrospective study reported in the Journal of Clinical Oncology, van Weelderen et al, of the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG), found that KMT2A fusion partners and measurable residual disease (MRD) at end of induction phase 2 were independent predictors of outcomes in childhood KMT2A-rearranged acute myeloid leukemia (AML).

As noted by the investigators, a prior I-BFM-SG study showed the prognostic value of KMT2A fusion partners in this setting.

Study Details

In the study, a total of 1,130 children diagnosed between January 2005 and December 2016 at sites in 23 countries were categorized into high-risk (n = 402) or non–high risk (n = 728) fusion partner–based groups. Prior findings indicated that high-risk fusion partners were 6q27 (KMT2A::AFDN), 4q21 (KMT2A::AFF1), 10p12 (KMT2A::MLLT10), 10p11.2 (KMT2A::ABI1), and 19p13.3 (KMT2A::MLLT1).

Flow cytometry–based MRD measurements at end of induction 1 and end of induction 2 were available for 456 patients and were considered negative (< 0.1%) or positive (≥ 0.1%). The study also evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission. The primary outcome measures were 5-year rates of event-free survival, cumulative incidence of relapse, and overall survival.

Key Findings

Compared with the non–high risk group, the high-risk group on the basis of fusion partners, had poorer 5-year event-free survival (30.3% vs 54.0%, P < .0001), cumulative incidence of relapse (59.7% vs 35.2%, P < .0001), and overall survival (49.2% vs 70.5%, P < .0001).  

Compared with MRD positivity at end of induction 2 (n = 43), MRD negativity (n =413) was associated with superior 5-year event-free survival (47.6% vs 16.3%, P < .0001) and overall survival (66.0% vs 27.9%, P < .0001), as well as a trend toward better cumulative incidence of relapse (46.1% vs 65.4%, P = .016).

Allo-SCT in first complete remission within the high-risk group reduced only cumulative incidence of relapse (hazard ratio [HR] = 0.5, 95% confidence interval [CI] = 0.4–0.8, P = .00096), with no improvement in overall survival observed.

In multivariable analyses, end of induction 2 MRD positivity and high-risk group were independently associated with poorer event-free survival (HR = 3.4, 95% CI = 2.4–4.9, P < .0001; HR = 2.0, 95% CI = 1.5–2.5, P < .0001), cumulative incidence of relapse (HR = 2.3, 95% CI = 1.4–3.7, P = .0013; HR = 2.1, 95% CI = 1.5–2.8, P < .0001), and overall survival (HR = 1.9, 95% CI = 1.6–2.3, P < .0001; HR = 2.1, 95% CI = 1.5–2.9, P < .0001).

The investigators concluded: “[End of induction 2 flow cytometry–based] MRD is an independent prognostic factor and should be included as a risk stratification factor in childhood KMT2A-[rearranged] AML. Treatment approaches other than allo-SCT in [first complete remission] are needed to improve prognosis.”

Gertjan J.L. Kaspers, MD, PhD, of the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, Associazione Italiana per la Ricerca sul Cancro, Swedish Childhood Cancer Foundation, and others. For full disclosures of the study authors, visit


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