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Awada, H.; Gurnari, C.; Xie, Z.; Bewersdorf, J.P.; Zeidan, A.M. Hypomethylating Agents Failure. Encyclopedia. Available online: (accessed on 21 June 2024).
Awada H, Gurnari C, Xie Z, Bewersdorf JP, Zeidan AM. Hypomethylating Agents Failure. Encyclopedia. Available at: Accessed June 21, 2024.
Awada, Hussein, Carmelo Gurnari, Zhuoer Xie, Jan Philipp Bewersdorf, Amer M. Zeidan. "Hypomethylating Agents Failure" Encyclopedia, (accessed June 21, 2024).
Awada, H., Gurnari, C., Xie, Z., Bewersdorf, J.P., & Zeidan, A.M. (2023, May 03). Hypomethylating Agents Failure. In Encyclopedia.
Awada, Hussein, et al. "Hypomethylating Agents Failure." Encyclopedia. Web. 03 May, 2023.
Hypomethylating Agents Failure

Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines.

hypomethylating agents myelodysplastic syndromes/neoplasms acute myeloid leukemia

1. Introduction

The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DEC) have been a mainstay of the treatment of myeloid neoplasms for almost two decades now. These two closely-related agents primarily act by epigenetic mechanisms, the disruption of which is central to the pathogenesis of these disorders, thereby reinducing the expression of silenced critical genes [1]. In particular, HMA inhibits DNA methyltransferase-1 (DNMT-1) by forming covalent bonds between this enzyme and the DNA containing the molecules, which are incorporated during DNA synthesis [1]. HMA also possesses direct cytotoxic effects, especially at higher doses [1]. Both HMAs have been approved in oral and injectable forms by the Food and Drug Administration (FDA) for specific indications that are not interchangeable in the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) [1][2][3][4]. While allogeneic hematopoietic cell transplant (Allo-HCT) remains the only potentially curative therapeutic modality for MDS, most patients are older and considered ineligible for intensive therapies such as Allo-HCT, and instead opt for lower-intensity treatments with palliative intent [5][6]. Indeed, AZA demonstrated superior overall survival (OS) vs. conventional care regimens including supportive care, and low or intensive chemotherapy in HR-MDS patients in a randomized trial setting [7][8][9]. Although DEC has not shown a similar statistically significant OS benefit versus physician choice (median OS 10.5 vs. 8.1 months, p = 0.38), yet it demonstrated clinically meaningful benefits such as improvements in leukemia-free survival (median 6.6 vs. 3.0, p = 0.004) and quality of life (QoL) endpoints [7][10]. The survival benefit of HMA is somewhat limited to HR-MDS, as neither agent has conclusive evidence of prolonging OS in low-risk LR-MDS (defined as IPSS-R < 3.5) despite increasing the hematological response and reducing the risk of leukemic progression [11][12][13][14][15]. Paralleling the observations in the HR setting, no differences with regards to the injectable type of HMA used exist also in LR-MDS (when available to be used according to local regulations) [16][17].
As for patients with AML, the use of HMA is confined to those deemed ‘medically unfit’ for intensive antileukemic chemotherapy. Medical fitness is typically determined by a comprehensive assessment that includes subjective and objective tools such as the Eastern Cooperative Oncology Group (ECOG) performance scale and Charlson comorbidity index (CCI) scores, in addition to the validated and objective Ferrara Consensus criteria [18][19][20]. Age has also often been used as a proxy for fitness, although the correlation is far from perfect. For older and unfit patients, HMA-based approaches provide an alternative, less toxic treatment options. The preference for HMA in this setting is based on several randomized trials and prospective cohorts, in which HMA led to superior clinical outcomes with limited toxicity versus other low-intensity agents such as low-dose cytarabine, other targeted therapies, or supportive care [7][21][22]. In contrast to MDS, DEC has a similar survival advantage to that of AZA in AML [23][24][25][26][27][28]. Furthermore, the enhanced survival benefits gained by combining AZA with other agents such as Venetoclax (VEN) in AML have made HMA-based combinations an even more popular therapeutic option compared to single-agent HMA [29].
Despite the encouraging evidence, long-term outcomes of HR-MDS and AML patients treated with HMA remain suboptimal, especially for patients diagnosed at an older age with 5-year survival rates not exceeding 6% [30][31][32][33][34]. Outcomes are even worse in patients who do not respond to HMA at all (i.e., primary resistance/failure) or who experience disease progression after a transient period of response (i.e., secondary resistance/failure) [35][36][37]. As such, the management of patients with HMA failure is challenging due to the aggressive nature of the disease and the lack of FDA-approved therapies, as well as the patient characteristics (elderly patients not usually fit for intensive treatments) [35].

