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The role of hypomethylating agents in the treatment of elderly patients with AML

Open AccessPublished:September 26, 2013DOI:https://doi.org/10.1016/j.jgo.2013.08.004

      Abstract

      There is a major unmet medical need for treatment options in elderly patients with acute myeloid leukemia (AML) who are deemed ineligible for intensive treatment. The recent approval of decitabine in the European Union for the treatment of patients with AML ≥ 65 years old highlights the potential for hypomethylating agents in this setting. Here, we review evidence to support the use of hypomethylating agents in elderly patients and emphasize the importance of tolerability and quality of life considerations. We focus on the rationale for the continued clinical development of the ribonucleoside analog azacitidine in this setting. We discuss potential differences in the activity of azacitidine and decitabine in different patient subgroups that could possibly be explained by important differences in mechanism of action. Finally, we assess practical challenges that will be faced when integrating hypomethylating agents into clinical practice, such as how to define ineligibility for intensive treatment.

      Keywords

      1. Introduction

      Acute myeloid leukemia (AML) is mostly a disease of the elderly with a median age at diagnosis of ~70 years.
      • Klepin H.D.
      • Balducci L.
      Acute myelogenous leukemia in older adults.
      Older patients with AML have significant comorbidities, a poorer performance status (PS), more unfavorable cytogenetic abnormalities, and a higher incidence of secondary AML than their younger counterparts.
      • Klepin H.D.
      • Balducci L.
      Acute myelogenous leukemia in older adults.
      The decision whether to allocate intensive or non-intensive treatment options to elderly patients with AML (>60 years old) is both challenging and complex and requires careful assessment of disease- and patient-related factors. In some elderly patients, intensive chemotherapy (IC) is an acceptable standard of care, leading to a 45–55% response rate with the potential of improving prognosis.
      • Lowenberg B.
      Prognostic factors in acute myeloid leukaemia.
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      • Antunovic P.
      • Derolf A.
      • Lehmann S.
      • Mollgard L.
      • Stockelberg D.
      • et al.
      Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry.
      • Lowenberg B.
      • Ossenkoppele G.J.
      • van P.W.
      • Schouten H.C.
      • Graux C.
      • Ferrant A.
      • et al.
      High-dose daunorubicin in older patients with acute myeloid leukemia.
      • Stone R.M.
      The difficult problem of acute myeloid leukemia in the older adult.
      However, long-term survival generally remains low due to a higher risk of relapse and treatment-related mortality compared with younger patients.
      • Jabbour E.J.
      • Estey E.
      • Kantarjian H.M.
      Adult acute myeloid leukemia.
      Patients deemed ‘unfit’ or ineligible for IC are frequently offered best supportive care (BSC) only. Unfortunately, prognosis in untreated elderly patients is dismal. In a Surveillance, Epidemiology, and End Results cancer registry analysis, median survival in 2657 adults ≥65 years was 2 months and the 2-year survival rate was 6%. For untreated patients, median survival was 1 month compared to 7 months for the 30% of patients who received chemotherapy.
      • Menzin J.
      • Lang K.
      • Earle C.C.
      • Kerney D.
      • Mallick R.
      The outcomes and costs of acute myeloid leukemia among the elderly.
      Alternatively, some frail patients are offered low-dose cytarabine (LDAC). Although more tolerable than IC, outcomes with LDAC are generally poor with a median survival time of only 4 months.
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      Therefore, there is an unmet need for well tolerated treatment options for these patients.
      Hypomethylating agents (HMA) may have the potential to improve survival and quality of life in elderly patients with AML. Indeed, quality of life and patient-reported outcomes are key considerations when selecting appropriate treatment for the elderly.
      • Sekeres M.A.
      • Steensma D.P.
      Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia.
      There is biological rationale for assessing HMA in these patients. Recent studies have demonstrated that gene hypermethylation is widespread in patients with AML and is implicated in the pathogenesis and progression of the disease.
      • Kroeger H.
      • Jelinek J.
      • Estecio M.R.
      • He R.
      • Kondo K.
      • Chung W.
      • et al.
      Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse.
      Moreover, extensive clinical experience with two HMA, azacitidine and decitabine, has demonstrated that the drugs are well tolerated in elderly and frail patients.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      • Kantarjian H.
      • Oki Y.
      • Garcia-Manero G.
      • Huang X.
      • O'Brien S.
      • Cortes J.
      • et al.
      Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia.
      • Lubbert M.
      • Suciu S.
      • Baila L.
      • Ruter B.H.
      • Platzbecker U.
      • Giagounidis A.
      • et al.
      Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group.
      • Seymour J.F.
      • Fenaux P.
      • Silverman L.R.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • et al.
      Effects of azacitidine compared with conventional care regimens in elderly (>/=75 years) patients with higher-risk myelodysplastic syndromes.
      In this review, we discuss available efficacy and safety data for both azacitidine and decitabine in patients with AML, as well as current understanding of the mechanism of action of these drugs. Furthermore, we assess the challenges that will be faced when integrating HMA into clinical practice, such as how to define ineligibility for IC.

