KMT2A-rearranged acute lymphoblastic leukemia in infants: current progress and challenges

Abstract

Chromosomal translocation of the KMT2A gene represents the cytogenetic hallmark of acute lymphoblastic leukemia diagnosed in infants (<1 year of age), driving a highly aggressive malignancy. For decades the event-free survival rates for these very young patients were at best ~40%. However, recent advances adding immunotherapy in the form of the bi-specific T-cell engager blinatumomab to the treatment led to encouraging results. In the present review we describe the current progress made, as well as the challenges that still lie ahead in terms of drug-related toxicity, the implementation of less toxic agents, acquired drug resistance, central nervous system involvement, and lineage switches. In addition, we touch on the benefit of preclinical models that can assist in guiding new treatment strategies.

Figure 1.

Representative luciferase-expressing patient-derived xenograft mouse model of KMT2A-rearranged infant acute lymphoblastic leukemia mimicking disease remission and leukemia re-emergence following induction therapy. (A) Schematic representation of the experimental design. Primary KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) cells with transgenic expression of luciferase were injected intravenously into immunodeficient NRGS mice. Engraftment was monitored by quantifying the fraction of human CD19/CD45-positive cells weekly in the peripheral blood and treatment was commenced upon reaching >1% human CD19/CD45-positive cells. Mice were treated with either vehicle, or a mouse-adapted version of the Interfant induction treatment (designated VXLC) consisting of vincristine (V), dexamethasone (X), L-asparaginase (L), and cytarabine (C). Experimental endpoints were reached after mice succumbed to leukemia in the case of ‘survival’ experiments or directly after treatment cessation in the case of ‘fixed endpoint’ experiments. (B) Graphical depiction of weekly bioluminescence imaging (ordered horizontally) of animals transplanted with a luciferase-expressing patient-derived xenograft model and treated with vehicle or VXLC. The images in the third row (VXLC) are of the same animals at the same timepoints as the second row (VXLC), however, the scale is enhanced by a factor of 100 to allow for visibility of minimal residual disease during treatment. The treatment period is depicted by the orange bar. (C) Overall disease burden quantified by determining the average radiance, in electrons/s/ sr, emitted per mouse monitored weekly until the experimental endpoint. (D) Disease development monitored by quantifying the fraction of human CD19/CD45-positive cells weekly in the peripheral blood, displaying a significant delay in reaching the experimental endpoint upon treatment. (E) Survival analysis illustrated by a Kaplan-Meier plot, with an event defined as reaching 50% of human CD19/CD45-positive cells in the peripheral blood. Similar to the clinical picture, animals appear to reach complete remission in peripheral blood in response to treatment, although leaving minimal residual disease visible according to the bioluminescent signal resulting in subsequent relapse. i.v.: intravenous; ALL: acute lymphoblastic leukemia; huCD45⁺: human CD19/ CD45-positive cells; IP: intraperitoneal; wk: week; BLI: bioluminescent imaging; PB: peripheral blood.