👤 Mareike Rasche

Pediatric AML with KMT2A::MLLT10 accounts for 10%-15% of KMT2A-rearranged AML and is associated with poor prognosis. Lately, the assessment of measurable residual disease (MRD) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) has become an important tool for disease management; however, in the pediatric setting, it lacks standardized protocols. Therefore, we investigated the prognostic relevance of MRD monitoring by RT-qPCR during high-dose polychemotherapy in pediatric patients with AML expressing KMT2A::MLLT10. Using RNA sequencing, we determined the fusion breakpoints and designed RT-qPCR assays for MRD monitoring. Bone marrow samples collected from 41 patients, who were treated in the AML-BFM or AIEOP study, were analyzed for MRD by RT-qPCR. MRD positivity after the second treatment course resulted in a significantly worse probability of overall survival (pOS) compared to MRD negative patients (33.3% ± 19.2% vs. 80.6% ± 7.8%, p = 0.032). Moreover, the probability of event-free survival (pEFS) (16.7% ± 15.2% vs. 76.9% ± 8.3%, p = 0.003) and cumulative incidence of relapse (CIR) (83.3% ± 40.8% vs. 19.2% ± 40.2%, p = 0.001) were significantly worse for patients in complete morphologic remission who remained MRD positive after the second treatment course. Thus, MRD monitoring enables the identification of a subgroup of pediatric patients with AML carrying KMT2A::MLLT10 in complete morphologic remission with a dismal prognosis despite the current intensive therapy regimen. AML-BFM study 2004: ClinicalTrials.gov Identifier: NCT00111345; AML-BFM registry 2012 and AML-BFM study 2012: EudraCT 2013-000018-39; AML-BFM registry 2017: DRKS number: DRKS00013030. Show less

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs. Show less