      2. Hypomethylating Agents in Elderly Patients with AML: Phase III Studies

      Both decitabine and azacitidine have been, or are being, assessed in phase III studies in elderly patients with AML (DACO-016 and AZA-AML-001 trials, respectively).

      2.1 DACO-016 Study

      The recently published DACO-016 study compared the efficacy and safety of decitabine (20 mg/m2/day for 5 days every 4 weeks) versus treatment choice (TC; LDAC [20 mg/m2/day for 10 days every 4 weeks] or BSC) in 485 patients who were deemed ineligible for IC.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      The primary endpoint was overall survival (OS); secondary endpoints included complete remission (CR) rate and adverse events (AEs). The median age of patients enrolled onto the DACO-016 trial was 73 years; 35% of patients had secondary AML, 36% had poor-risk cytogenetics and 24% had an Eastern Cooperative Oncology Group (ECOG) PS of 2.
      The preplanned primary efficacy analysis was undertaken in October 2009 following 396 deaths (Fig. 1). This analysis demonstrated a non-significant trend towards improved OS in the decitabine arm versus TC (7.7 vs 5.0 months; p = 0.108). A year after the initial analysis, an unplanned ad hoc efficacy analysis was performed following 446 deaths. The median OS for both arms was the same as in the initial analysis, but the difference between the decitabine arm and the TC arm was now nominally significant (p = 0.037; Fig. 1).
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      Following adjustment for study drug exposure, the overall death rate (per patient year) was lower for decitabine than for LDAC (0.57 vs 0.73). Based on a subanalysis of the trial, decitabine has not shown any evidence of improving OS in patients with 20–30% blasts. Incidence of AEs was similar between arms. The most common grades 3–4 treatment-emergent AEs were thrombocytopenia and anemia. Drug-related AEs occurred in 74% of patients treated with decitabine and 73% of patients treated with LDAC with the most common being thrombocytopenia (27%), anemia (21%), neutropenia (24%) and febrile neutropenia (21%).
      Figure thumbnail gr1
      Fig. 1Predesignated and ad-hoc analyses of overall survival in the DACO-016 trial.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      Decitabine was recently approved by the European Medicines Agency (EMA) for the treatment of AML in patients aged ≥65 years with de novo/secondary AML who are not candidates for IC. In contrast, the US Food and Drug Agency (FDA) Oncologic Drugs Advisory Committee (ODAC) did not recommend approval of decitabine based on concerns regarding the statistical validity and robustness of the data. Several issues including the interpretation of the data of the TC arm of the trial were raised. For example, patients who received BSC, although few in number (n = 28), were grouped together with patients treated with LDAC when TC was compared to decitabine. The negative impact of this fact on OS in the TC arm could not be excluded. The FDA ODAC highlighted a number of concerns regarding the results of DACO-016 which, in their view, precluded marketing approval: i) a lower than expected response rate in the LDAC arm; ii) inexplicable variation in efficacy across different geographical regions; in Western Europe, for example, the CR rate with LDAC was higher than the response rate with decitabine. iii) unplanned and exploratory ad hoc analysis of OS; iv) failure to achieve primary endpoint. Additionally, concerns regarding the lack of strict criteria for entry to the study were expressed. About 10% of patients who supposedly were deemed not to be fit for IC ultimately received IC following randomization in the study. This may encourage some physicians to use decitabine in patients who may be better candidates for IC.
      • Sekeres M.A.
      • Steensma D.P.
      Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia.
      Minutes for the February 9 2012 meeting of the FDA Oncologic Drugs Advisory Committee.

      2.2 AZA-AML-001 Study

      In the ongoing AZA-AML-001 trial, patients (target enrolment of 480 patients) were randomized 1:1 to receive either azacitidine (75 mg/m2/day for 7 days every 4 weeks) or conventional care regimen (CCR; BSC, LDAC [40 mg/day for 10 days every 4 weeks] or IC). Choice of CCR was assigned by the treating physician. The primary endpoint of AZA-AML-001 is OS. Secondary endpoints include remission rate, event-free survival, safety and, importantly, patient-reported quality of life outcomes. Inclusion criteria for AZA-AML-001 were similar to DACO-016, although there were some notable differences. Firstly, patients in the control arm of AZA-AML-001 could receive IC, LDAC or BSC rather than just LDAC or BSC. Secondly, a bone marrow (BM) blast count of >30%, rather than ≥20%, was required.
      The AZA-AML-001 trial is scheduled to be completed (including final data collection for primary outcome measure) late 2013. These data will be instrumental in defining the future role of azacitidine in patients with AML and >30% blasts. Azacitidine is already approved for the treatment of patients with AML and 20–30% blasts, based on a subanalysis of the phase III AZA-001 trial (described below).
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.