2. Hypomethylating Agents Failure: Definition, Mechanisms, and Prognosis

HMA failure is generally categorized into primary or secondary based on the patient’s initial response to treatment. In MDS, primary failure is generally defined as the lack of benefit defined by blast reduction or improvement in blood counts after at least four to six cycles of initial therapy, or MDS progression to higher-risk categories or transformation to AML. Secondary failure occurs in patients who progress despite initially responding to HMA. It is defined as worsening blood counts or progression of MDS to higher-risk categories or AML following the initial response to HMA. In AML, primary HMA failure is instead defined as failure to achieve a complete remission- or complete remission with incomplete count recovery (CR/CRi) while secondary failure occurs with the loss of CR/CRi [38]. To date, studies have suggested that the primary response to HMA in HR-MDS occurs in approximately 50%, while around 36% eventually become resistant and thus develop secondary failure [36][39][40]. Indeed, long-lasting remissions are achieved in only a minority of HR-MDS and AML patients receiving HMA [7][21].
Resistance to HMA remains poorly understood with several proposed mechanisms, most likely secondary to changes in the metabolism of these drugs [41]. Indeed, HMAs are prodrugs, whose activation requires phosphorylation by the uridine-cytidine kinase (UCK) and deoxycytidine kinase (DCK) [42]. Cell-line gene knock-out experiments suggest that silencing the expression of UCK and DCK correlate with decreased AZA and DEC activities, respectively [42][43]. Valencia et al. further corroborated this finding in a study of 57 MDS patients in whom resistant patients had lower UCK expression [44]. Similarly, Wu et al. noted a significant decrease in DCK at relapse (p = 0.012) among MDS patients with secondary failure, while no changes were noted in those with an ongoing response [45]. Alternatively, HMAs may lose their therapeutic effect if rapidly cleared by the cytidine deaminase (CDA) enzyme. CDA catalyzes the hydrolytic cleavage which results in the deamination-mediated inactivation of HMA [46]. Mahfouz et al. studied 90 MDS patients and observed that males had higher CDA levels compared to females [47]. Higher CDA levels were associated with HMA resistance and lower survival (median 563 vs. 1033 days, p = 0.01) [47]. Another mechanism generating a reduction in HMA potency may be a decrease in their influx or an increase in their efflux from leukemia cells, even though reports remain conflicting as of today. Indeed, two studies have unmasked significantly higher mRNA expression of the human equilibrative nucleoside transporter (hENT1), an HMA importer, in responders vs. non-responders [45][48]. However, a third study by Qin et al. did not observe such a correlation, concluding that hENT1 downregulation does not seem to play a significant role in developing resistance to HMA [44][49]. HMA resistance through increased cellular efflux is less studied, however, in vitro models suggest that the multidrug resistance-associated protein seven (MRP7) reduces HMA accumulation in the target cells [50]. Other proposed resistance mechanisms include altered responses to DNA damage, and changes in endosomal/exosomal and microvesicular cell communication [41].
As aforementioned, HMA failure is highly associated with reduced survival. Even for LR-MDS, the post-HMA median transformation-free survival reaches only 15 months while OS barely exceeds 17 months [35]. Among HR-MDS patients, the median OS is <6 months, with only 15% alive at 2 years [36]. Factors such as increasing age, male gender, high-risk cytogenetics and mutations, bone marrow blast count, and secondary rather than primary resistance influence post-HMA outcome [36]. In contrast, undergoing subsequent Allo-HCT or using investigational agents appear to marginally improve outcomes in HR-MDS post-HMA resistance [36]. Outcomes are even worse for AML patients, who after HMA failure have a median survival between 1.3 and 2 months [36][37].


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