Targeted therapy with a selective BCL-2 inhibitor in older patients with acute myeloid leukemia

Abstract

Background Older patients with acute myeloid leukemia are particularly difficult to treat, as they have a high risk of comorbidities, poor performance status and less tolerability to chemotherapy, as well as a more aggressive disease biology, responsible for the resistance to treatment. There is a need to explore novel therapeutic agents that are more effective and tolerable. Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. Objective To review the available data about venetoclax in acute myeloid leukemia and how it can influence the treatment in older patients. Methods Using the Pubmed database, we selected 29 articles published within the last 15 years, considering preclinical and clinical trials and review studies that combined venetoclax with acute myeloid leukemia. Results Venetoclax has demonstrated promising results in preclinical and clinical trials, especially in patients with poor prognosis and the IDH mutation, with an excellent side-effect profile. However, resistance seems to develop rapidly with venetoclax monotherapy, because of antiapoptotic escape mechanisms. Conclusions While the results with the use of venetoclax seem encouraging, it is not likely that targeting a single pathway will result in long-term disease control. The solution includes the use of combined therapy to block resistance mechanisms and enhance apoptosis, by reducing MCL-1, increasing BIM or inhibiting the complex IV in the mitochondria.

B-cell lymphoma-2 inhibition and resistance in acute myeloid leukemia

“…Reductions in Bcl-2 expression have been shown to promote primary and acquired resistance to venetoclax by alternate pathway activation and upregulated expression of other anti-apoptotic proteins such as MCL-1 and Bcl-xL[ 53 ]. A study of AML cell lines in vitro showed a definite and inverse correlation with the ratios of Bcl-2/MCL-1 transcripts and venetoclax sensitivity suggesting the importance of MCL-1 effect on sensitivity[ 54 ]. Similarly, Niu et al[ 55 ] demonstrated that Bcl-2/MCL-1 transcript ratio may represent a potential biomarker in predicting response[ 55 ].…”

The Development of Personalized Medicine: Acute Myeloid Leukemia as a Model

“…Many agents can reduce MCL1 expression in vitro including chemotherapy and HMA. 28 Venetoclax in combination with HMA in newly diagnosed elderly AML patients demonstrated 67% CR and median OS of 17.5 months. 29 The responses occurred in patients with poor risk mutations; TP53 and FLT3 mutations, similar to those with IDH and NPM1 mutations.…”

Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

“…Another important, but less understood, aspect of cancer cells sensitivity to venetoclax is their genetic backgrounds. Cancer cells baring some types of genetic aberrations such as chromosomal rearrangement [ 71 ], IDH1/2, or WT1 point mutations [ 70 , 91 ] are exquisitely sensitive to venetoclax. The molecular basis of this sensitivity has been linked to high level of BCL-2 in these cells; however, additional factors might be determinant in this phenomenon.…”