Cytogenetic abnormality associated with a variable prognosis: KMT2A (MLL) gene rearrangements

KMT2A gene rearrangements occur in approximately 20% of children with AML.[210,211] These cases, including most AMLs secondary to epipodophyllotoxin exposure,[264] are generally associated with monocytic differentiation (FAB M4 and M5). KMT2A rearrangements are also reported in approximately 10% of FAB M7 (AMKL) patients.[265,266]

The median age for 11q23/KMT2A-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years.[267] However, significantly older median ages are seen at presentation of pediatric cases with t(6;11)(q27;q23) (12 years) and t(11;17)(q23;q21) (9 years).[267]

Outcomes for patients with de novo AML and KMT2A gene rearrangements are generally similar to or slightly worse than the outcomes observed in other patients with AML.[209,210,267-269] As the KMT2A gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis. This finding was demonstrated by two large international retrospective studies [270] of KMT2A-rearranged AML and another COG analysis that studied outcomes of patients with KMT2A rearrangements who were treated more uniformly within the context of the AAML0531 trial.[267,269]

The most common translocation, representing approximately 50% of KMT2A-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the KMT2A gene is fused with the MLLT3 gene.[267,269] The overall prognosis of these patients has been debated. Single clinical trial groups have variably described a more favorable prognosis for these patients, but two large international retrospective studies and the COG AAML0531 experience suggested their outcomes were less favorable.[209,210,267,269] This fusion, which is associated with an intermediate prognosis, is not currently classified as high risk, at least within the COG, unless minimal residual disease (MRD) remains at the end of induction 1.

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

Cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS.[209,211] Some cases with the t(10;11) translocation have fusion of the KMT2A gene with the MLLT10 gene at 10p12, while others have fusion of KMT2A with ABI1 at 10p11.2. An international retrospective study found that these cases, which present at a median age of approximately 1 to 3 years, have a 5-year EFS rate of 17% to 30%.[267,269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

Patients with t(6;11)(q27;q23) (KMT2A::AFDN) have poor outcomes, with 5-year EFS rates of 11% to 15%.[269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

Patients with t(4;11)(q21;q23) (KMT2A::AFF1) often present with hyperleukocytosis and also have poor outcomes, with 5-year EFS rates of 0% to 29%.[267,269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

Patients with t(11;19)(q23;p13.3) (KMT2A::MLLT1) have poor outcomes, with a 5-year EFS rate of 14%.[269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

Based on the data above, the International Berlin-Frankfurt-Münster (iBFM) study group analyzed data regarding outcomes in patients with KMT2A rearrangements enrolled in BFM, COG, and other European cooperative group studies.[270] In keeping with earlier papers,[270] this study classified patients with 6q27 (KMT2A::AFDN, i.e., MLLT4), 4q21 (KMT2A::AFF1, i.e., MLL::MLLT2), 10p12.3 (KMT2A::MLLT10), 10p12.1 (KMT2A::ABI1), and 19p13.3 (KMT2A::MLLT1, i.e., MLL::ENL) as high risk, while all others were considered in the non–high-risk group.[267,269,270] Using this classification, the 5-year EFS rates for patients with non–high-risk, KMT2A-rearranged AML is 54%, compared with 30.3% for patients with high-risk disease.[270] MRD assessment after induction 2 imparts further prognostic significance within the iBFM analysis. In a large study, the presence of additional cytogenetic aberrations appeared to have variable prognostic impact.[271] However, given the heterogenous treatment of this study cohort, it is not clear whether this is an independent predictor of outcome, particularly when patients received gemtuzumab ozogamicin, which has therapeutic benefits in KMT2A-rearranged AML.[269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

With this distinction, non–high-risk KMT2A fusions are, in most cooperative groups, upstaged to high-risk if MRD is noted after induction treatment.[269]

KMT2A-rearranged AML subgroups that are associated with poor outcomes include the following:

When examining outcomes for patients with KMT2A rearrangements, both overall and within the context of high-risk and non–high-risk fusions, treatment with gemtuzumab ozogamicin appeared to abrogate the negative prognostic impact of the variant. Specifically, the EFS rate for patients with KMT2A-rearranged AML was superior with gemtuzumab ozogamicin treatment than without this treatment (48% vs. 29%; P = .003) and comparable with the outcomes observed in patients without KMT2A rearrangements.[269]