**4. Treatment of patients considered unfit for intensive chemotherapy: hypomethylating agents**

For patients not eligible for intensive chemotherapy treatment a choice can be made between best supportive care (BSC), low dose chemotherapy (LDAC) or hypomethylating agents (HMAs). Several studies have shown the efficacy of the HMAs azacitidine and decitabine. In addition, HMAs are well-tolerated and have low extra-medullary toxicity. Therefore HMAs are very suitable for the treatment of older patients with AML.

Azacitidine was first studied in the context of high-risk myelodysplastic syndromes (MDS). A phase III trial conducted in intermediate-2 and high-risk MDS patients included a subset of patients with 20–30% blasts, who were reclassified to AML according to redefined WHO criteria [38, 39]. The relative efficacy and safety of azacitidine versus conventional care regimens (CCR; comprising prespecified allocation to BSC, LDAC, or IC) was thus compared in this subgroup of patients (n = 113) and showed an increased median OS (24.5 vs. 16.0 months, P = 0.005) and increased 2-year survival (50% vs. 16%, P = 0.001) for azacitidine-treated patients compared with CCR patients [40]. In addition, a phase III study on the efficacy of azacitidine versus CCR (standard IC, LDAC or BSC) in newly diagnosed AML patients with >30% blasts was conducted [17]. The median OS was longer in the azacitidine group compared to the CCR group (10.4 vs. 6.5 months), although in multivariate analysis significance was lost (HR 0.85 [95% CI 0.69–1.03], P = 0.101). However, in a pre-planned sensitivity analysis censoring for subsequent AML therapy, the median OS was 12.1 months versus 6.9 months in the azacitidine-arm and CCR-arm respectively, with a stratified HR 0.76 (95% CI 0.60–0.96, P = 0.019). Azacitidine was well tolerated as more than half of the patients received six or more treatment cycles. The difference in median OS between the two reported studies (24.5 months vs. 12.1 months) could be explained by the lower blast count in the first study and thereby selection of more indolent disease. Unfortunately both studies were not powered to detect direct differences between azacitidine treatment and intensive chemotherapy.

Decitabine is another hypomethylating agent registered for treatment of AML. Two decitabine schedules are currently in use in clinical practice: the 5-day schedule and the 10-day schedule. A randomised phase III trial compared the efficacy and safety of 5-day decitabine (20 mg/m2 ) (n = 242) with treatment choice of BSC (n = 28) or LDAC (n = 215) in older patients(≥ 65 years) with newly diagnosed AML and poor- or intermediate-risk cytogenetics [18]. The CR rate in the decitabine group was 15.7%. Although the planned primary analysis after 396 deaths did not show a significant improvement of OS with decitabine versus treatment choice (median OS 7.7 months vs. 5.0 months), an unplanned analysis after 446 deaths showed a significant benefit for decitabine (HR 0.82 [95% CI 0.68–0.99], P = 0.037). A small but pivotal phase II trial in 53 patients evaluated the effect of a longer 10-day decitabine schedule and found an increased CR rate of 47% and overall response of 64% with a median OS of 13 months [41]. The beneficial effects of the 10-day decitabine schedule were confirmed in two large single-centre retrospective studies that found response rates and median OS of 40% and 11 months, and 35% and 11 months, respectively [42, 43]. Recently, the result

**171**

*Treatment of AML in Older Patients*

(5 days 60 mg/m<sup>2</sup>

treatment for CR or OS [45].

*DOI: http://dx.doi.org/10.5772/intechopen.94979*

of a phase II trial directly comparing 5-day versus 10-day decitabine treatment was reported. The researchers concluded both schedules have similar efficacy (CR rates 29% vs. 30% [P = 0.88], median OS 5.5 vs. 6.0 months [P = 0.47]), although there was an uncorrected imbalance in disease characteristics favouring the 5-day schedule and the randomisation allocation was skewed towards the 10-day schedule [44]. Therefore caution has to be taken when interpreting the results. However, these data show that decitabine, both in 5-day and 10-day schedules, is efficient and suggest that decitabine as a single agent might provide a framework upon which to build

Guadecitabine is a next generation HMA given subcutaneously which provides

showed that guadecitabine is an effective drug, the trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine vs. preselected

ASTX727 is a next generation HMA with a unique fixed-dose combination of the hypomethylating agent decitabine and the novel cytidine deaminase inhibitor, E7727 (cedazuridine). ASTX727 was designed to deliver decitabine by oral administration. By inhibiting cytidine deaminase, cedazuridine inhibits the major mechanism by which decitabine is degraded in the gastrointestinal tract and liver, and the combination therefore permits the efficient delivery of decitabine orally. It has shown promising effects in a phase II trial conducted in intermediate- and high-risk myelodysplastic syndromes and chronic myelomonocytic leukaemia patients [46].