      2.3 AZA-001 Study

      The AZA-001 trial compared the efficacy and safety of azacitidine with CCR (BSC, LDAC, IC) in 358 patients with predominantly int-2-/high-risk MDS.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Finelli C.
      • Giagounidis A.
      • et al.
      Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.
      However, 113 patients with WHO-AML (20–30% blasts) were also included.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      The efficacy population included 55 patients randomly assigned to azacitidine and 58 patients randomly assigned to CCR. Of the 58 patients in the CCR group, 27 (47%), 20 (34%), and 11 (19%) were preselected by their treating physicians to receive BSC, LDAC, and IC, respectively. Baseline characteristics were comparable between the two treatment groups. In these patients: i) azacitidine halved the risk of death compared with CCR. After a median follow-up of 20.1 months, OS was 24.5 months in the azacitidine group and 16.0 months in the CCR group (HR [95%CI] = 0.47 [0.28–0.79]; p = 0.005; Fig. 2); further, a survival comparison between azacitidine vs CCR according to investigator pre-selection was conducted. A significant difference in OS favoring azacitidine (n = 36) vs BSC (n = 27), with median OS of 19.1 vs 13.4 months, respectively (p = 0.03) was detected. Median OS for azacitidine (n = 14) was 24.5 vs 17 months for LDAC (n = 20) (p = 0.08). Median OS was not reached for azacitidine (n = 5) compared with 14.2 months for IC (n = 11) (p = 0.97). Although interesting, the data must be interpreted with caution because of the small number of patients in each CCR regimen. ii) Significantly more patients who were red blood cell transfusion-dependent (RBC-TD) at baseline achieved transfusion independence with azacitidine compared with CCR (41% vs 18%, respectively; p = 0.04); iii) AEs were generally predictable (predominantly hematological, gastrointestinal or injection site reactions) and manageable on treatment; iv) the CR rate in the azacitidine arm was 18% compared with 16% in the CCR arm, indicating that CR is not a prerequisite for survival benefit in patients treated with azacitidine.
      Figure thumbnail gr2
      Fig. 2AZA-001: Overall survival in WHO-defined patients with AML (20–30% blasts).
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      Based on this analysis, azacitidine has become established as a treatment option in patients with WHO-AML (20–30% blasts) who are ineligible for intensive treatment.

