New directions for emerging therapies in acute myeloid leukemia: the next chapter

Abstract

Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

“…Novel treatment modalities based on targeting of e.g. FLT3 (FMS-like tyrosine kinase), CD33 or BCL-2 (B cell lymphoma 2) have been introduced, but still fail to achieve efficiency comparable to that of imatinib in CML [ 13 ]. Significant challenge in therapy of leukemias is eradication of leukemia stem cells (LSCs), as they present self-renewal capacity and strong drug-resistance.…”

IDH1/IDH2 Inhibition in Acute Myeloid Leukemia

“…In AML patients, IDH1 / IDH2 gene mutations are heterozygous missense mutations involving a single arginine (R) residue in the enzyme active site ( 9 ), R132 in IDH1 and R140 or R172 in IDH2 , restructuring the enzyme and leading to a reduced affinity of the mutant enzymes for isocitrate while increased affinity for α-ketoglutarate (αKG) and nicotinamide adenine dinucleotide phosphate (NADPH) with production of R-2HG ( 17 ), as extensively reviewed elsewhere ( 18 ).…”

“…Despite the improvements in understanding its genomic basis, AML is still a therapeutic challenge for older adults, not eligible to allogeneic stem cell transplantation, with less than 10% chance of long-term survival (2,5). The therapeutic scenario of AML is transitioning from a standard chemotherapy regimen in all patients toward individualized therapeutic strategies (6)(7)(8)(9).…”

Immunotherapeutic Potential of m6A-Modifiers in Controlling Acute Myeloid Leukemia

“…For some time now, several conventional therapies have been employed to treat AML including chemotherapy and rarely surgery and radiation [11]. Cytotoxic chemotherapy or remission-induction with chemotherapeutic agents (anthracycline and cytarabine) followed by consolidation-therapy involving an allogeneic stem cell transfer (SCT), bone-marrow transplant (BMT) or hematopoietic stem cell transplantation (HSCT) have been used as a standard therapy regimen for prolonged remission of AML [12]. However, due to the delayed diagnosis of AML and the therapy-related morbidity and mortality, these conventional means of treating AML have fallen short when it comes to "do no harm" approach.…”