Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy

Abstract

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey

“…This is consistent with efforts from several pre-clinical studies that highlighted genetic backgrounds associated with high BH3-dependance and BH3 mimetic sensitivity. Thus far, in the setting of ALL and to a lesser extent in AML, the pre-clinical experimental data have pointed to several molecular subtypes which may display therapeutically applicable venetoclax vulnerabilities [ 21 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

“…BH3 mimetics, and in particular venetoclax, were also highlighted as potential interventions to target specific vulnerabilities in some aggressive molecular subtypes of ALL, including hypodiploid, KMT2A -rearranged or ALL with TCF3::HLF fusion, or early T-precursor (ETP)-ALL that are associated with poor or very poor outcomes. With respect to TCF3::HLF subtype venetoclax vulnerability, while striking, this is only a correlative link without mechanistic explanation, whereas KMT2A rearrangements seem to be due to epigenetic regulation of the expression of BCL2 via histone modifications [ 21 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia

“…This might be due to no additional novel agents being covered by the National Insurance company and the intensity of chemotherapy for high‐risk patients, which was similar in these two protocols. More targeted therapy or new chemotherapeutic agents proved to be beneficial in some high‐risk subtypes of ALL 42–46 . Based on these observations, more intensified chemotherapy and appropriate targets or novel chemotherapeutic agents might be indicated for high‐risk patients in future ALL trials in Taiwan.…”

“…41 In comparison with proved to be beneficial in some high-risk subtypes of ALL. [42][43][44][45][46] Based on these observations, more intensified chemotherapy and appropriate targets or novel chemotherapeutic agents might be indicated for high-risk patients in future ALL trials in Taiwan.…”

“…However, the treatment results for some subsets, such as the T-ALL, ZNF384rearranged, KMT2A-rearranged, MEF2D-rearranged, and BCR-ABL1like subtypes, were not sufficiently effective and robust. With the advent of effective molecular therapeutics and immunotherapy drugs, [42][43][44][45] it is hopeful that the outcomes will be improved for these patients in future clinical trials.…”