      3. Hypomethylating Agents in Elderly Patients with AML: Phase II Studies

      To date, there are no prospective data available that directly compare the efficacy and safety of azacitidine and decitabine in patients with AML. To date, three phase II studies have been reported for decitabine in patients with AML (all first-line elderly patients deemed ineligible for IC; Table 1).
      • Blum W.
      • Garzon R.
      • Klisovic R.B.
      • Schwind S.
      • Walker A.
      • Geyer S.
      • et al.
      Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine.
      • Cashen A.F.
      • Schiller G.J.
      • O'Donnell M.R.
      • DiPersio J.F.
      Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia.
      • Lubbert M.
      • Ruter B.H.
      • Claus R.
      • Schmoor C.
      • Schmid M.
      • Germing U.
      • et al.
      A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.
      One phase II study of azacitidine monotherapy in patients with AML (in both first-line and relapsed/refractory patients) has been published.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      Table 1Summary of phase II trials of decitabine and azacitidine in patients with AML.
      StudyInclusion criteriaBaseline characteristicsTreatmentResponseSurvivalSafety
      Lubbert et al.
      • Lubbert M.
      • Ruter B.H.
      • Claus R.
      • Schmoor C.
      • Schmid M.
      • Germing U.
      • et al.
      A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy.
      • First-line patients
      • >60 years old
      • ECOG PS: 0–2
      • >30% blasts
      • Any cytogenetics
      • Patients, n: 227
      • Median age, years (range): 72 (56–86)
      • ECOG PS, 0/1/2, %: 19/58/22
      • HCT-CI, 0/1–2/>3, %: 21/42/37
      • AML type, p/s: 49/51
      • Median WBC, ×109/L (range): 4.4 (<1–241)
      • Median blasts,%: 56 (10–100)
      • Decitabine 135 mg/m2 total dose every 6 weeks
      • ATRA given to 100 patients during cycle 2
      • Median cycles, n (range): 2 (1–4)
      • ORR: 52%
      • CR: 13%
      • PR: 13%
      • HI: 26%
      • Median OS, months: 5.5
      • 1 year OS, % (95% CI): 28 (22–34)
      • Parameters associated with worse outcome: low platelets, age, ECOG-PS and high LDH
      • Grade 3–4 neutropenia, %: 51
      • Grade 3–4 thrombocytopenia, %: 51
      Cashen et al.
      • Cashen A.F.
      • Schiller G.J.
      • O'Donnell M.R.
      • DiPersio J.F.
      Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia.
      • First-line patients
      • >60 years old
      • Int/poor cytogenetics
      • ECOG PS: 0–2
      • Ineligible for IC or HCT
      • >20% blasts
      • Patients, n: 55
      • Median age, years (range): 74 (61–87)
      • ECOG PS, 0/1/2: 47/35/18
      • Cytogenetics, int/poor/na: 53/45/2
      • AML type, p/s/t: 55/35/7
      • Median WBC, ×109/L: 2.7 (1–111)
      • Median blasts,%: 50
        (0–99)
      • Decitabine 20 mg/m2 for 5 days every 4 weeks
      • Median cycles: 3 (1–25)
      • ORR: 25%
      • CR: 24%
      • CRi: 2%
      • SD: 29%
      • Failure: 31%
      • n/a: 15%
      • Median time to response, days: 126 (4.5 cycles)
      • Minimum follow up: 1 year
      • Median OS, months (95% CI): 7.7 (5.7–11.6)
      • Median EFS, months (range): 5.8 (3 days to 23.6 months)
      • Median OS in responders, months: 14
      • Factors that predicted short survival: ECOG PS of 2, male gender, high blasts
      • Grade 3–4 neutropenia, %: 20
      • Grade 3–4 febrile neutropenia, %: 29
      • Grade 3–4 thrombocytopenia, %: 22
      • Delayed cycles, %: 27
      • Dose reductions: uncommon
      Blum et al.
      • Blum W.
      • Garzon R.
      • Klisovic R.B.
      • Schwind S.
      • Walker A.
      • Geyer S.
      • et al.
      Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine.
      • First-line patients
      • 60 years old
      • Ineligible or refused IC
      • WBC <40 × 109/L
      • Patients, n: 53
      • Median age, years (range): 74 (60–85)
      • MRC prognostic score, good/standard/poor: 19/32/49
      • Cytogenetics, normal/complex/other: 40/30/26
      • AML type, p/s/t: 64/25/11
      • Median WBC, ×109/L (range): 2.7 (0.4–150)
      • Median blasts,% (range): 52 (20–92)
      • Decitabine 20 mg/m2 for 10 days every 4 weeks (dose subsequently reduced if blasts <5% or if grade 4 neutropenia experienced)
      • Median cycles, n (range): 4 (1–21+)
      • ORR: 64%
      • CR: 47%
      • CRi: 17%
      • CR in patients with WBC ≥15 × 109/L: 57%
      • CRs occurred in all cytogenetic subgroups
      • Median OS, weeks (95% CI): 55 (36–72)
      • Median DFS, weeks (95% CI): 46 (30–NR)
      • Four patients received non-myeloablative HCT after CR
      • Grade 3–4 febrile neutropenia, %: 68
        (during first two cycles)
      Al-Ali et al. (first-line)
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      • 18 years old
      • Ineligible or refused IC
      • 20% BM blasts
