MLL-Rearranged Acute Leukemia with t(4;11)(q21;q23)—Current Treatment Options. Is There a Role for CAR-T Cell Therapy?

Abstract

The MLL (mixed-lineage leukemia) gene, located on chromosome 11q23, is involved in chromosomal translocations in a subtype of acute leukemia, which represents approximately 10% of acute lymphoblastic leukemia and 2.8% of acute myeloid leukemia cases. These translocations form fusions with various genes, of which more than 80 partner genes for MLL have been identified. The most recurrent fusion partner in MLL rearrangements (MLL-r) is AF4, mapping at chromosome 4q21, accounting for approximately 36% of MLL-r leukemia and particularly prevalent in MLL-r acute lymphoblastic leukemia (ALL) cases (57%). MLL-r leukemia is associated with a sudden onset, aggressive progression, and notoriously poor prognosis in comparison to non-MLL-r leukemias. Despite modern chemotherapeutic interventions and the use of hematopoietic stem cell transplantations, infants, children, and adults with MLL-r leukemia generally have poor prognosis and response to these treatments. Based on the frequency of patients who relapse, do not achieve complete remission, or have brief event-free survival, there is a clear clinical need for a new effective therapy. In this review, we outline the current therapy options for MLL-r patients and the potential application of CAR-T therapy.

Infant Acute Myeloid Leukemia: A Unique Clinical and Biological Entity

“…The resulting KMT2A chimeras are capable of subverting crucial transcriptional machinery, altering global gene expression and epigenetic signatures of the affected cells. This ultimately results in strongly enhanced and improper expression of genes involved in proliferation and lineage identity, conferring stem cell-like properties and consequent transformation [ 35 ]. Among impacted genes the HOX gene cluster plays a crucial role.…”

“…Infant acute leukemia is frequently associated with translocations involving the KMT2A gene at 11q23, with approximately 40–60% of infants with AML harboring KMT2A rearrangements (e.g., MLL-ENL, MLL-AF4, or MLL-AF9) [ 1 , 2 , 8 , 13 , 35 , 36 ]. Most of these KMT2A -R AML are morphologically classified as FAB-M4 or M5 [ 37 ].…”

Prolonged remission using CD19 chimeric antigen receptor-T cell therapy followed by haploidentical transplantation in a 5-month-old patient with infantile acute lymphoblastic leukemia

“…Infants younger than 6-months of age diagnosed with precursor B-cell acute lymphoblastic leukemia (ALL) have a rare and aggressive form of leukemia associated with inferior outcomes, especially if associated with KMT2A gene rearrangements (KMT2A-r). [1][2][3][4] Dismal outcomes are observed despite intensive therapies including allogeneic hematopoietic stem cell transplantation (HSCT). [1,[5][6][7][8][9] While a therapeutic advantage exists for early HSCT in a subset of high-risk infants with KMT2A-r ALL transplanted in a first complete remission, early disease recurrence, refractory or progressive disease often limits this approach.…”

“…[1][2][3][4] Dismal outcomes are observed despite intensive therapies including allogeneic hematopoietic stem cell transplantation (HSCT). [1,[5][6][7][8][9] While a therapeutic advantage exists for early HSCT in a subset of high-risk infants with KMT2A-r ALL transplanted in a first complete remission, early disease recurrence, refractory or progressive disease often limits this approach. [6,[8][9][10][11][12] Those who do proceed to HSCT frequently relapse without curative treatment options.…”

“…[14][15][16] However, there is limited experience utilizing CAR-T in infants resulting from the exclusion of children <1 year of age from initial clinical trials. [1] The approach has been limited due to an infant's smaller size and blood volume; concerns include cellular collection safety, the timing of autologous T-cell harvest during a patient's treatment course, the optimal infusion dose, and the management of post-infusion toxicities. [10,[17][18][19] There are inherent difficulties in obtaining sufficient autologous T-cells in infants to generate a suitable CAR-T product.…”