An important question is whether intensive chemotherapy is superior to hypomethylating agents in older AML patients. The results of the above reported clinical trials cannot be directly compared due to differences in patient population studied. The MD Anderson Cancer Center reported the results of a retrospective cohort study of 671 patients, including 114 patients treated with HMAs (either azacitidine or decitabine) and 557 patients treated with IC [47]. Both groups were balanced according to cytogenetics and performance status and were older than 65 years. Patients who had received IC had a higher CR rate compared to patients who had received HMAs (42% vs. 28% [P = 0.001], respectively). However, the median OS was comparable in the 2 groups (6.7 vs. 6.5 months, P = 0.41). Multivariate analysis confirmed that type of AML therapy (IC or HMAs) was not an independent prognostic factor for survival. Interestingly, this study revealed that decitabine was associated with improved median OS compared with azacitidine (8.8 vs. 5.5 months, respectively, P = .03), also in multivariate analysis. No published prospective randomised trials have compared the efficacy of azacitidine with decitabine nor the efficacy of intensive chemotherapy ('3 + 7') with hypomethylating agents. The results of the EORTC-1301 phase III trial, comparing upfront treatment with intensive chemotherapy or decitabine, are eagerly awaited (NCT02172872).

every 4 weeks) or a preselected treatment of azacitidine,

future combination studies to improve outcomes for older AML patients.

prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. In a large randomised trial 815 untreated AML patients not eligible for IC were randomised to either guadecitabine

decitabine, or LDAC (ASTRAL-1 trial, NCT02920008). Although this trial

This trial is now expanding to include AML patients (NCT04093570).

**5. Treatment of patients considered not to be fit: LDAC**

Low-dose cytarabine (LDAC) (20 mg twice daily for 10 days) has been used in the treatment of AML for several years. Treatment with LDAC has low toxicity and a higher CR rate than best supportive care (18% vs. 1%) [15]. Although the OS for the LDAC-treated group has been demonstrated to be statistically

#### *Treatment of AML in Older Patients DOI: http://dx.doi.org/10.5772/intechopen.94979*

*Acute Leukemias*

challenging.

**hypomethylating agents**

older patients with AML.

and intensive chemotherapy.

efficacy and safety of 5-day decitabine (20 mg/m2

between 1997 and 2006 and concluded that older patients do benefit from intensive treatment with a median OS in *de novo* AML of over 1 year [13]. This highlights that choosing the optimal treatment for older patients with AML remains

**4. Treatment of patients considered unfit for intensive chemotherapy:** 

For patients not eligible for intensive chemotherapy treatment a choice can be made between best supportive care (BSC), low dose chemotherapy (LDAC) or hypomethylating agents (HMAs). Several studies have shown the efficacy of the HMAs azacitidine and decitabine. In addition, HMAs are well-tolerated and have low extra-medullary toxicity. Therefore HMAs are very suitable for the treatment of

Azacitidine was first studied in the context of high-risk myelodysplastic syndromes (MDS). A phase III trial conducted in intermediate-2 and high-risk MDS patients included a subset of patients with 20–30% blasts, who were reclassified to AML according to redefined WHO criteria [38, 39]. The relative efficacy and safety of azacitidine versus conventional care regimens (CCR; comprising prespecified allocation to BSC, LDAC, or IC) was thus compared in this subgroup of patients (n = 113) and showed an increased median OS (24.5 vs. 16.0 months, P = 0.005) and increased 2-year survival (50% vs. 16%, P = 0.001) for azacitidine-treated patients compared with CCR patients [40]. In addition, a phase III study on the efficacy of azacitidine versus CCR (standard IC, LDAC or BSC) in newly diagnosed AML patients with >30% blasts was conducted [17]. The median OS was longer in the azacitidine group compared to the CCR group (10.4 vs. 6.5 months), although in multivariate analysis significance was lost (HR 0.85 [95% CI 0.69–1.03], P = 0.101). However, in a pre-planned sensitivity analysis censoring for subsequent AML therapy, the median OS was 12.1 months versus 6.9 months in the azacitidine-arm and CCR-arm respectively, with a stratified HR 0.76 (95% CI 0.60–0.96, P = 0.019). Azacitidine was well tolerated as more than half of the patients received six or more treatment cycles. The difference in median OS between the two reported studies (24.5 months vs. 12.1 months) could be explained by the lower blast count in the first study and thereby selection of more indolent disease. Unfortunately both studies were not powered to detect direct differences between azacitidine treatment