      • Medically unfit for induction chemotherapy
      • Patients either had serious comorbidity, or severe uncontrolled infections
      • Patients, n: 20
      • Median age, years (range): 78 (64–84)
      • Cytogenetic risk, int/high, %: 75/25
      • AML type, p/s, %: 40/60
      • Median WBC, ×109/L (range): 3.4 (0.8–187)
      • Median blasts, % (range): 44 (10–90)
      • Azacitidine 75 mg/m2 for 5 days every 4 weeks until progressive disease or relapse
      • Median cycles, n: 6
      • ORR: 50%
      • SD: 25%
      • PD: 0%
      • Early death: 25%
      • Median time to response, months (range): 3.5 (2–7)
      • Median duration of response; months (range): 5.5 (1–NR)
      • Median follow-up, months (range): 13 (9–16)
      • Median OS, months (range): 7.7 (0.2–NR)
      • OS similar between pAML and sAML
      • OS in responding patients: not reached
      • OS in patients with SD, months: 10
      • 1 year OS, %: 39
      • Grade 3/4 thrombocytopenia,%: ~70
      • Grade 3/4 neutropenia, %: ~65
      • Hematological AEs were reversible in all patients, mainly by dose delays
      • Delayed cycles, %: 11
      • Patients requiring dose reduction, %: 13
      • Non-hematological AEs were generally mild and manageable
      Al-Ali et al. (second-line)
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      • Same as above
      • Patients, n: 20
      • Median age, years (range): 67 (32–83)
      • Cytogenetic risk, int/high, %: 65/35
      • AML type, p/s/NA, %: 70/25/5
      • Median WBC, ×109/L: 3.6 (0.7–36)
      • Median blasts, %: 40 (15–80)
      • Relapsed/refractory,%: 65/35
      • As above, except median cycles, n: 2
      • ORR: 10%
      • SD: 50%
      • PD: 10%
      • Early death: 30%
      • Median time to response, months (range): 1.5 (1–2)
      • Median duration of response; months (range): 4.5 (4–5)
      • Median follow-up, months (range): 13 (9–16)
      • Median OS, months (range): 2.9 (0.7–NR)
      • OS similar between refractory and relapsed patients
      • Grade 3/4 thrombocytopenia,%: ~70
      • Grade 3/4 neutropenia, %: ~65
      • Hematological AEs were reversible in all patients, mainly by dose delays
      • Delayed cycles, %: 11
      • Patients requiring dose reduction, %: 13
      • Non-hematological AEs were generally mild and manageable
      ATRA: all-trans retinoic acid, CR: complete response, EFS: event free survival, HI: hematological improvement, LDH: lactate dehydrogenase, n/a: not available, NR: not reported, mCR: complete marrow response, ORR: overall response rate, OS: overall survival, p: primary, PD: progressive disease, PR: partial response, s: secondary, and t: therapy-related.
      Our study assessed the efficacy and safety of azacitidine (75 mg/m2/day for 5 days every 28 days) in patients with AML and ≥20% BM blasts who were deemed medically unfit for IC, based on comorbidity profile.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      The study demonstrated that azacitidine was generally well tolerated; all treatment-related AEs were reversible and effectively managed with supportive measures and dose delays. Median OS in patients treated with first-line azacitidine (7.7 months) compared favorably with OS rates historically achieved with LDAC (median survival of 4 months).
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      Median OS in patients who achieved stable disease (SD) was 10 months, which was similar to that achieved in patients with CR, partial response (PR) or hematological improvement (HI). Again, these data suggest that CR is not a prerequisite for improved survival in patients with AML given azacitidine, as is also the case in patients with MDS and WHO-AML (20–30% blasts).
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Finelli C.
      • Giagounidis A.
      • et al.
      Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.
      The response rate in patients with previously untreated AML was 50%. There was also some evidence of clinical activity in patients with relapsed/refractory AML (response rate of 10%). An important observation was that hematological responses were rapid (median time to response was 2.5 months); furthermore, early reductions in BM blast count by day 15 of the first cycle were highly predictive of subsequent response.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      This suggests that azacitidine elicits early anti-leukemia responses, which is clearly an important consideration when treating patients with high-risk disease and very dismal prognosis.
      Based on the three published phase II decitabine studies (Table 1) survival with azacitidine seems comparable with that observed in decitabine trials which reported median OS ranging from 5.5 months to ~1 year and 1-year OS of ~30–50%. However, it is not possible to come to any definitive conclusions regarding the relative efficacy and safety of the two drugs based on these small phase II studies.

