Over the past 50 years, our understanding of leukemogenesis has evolved, including as it relates to NPM1-mutated and KMT2A-rearranged acute leukemias. This advancement has aided in the development of targeted agents that are being studied in combination with other treatments, particularly for these forms of acute myeloid leukemia (AML).

Our understanding of leukemogenesis has increased over the past several decades. Initially, we were able to characterize some of the genetic changes in leukemic cells in the form of chromosomal aberrations (ie, as either chromosomal deletions or translocations). Beginning in the 1980s, we started recognizing that different subtypes of AML could have different clinical characteristics, depending on the cytogenetic abnormalities that were present. These abnormalities were recurring in similar patterns of translocations, deletions, or chromosomal losses across different patients. Later, individual gene mutations were then identified and were noted to be relevant prognostically. Now, with the development of next-generation sequencing assays, we can observe molecular aberrations as a whole. This is important because most aberrations are co-occurring; very few patients have a single mutation.

It is clear that many of these mutations are drivers of tumorigenesis and AML development. Therefore, they are excellent potential targets for developing therapeutic agents, specifically molecularly targeted drugs. Some of these agents are already highly successful, such as FLT3 inhibitors, IDH inhibitors, and, more recently, menin inhibitors, which are important in KMT2A-rearranged and NPM1-mutated leukemias.

KMT2A-rearranged leukemias are relatively uncommon, occurring in approximately 5% to 15% of patients with acute leukemias. The KMT2A gene can be rearranged as a result of chromosomal translocation, and this translocation can happen in many different chromosomes. KMT2A and menin interaction leads to the overexpression of HOX and MEIS1 transcription factors, which then interferes with normal cellular differentiation and leads to leukemogenesis.

In general, KMT2A rearrangement is associated with very poor outcomes, mainly because traditional chemotherapy agents are not highly effective. Most patients need a transplant, but many will relapse despite undergoing transplantation during first remission. Therapeutic advances that inhibit the menin-KMT2A interaction can resolve the blocking of differentiation and can potentially reverse the leukemogenic potential of the KMT2A-rearranged protein.

In NPM1-mutated AML, the interaction between wild-type KMT2A and menin, again, leads to the overexpression of HOX and MEIS1 transcription factors and causes leukemogenesis. NPM1 mutations occur in approximately 30% of patients with AML. The presence of an NPM1 mutation, particularly in the absence of an FLT3 mutation and with a normal karyotype, is associated with a favorable prognosis. Traditional treatments have the potential to achieve durable remission in the majority of patients, and the more recent development of azacitidine plus venetoclax for frontline therapy in older patients has helped to put even more patients in remission. However, all these patients are at risk for relapse—and many of them do relapse. When patients with NPM1-mutated AML experience relapse, their prognosis becomes less favorable, and their disease becomes more problematic to treat.

Our patients with KMT2A-rearranged and NPM1-mutated AML need better treatment options. However, as I mentioned earlier, there are promising strategies in development, such as FLT3 inhibitors, IDH inhibitors, and menin inhibitors. I believe that these drugs are going to be very useful as we continue to study the possibility of combining them with other treatments (particularly with either chemotherapy or azacitidine plus venetoclax) in these forms of AML.