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Page 126 Saliba et al. Cancer Drug Resist 2021;4:125-42 I http://dx.doi.org/10.20517/cdr.2020.95

has been induction therapy with cytarabine and an anthracycline followed by consolidation with high-dose
cytarabine chemotherapy or hematopoietic stem cell transplant (HSCT). Most patients with AML respond
to initial induction chemotherapy and achieve a complete remission (CR), with rates ranging between
[2-5]
40 and 90% in different studies . However, long-term survival rates remain significantly lower at about
[5,6]
40%-50% for adults younger than 60 years of age and less than 10% in adults age 60 years and older . The
high rate of relapse in older patients has been attributed to several factors, including lower tolerance to
chemotherapy, poor performance status, comorbid diseases, a higher incidence of secondary AML, a higher
[7,8]
incidence of adverse karyotypes, and acquired drug resistance . In addition, 20% of patients treated with
standard chemotherapy experience primary induction failure [9,10] . Therefore, mechanisms of de novo and
acquired resistance to chemotherapy remain central barriers to achieving long-term remission.

The biological basis for this therapy resistance has been extensively studied. Certain cytogenetic
abnormalities and genetic mutations are predictive of clinical course, prognosis, and response to
conventional chemotherapy or more novel targeted therapies [11-14] . For instance, the presence of the
genetic abnormalities t(8;21) or inv(16)/t(16;16) is associated with a high rate of response to conventional
combination chemotherapy and a favorable prognosis [3,11] . Conversely, a complex karyotype or aneuploidy
is associated with resistance to chemotherapy and a poor prognosis [6,11] . Although the relatively high
proportion of patients with cytogenetically normal AML limits the prognostic and clinical utility of these
[11]
cytogenetically defined groups , recent advances in the understanding of the molecular landscape of AML
have simultaneously expanded our prognostic ability and facilitated the development of agents targeting
specific actionable alterations, including mutations of fms-like tyrosine kinase 3 (FLT3) and isocitrate
dehydrogenase 1 and 2 (IDH1 and IDH2) [15-17] . Agents that target these abnormalities, including IDH
inhibitors (e.g., ivosidenib and enasidenib), FLT3 inhibitors (e.g., midostaurin, gilteritinib, quizartinib,
and sorafenib), and others, have offered an opportunity for remission with AML harboring targetable
mutations [17,18] . Because targetable genetic mutations are found in only a minority of patients with AML,
the parallel introduction of apoptosis-inducing therapies has shown promise in overcoming conventional
chemotherapy resistance and can be used irrespective of the genetic signature [19,20] .

The “hypomethylating agents” (HMAs) azacitidine (5-azacitidine) and decitabine (5-aza-2′-deoxycytidine)
are nucleoside derivatives that are incorporated into DNA, where they inhibit DNA methyltransferases
(DNMT). HMAs have been primarily used to treat AML patients who are 60 years of age and older or
those who are unable to withstand the rigors of conventional chemotherapy. In comparison to conventional
combination chemotherapy, single-agent HMA or low-dose cytarabine (LDAC) regimens are usually better
[21]
tolerated and are associated with lower rates of treatment-related mortality . However, response rates to
HMAs alone are low (10%-50%), with a median survival of about 6-10 months [21-25] . The observation that
antiapoptotic proteins, including BCL2, BCLX , and MCL1, are frequently overexpressed in AML and are
L
associated with resistance to chemotherapy, eventually led to the addition of venetoclax, an oral selective
small molecule inhibitor of BCL2, to LDAC or HMA therapy, initially in older adults with primary or
[26]
secondary AML who were ineligible for conventional chemotherapy . Rates of CR or CR with incomplete
hematologic recovery (CRi) were 54% for the LDAC/venetoclax regimen and 67% for the HMA/venetoclax
[27]
doublet, with a significant extension in overall survival (OS) to a median of 10-18 months . These findings
were more recently confirmed by the results of the phase III randomized placebo-controlled trial showing
superiority of the combination of azacitidine and venetoclax over single-agent azacitidine in a group of
previously untreated patients with AML who were not eligible for standard induction chemotherapy .
[28]
With a CR/CRi rate of 66% in the azacitidine/venetoclax group vs. 28% in the control group, a significant
[28]
prolongation in median OS was achieved (14.7 months vs. 9.6 months respectively) .

Despite these promising results, about half of the responders to azacitidine/venetoclax relapse after a
[28]
median duration of about 18 months . Therefore, although the last few years have witnessed important