      4. Hypomethylating Agents in Elderly Patients with AML: Retrospective Studies

      A number of retrospective single-center studies or national/international patient registries have assessed HMA in patients with AML (Table 2, Table 3). The majority of these studies reported outcomes in patients treated with azacitidine (Table 2) and are the focus of the following discussion.
      Table 2Overview of retrospective studies of azacitidine in patients with AML.
      StudyBaseline characteristicsTreatmentResponseSurvival
      • a)
        Patients with previously untreated AML
      Bories et al.
      • Bories P.
      • Bertoli S.
      • Huguet F.
      • Dobbelstein S.
      • Fornecker L.
      • Rauzy O.B.
      • et al.
      Efficacy of frontline 5-azacytidine in older AML patients unfit for chemotherapy [abstract].
      • Patients, n: 98
      • Median age, years (range): 76 (60–89)
      • ECOG PS, ≥2, %: 29
      • AML type, p/s: 72/28
      • WBC, >10 × 109/L, %: 14
      • Median blasts,% (range):35
      • (0–99)
      • Cytogenetics, int/poor, %: 49/45
      • Azacitidine 75 mg/m2/day for 7 days every 28 days
      • Median cycles, n (range): 6 (1–27)
      • ORR: 51%
      • CR: 13%
      • CRi: 5%
      • PR: 6%
      • HI: 27%
      • Median cycles to best response, n: 6
      • Median OS, months: ~12
      • 1 year OS, %: 50
      • Parameters associated with worse OS (multivariate): high LDH, adverse cytogenetics
      • Parameters with no effect on OS (multivariate): age, ECOG PS, WBC
      Serrano et al.
      • Serrano J.
      • de la Fuent A.
      • Bergua J.
      • et al.
      5-Azacytidine versus intensive chemotherapy or BSC in elderly (>60 years) AML patients: a retrospective analysis [abstract].
      • Patients, n: 67
      • Median age, years (range): 71 (60–84)
      • ECOG PS, ≥2, %: 67
      • Cytogenetics, int/poor, %: 69/22
      • AML type, p/s, %: 49/51
      • Median WBC, ×109/L (range): 4.4 (0.2–18)
      • Median blasts,% (range): 34 (20–84)
      • Azacitidine 75–100 mg/m2 for 7 days every 4 weeks
      • Median cycles, n (range): 6 (1–24)
      • ORR: 38%
      • CR: 13%
      • PR: 13%
      • HI: 16%
      • Median follow up, months (range): 7.4 (1–28.3)
      • Median OS, months: 13.7
      • OS was significantly higher in patients who responded than patients who did not respond
      • OS was significantly higher in patients with HI than patients who did not respond
      Sudan et al.
      • Sudan N.
      • Rossetti J.M.
      • Shadduck R.K.
      • Latsko J.
      • Lech J.A.
      • Kaplan R.B.
      • et al.
      Treatment of acute myelogenous leukemia with outpatient azacitidine.
      • Patients, n: 20
      • Mean age, years (range): 68 (44–80)
      • Cytogenetics, normal/simple/complex, %: 35/25/40
      • ECOG ≤1, %: 100
      • Median WBC, ×109/L (range): 4.0 (0.65–105)
      • Blasts, ≥30%, %: 40
      • Azacitidine 75 mg/m2/day for 7 days every 4 weeks
      • ORR: 60%
      • CR: 20%
      • PR: 25%
      • HI: 15%
      • Median time to response, months (range): 3 (2–5)
      • RBC-TI: 61%
      • Median survival in responders, months (range): 15+ (10–36+)
      • Median survival in non-responders, months: 2.5
      • No significant difference in OS between patients who achieved CR/PR and those who achieved HI
      Maurillo et al.
      • Maurillo L.
      • Venditti A.
      • Spagnoli A.
      • Gaidano G.
      • Ferrero D.
      • Oliva E.
      • et al.
      Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.
      • Patients, n: 35
      • Median age, years (range): 77 (46–87)
      • Cytogenetics, int/poor/fail, %: 37/23/40
      • AML type, p/s/t, %: 77/20/3
      • Median WBC, ×109/L (range): 4.0 (0.65–105)
      • Median blasts,% (range): 35 (20–80)
      • Azacitidine 75 mg/m2/day for 7 days every 4 weeks: 66%
      • Azacitidine 100 mg/day for 7 days every 4 weeks: 34%
      • Median cycles, n (range): 6 (1–18)
      • ORR: 48%
      • CR: 23%
      • CRi: 8%
      • PR: 17%
      • SD: 23%
      • Median duration of response, months: 6
      • Median follow up, months: 12
      • Median OS, months: 9
      • 1 year OS, %: 35
      • Median OS in responders, months: 13
      • Median OS in non-responders, months: 5
      • Elevated WBC count (>109/L) was associated with poor survival (4 vs 9 months; p = 0.011)
      • No significant difference in OS in patients with <30 and ≥30% blasts
      Ramos et al.
      • Ramos F.
      • Martinez-Robles V.
      • Bargay J.
      • Deben G.
      • Garrido A.
      • Serrano J.
      • et al.
      Azacitidine as front-line therapy in AML: results from the Spanish National Registry. Alma Study Investigators [abstract].
      • Patients, n: 110
      • Median age, years (range):75 (56–89)
      • Cytogenetics, favorable/int/adverse, %: 1/58/27
      • ECOG ≥2, %: 30
      • sAML, %: 55
      • Comorbidities, %: 87
      • Median dose: 73.6 mg/m2/day
      • 7-day schedule: 64%
      • Median cycles, n (range):4(1–29)
      • Median follow-up, months: 8.6
      • ORR: 45%
      • CR: 16%
      • Median OS, months: 8.1
      • 1 year OS, %: 37
