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Saliba et al. Cancer Drug Resist 2021;4:125-42 I http://dx.doi.org/10.20517/cdr.2020.95 Page 129

Activity of hypomethylating agents in myelodysplastic syndrome and AML
HMAs have been used for the treatment of myeloid malignancies for more than a decade. The role of HMAs
is currently expanding across wider age groups for various therapeutic indications (including preemptive
and maintenance therapies), in novel formulations (including oral), and in combination with multiple
other agents (including venetoclax, lenalidomide, and IDH inhibitors) [15,33,68-72] . The initial observation that
a variety of tumor suppressor genes are silenced as a consequence of promoter hypermethylation in MDS
[73]
and AML prompted the investigation of HMAs as epigenetic drugs in these hematological diseases .
2
When initially tested in phase I studies in AML at higher doses (1500-2500 mg/m of decitabine per
course), HMAs caused prolonged and dose-limiting myelosuppression with overall response rates of 30%-
60% [74,75] . The mechanism of action at those higher doses was thought to reflect formation of DNA-protein
cross-links, activation of the DNA damage response, and direct cytotoxicity. Lower doses of decitabine (45
mg/m /day, every 8 h, for 3 consecutive days, every 6 weeks) were subsequently found to have an overall
2
response rate of 49% in patients with high-risk MDS in phase II studies [76,77] . Subsequent phase III studies
confirmed the clinical effectiveness of decitabine in the treatment of patients with MDS, with an overall
[78]
response rate of 73% with decitabine vs. 0% with supportive care in the initial phase III trial , and 54%
with decitabine in a follow-up phase II trial in elderly patients with intermediate- or high-risk MDS .
[79]
Additional randomized trials have also shown a survival advantage in patients receiving azacitidine, with
a median survival of 18 months in the azacitidine arm vs. 11 months in the supportive care arm in the
[80]
Cancer and Leukemia Group B (CALGB) 9221 trial , and 24.5 months vs. 15 months in patients with
intermediate-2- or high-risk MDS in the AZA-001 trial .
[32]
As indicated earlier in the Introduction, HMAs are also used to treat AML. Azacitidine monotherapy
2
was first evaluated at 150-200 mg/m /day for five days in phase I and II studies in the pediatric patient
[81]
population with AML and acute lymphoblastic leukemia . Six out of the 14 patients with refractory
[81]
AML achieved remission, but prolonged marrow suppression was a significant adverse event . Prolonged
myelosuppression was also dose limiting in a study of 154 adult patients with refractory AML treated
2
[82]
with 150-700 mg/m /day for 1-7 days . After a hiatus of several decades, decitabine and azacitidine were
studied again in patients with AML, but at the lower doses that proved effective in MDS. In the AZA-001
trial, analysis of outcomes in a subgroup of patients with 20%-30% bone marrow blasts, who were originally
classified as RAEB-t (i.e., refractory anemia with excess blasts in transformation) and subsequently
considered as AML by the 2000 World Health Organization classification [83,84] , indicated prolonged median
overall survival with azacitidine (24.5 months) compared to conventional care regimens such as LDAC,
[83]
conventional chemotherapy, or best supportive care (16.0 months) . An analysis of three CALGB trials
with azacitidine 75 mg/m /day for seven days every 28 days by intravenous (CALGB 8421) or subcutaneous
2
routes (CALGB 8921 and CALGB 9221) showed an overall response rates of 36%-48% and median
survival of 19.3 months in the azacitidine group compared to 12.9 months for the observation group .
[85]
Retrospective data from European registries showed median overall survival estimates of 9-10 months [86,87] .
A large phase III study, AZA-AML-001, randomized patients older than 65 years and with > 30% bone
2
marrow blast counts to azacitidine (75 mg/m /day subcutaneously for 7 days every 28 days) or conventional
[22]
care regimens . Although there was no statistically significant difference in survival in the overall study
population (10.4 months for azacitidine vs. 6.5 months for conventional care), survival was significantly
prolonged in the subgroups with poor-risk cytogenetics or AML with myelodysplasia-related changes ,
[22]
leading to the European Medicines Agency approval of azacitidine for the treatment of AML in adults
[22]
above 65 years of age . A phase III study (DACO-16) that randomized 485 patients age 65 years or
2
older to decitabine (20 mg/m /day intravenously for 5 days every 28 days) or conventional care regimens
(supportive care or LDAC) likewise failed to show a significant improvement in the primary endpoint
of overall survival (7.7 months vs. 5.0 months, respectively) but showed a higher rate of CR/CRp (CR
with incomplete platelet recovery) with decitabine (17.8% vs. 7.8%, respectively; P = 0.001) , leading to
[24]
approval of single-agent decitabine for the treatment of AML in the older adults in Europe. More recently,