Decitabine is another hypomethylating agent registered for treatment of AML. Two decitabine schedules are currently in use in clinical practice: the 5-day schedule and the 10-day schedule. A randomised phase III trial compared the

choice of BSC (n = 28) or LDAC (n = 215) in older patients(≥ 65 years) with newly diagnosed AML and poor- or intermediate-risk cytogenetics [18]. The CR rate in the decitabine group was 15.7%. Although the planned primary analysis after 396 deaths did not show a significant improvement of OS with decitabine versus treatment choice (median OS 7.7 months vs. 5.0 months), an unplanned analysis after 446 deaths showed a significant benefit for decitabine (HR 0.82 [95% CI 0.68–0.99], P = 0.037). A small but pivotal phase II trial in 53 patients evaluated the effect of a longer 10-day decitabine schedule and found an increased CR rate of 47% and overall response of 64% with a median OS of 13 months [41]. The beneficial effects of the 10-day decitabine schedule were confirmed in two large single-centre retrospective studies that found response rates and median OS of 40% and 11 months, and 35% and 11 months, respectively [42, 43]. Recently, the result

) (n = 242) with treatment

**170**

of a phase II trial directly comparing 5-day versus 10-day decitabine treatment was reported. The researchers concluded both schedules have similar efficacy (CR rates 29% vs. 30% [P = 0.88], median OS 5.5 vs. 6.0 months [P = 0.47]), although there was an uncorrected imbalance in disease characteristics favouring the 5-day schedule and the randomisation allocation was skewed towards the 10-day schedule [44]. Therefore caution has to be taken when interpreting the results. However, these data show that decitabine, both in 5-day and 10-day schedules, is efficient and suggest that decitabine as a single agent might provide a framework upon which to build future combination studies to improve outcomes for older AML patients.

Guadecitabine is a next generation HMA given subcutaneously which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. In a large randomised trial 815 untreated AML patients not eligible for IC were randomised to either guadecitabine (5 days 60 mg/m<sup>2</sup> every 4 weeks) or a preselected treatment of azacitidine, decitabine, or LDAC (ASTRAL-1 trial, NCT02920008). Although this trial showed that guadecitabine is an effective drug, the trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine vs. preselected treatment for CR or OS [45].

ASTX727 is a next generation HMA with a unique fixed-dose combination of the hypomethylating agent decitabine and the novel cytidine deaminase inhibitor, E7727 (cedazuridine). ASTX727 was designed to deliver decitabine by oral administration. By inhibiting cytidine deaminase, cedazuridine inhibits the major mechanism by which decitabine is degraded in the gastrointestinal tract and liver, and the combination therefore permits the efficient delivery of decitabine orally. It has shown promising effects in a phase II trial conducted in intermediate- and high-risk myelodysplastic syndromes and chronic myelomonocytic leukaemia patients [46]. This trial is now expanding to include AML patients (NCT04093570).

An important question is whether intensive chemotherapy is superior to hypomethylating agents in older AML patients. The results of the above reported clinical trials cannot be directly compared due to differences in patient population studied. The MD Anderson Cancer Center reported the results of a retrospective cohort study of 671 patients, including 114 patients treated with HMAs (either azacitidine or decitabine) and 557 patients treated with IC [47]. Both groups were balanced according to cytogenetics and performance status and were older than 65 years. Patients who had received IC had a higher CR rate compared to patients who had received HMAs (42% vs. 28% [P = 0.001], respectively). However, the median OS was comparable in the 2 groups (6.7 vs. 6.5 months, P = 0.41). Multivariate analysis confirmed that type of AML therapy (IC or HMAs) was not an independent prognostic factor for survival. Interestingly, this study revealed that decitabine was associated with improved median OS compared with azacitidine (8.8 vs. 5.5 months, respectively, P = .03), also in multivariate analysis. No published prospective randomised trials have compared the efficacy of azacitidine with decitabine nor the efficacy of intensive chemotherapy ('3 + 7') with hypomethylating agents. The results of the EORTC-1301 phase III trial, comparing upfront treatment with intensive chemotherapy or decitabine, are eagerly awaited (NCT02172872).