      • OS was significantly higher in patients who responded than patients who did not respond, in patients with ECOG ≤1 and in patients with BM blasts ≤30%
      • b)
        Patients with previously untreated or relapsed/refractory AML
      Gavillet et al.
      • Gavillet M.
      • Noetzli J.
      • Blum S.
      • Duchosal M.A.
      • Spertini O.
      • Lambert J.F.
      Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine.
      • Patients, n: 38
      • Median age, years (range): 68 (25–86)
      • Cytogenetics, favorable/int/poor, %: 8/64/29
      • AML type, p/s/rr, %: 42/45/13
      • Median WBC, ×109/L (range): 3.1 (0.6–37)
      • Median blasts, % (range): 70 (20–90)
      • Baseline or acquired RBC-TI, %: 58%
      • Azacitidine 100 mg/m2/day for 5 days every 4 weeks
      • Median cycles, n (range): 6 (3–20)
      • ORR: 23%
      • CRi: 18%
      • PR: 5%
      • Median OS in RBC-TI patients, months: 11.1
      • 1 year OS in RBC-TI patients, %: 40
      • Median OS in RBC-TD patients, months: 5
      • 1 year OS in RBC-TD patients, %: 13
      • Parameters associated with worse OS (multivariate): RBC-TD
      • Parameters with no effect on OS (multivariate): peripheral blasts ≥20%, relapsed/refractory disease
      Pleyer et al.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Patients, n: 155
      • Median age, years (range): 73 (33–91)
      • Cytogenetics (IPSS), good/int/poor, %: 59/16/17
      • Prior chemotherapy, y/n: 39/61
      • AML type, p/s/t, %: 37/48/10
      • WBC, >10 × 109/L, %: 21
      • Blasts, >30%, %: 63
      • ECOG PS >1, %: 26
      • Comorbidities, 0-1/2-3/>3, %: 43/39/18
      • Azacitidine 75 mg/m2/day for 7 days every 4 weeks: 57%
      • Azacitidine 75 mg/m2/day, 5-2-2 schedule every 4 weeks: 22%
      • Azacitidine 75 mg/m2 for 5 days every 4 weeks: 16%
      • Other: 5%
      • Median cycles, n (range): 4 (1–24)
      • ORR: 45%
      • CR: 10%
      • mCR: 3%
      • PR: 21%
      • SD with HI: 3%
      • HI only: 9%
      • RBC-TI (in patients RBC-TD at baseline; n = 97): 36%
      • Median time to response, months: 4
      • Median OS from initiation of azacitidine, months: 9.8
      • Median OS according to
        • o
          RBC-TI: 19.3 vs 9.6 months
        • o
          HI: 18.9 vs 6.0 months
        • o
          CR/SD/PD: 24.7 vs 15.2 vs 2.3 months
      • Parameters associated with worse OS (multivariate): no HI, no (any) response to azacitidine, intermediate or high ‘Itzykson’ prognostic score
        • Itzykson R.
        • Thepot S.
        • Quesnel B.
        • Dreyfus F.
        • Beyne-Rauzy O.
        • Turlure P.
        • et al.
        Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine.
      • Parameters with no effect on OS (multivariate): age, WBC count, BM blasts, number of comorbidities, prior IC
      • c)
        Patients with relapsed/refractory AML
      Maurillo et al.
      • Maurillo L.
      • Venditti A.
      • Spagnoli A.
      • Gaidano G.
      • Ferrero D.
      • Oliva E.
      • et al.
      Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.
      • Patients, n: 47
      • Median age, years (range): 67 (29–81)
      • Cytogenetics, int/poor/fail, %: 66/21/13
      • AML type, p/s/t, %: 60/38/2
      • Median WBC, ×109/L (range): 8.0 (0.60–85)
      • Median blasts,% (range): 30 (20–90)
      • Azacitidine 75 mg/m2/day for 7 days every 4 weeks: 38%
      • Azacitidine 100 mg/day for 7 days every 4 weeks: 62%
      • Median cycles, n (range): 4 (1–22)
      • ORR: 19%
      • CR: 8%
      • CRi: 3%
      • PR: 8%
      • HI: 6%
      • SD: 30%
      • Median DOR, months: 5
      • Median follow up, months: 12
      • Median OS, months: 7
      • 1 year OS, %: 18
      • Median OS in responders, months: 8
      • Median OS in non-responders, months: 7
      BM: bone marrow, CR: complete response, CRi: complete response with incomplete blast recovery, DOR: duration of response, ECOG PS: European Cooperative Oncology Group performance status, HI: hematological improvement, IC: intensive care, IPSS: international prognostic scoring system, LDH: lactate dehydrogenase, mCR: complete marrow response, ORR: overall response rate, OS: overall survival, p: primary, PD: progressive disease, PR: partial response, RBC-TD: red blood cell transfusion dependence, RBC-TI: red blood cell-transfusion independence, rr: relapsed/refractory, s: secondary, SD: stable disease, t: therapy-related, and WBC: white blood cells.
      Table 3Overview of retrospective studies of decitabine in patients with AML.
      StudyBaseline characteristicsTreatmentResponseSurvival
      • a)
        Patients with previously untreated AML
      Gourdin et al.
      • Gourdin T.S.
      • Bhatnagar B.
      • Duffy A.P.
      • Tidwell M.
      • Ning Y.
      • Sausville E.A.
      • et al.
      Disease response and survival outcomes in acute myeloid leukemia (AML) patients unfit for chemotherapy treated with 10-day decitabine as initial therapy [abstract].
      • Patients, n: 32
      • Median age, years (range): 74 (52–86)
      • ECOG PS, ≥2, %: 31
      • Karyotype, unfavorable/int/na, n: 17/14/1
      • Comorbidities, %: 100
      • Decitabine 20 mg/m2/day for 10 days
      • Subsequent 5-day cycles until disease progression if patients attained <5% BM blasts
      • Median cycles, n (range): 2 (1–4)
      • ORR: 31%
      • CR: 28%
      • PR: 3%
      • Median DFS, days (range): 390 (87 + −468+)
      • Median OS, days (range): 180 (15–623+)
      • 6 month OS, %: 37.5
      • 1 year OS, %: 16.5
      • b)
        Patients with previously untreated or relapsed/refractory AML
      Ganetsky et al.
      • Ganetsky A.
      • Adel N.G.
      • Frattini M.G.
      • Maslak P.G.
      • Heaney M.L.
      • Jurcic J.G.
      • et al.
      Decitabine for the treatment of acute myeloid leukemia (AML): Memorial Sloan-Kettering Cancer Center experience [abstract].
      • Patients, n: 60
      • Median age, years (range): 62 (28–80)
      • Prior chemotherapy, y/n, %: 78/22
      • Of patients who received prior chemotherapy:
      • Mean chemotherapy regimens: 2.5
      • Post HCT: 30%
      • Decitabine 20 mg/m2/day for 5 days
      • Overall
      • ORR: 13%
      • CR: 12%
      • PR: 2%
      • Mean cycles to achieve maximal response, n: 3.25
      • Relapsed/refractory AML
      • CR: 8.5%
      • Untreated
      • CR: 23%
      • Not reported
      • c)
        Patients with relapsed/refractory AML
      Fernandez et al.
      • Fernandez A.
      • Shah D.
      • Liu D.
      • Ahmed N.
      • Lulaj E.
      • Seiter K.
      High response rate and prolonged survival in patients with primary refractory acute myelogenous leukemia treated with decitabine salvage therapy [abstract].
      • Patients, n: 9
      • Median age, years (range): 59 (40–83)
      • AML type, primary, % 100
      • Median BM blasts, % (range): 22 (7–73)
      • Cytogenetics, normal/int/poor, n: 2/3/4
      • Decitabine 20 mg/m2/day for 5 days every 4–5 weeks
      • Median cycles, n (range):
        6 (1–12)
      • CR: 56%
      • PR: 22%
      • PD: 22%
      • Median TTP, months (range): 11 (1–20)
      • Median OS, months (range): 12 (10–20)
      George et al.
      • George T.J.
      • Woolery J.E.
      • Wetzstein G.A.
      • Ho V.Q.
      • Lancet J.E.
      • List A.F.
      • et al.
      A Retrospective Study of Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia: Lack of Response Observed In a Heavily Pretreated Population [abstract].
      • Patients, n: 19
      • Median age, years (range): 61 (22–78)
      • All patients had intermediate or poor risk cytogenetics
      • >3 chemotherapy regimens, %: 79%
      • Post HCT, %: 21
      • Decitabine 20 mg/m2/day for 5 days
      • Median cycles, n: 2
      • No patients achieved CR or CRi
      • Discontinuation due to disease progression or death, %: 95
      • Median OS, months: 3.1
      • Mortality at 30 days, n: 0
      CR: complete response, DFS: disease free survival, HCT: hematopoietic stem cell transplantation, ORR: overall response rate, OS: overall survival, PD: progressive disease, PR: partial response, SD: stable disease, and TTP: time to progression.
      Most studies demonstrated that response to azacitidine was strongly associated with prolonged OS.
      • Serrano J.
      • de la Fuent A.
      • Bergua J.
      • et al.
      5-Azacytidine versus intensive chemotherapy or BSC in elderly (>60 years) AML patients: a retrospective analysis [abstract].
      • Sudan N.
      • Rossetti J.M.
      • Shadduck R.K.
      • Latsko J.
      • Lech J.A.
      • Kaplan R.B.
      • et al.
      Treatment of acute myelogenous leukemia with outpatient azacitidine.
      Furthermore, as in the phase II trial, any kind of response to azacitidine appeared to be sufficient to confer a survival advantage. For example, in a study of 128 patients treated with azacitidine, Pleyer et al. demonstrated that achievement of any kind of HI was associated with longer OS than that observed in patients who did not achieve HI (18.9 vs 6.0 months; p < 0.001).
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      Given the heterogeneity of AML, retrospective studies of large cohorts of patients may be invaluable for generating hypotheses regarding the appropriate patient population to be treated with HMA. It is important to note that the retrospective studies listed in Table 2, Table 3 encompassed a wide range of AML patients with diverse risk factor profiles. For example, in patients treated with azacitidine, the following characteristics ranged from: ECOG PS ≥2: 0–67%; secondary AML: 20–51%; poor-risk cytogenetics: 18–55%; median BM blast count: 34–70%. Clearly, many patients included in the retrospective studies had high-risk disease. The impacts of specific disease- and patient-related characteristics on clinical outcome in AML patients treated with azacitidine are discussed below.

      5. Impact of Patient-Related Factors on Treatment Choice in Elderly Patients with AML

      5.1 Age

      Increased age is a negative prognostic factor in patients with AML but should not be considered in isolation. PS and comorbidities must also be considered when deciding treatment.
      • Juliusson G.
      • Antunovic P.
      • Derolf A.
      • Lehmann S.
      • Mollgard L.
      • Stockelberg D.
      • et al.
      Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry.
      Importantly, in several retrospective studies, age per se did not predict OS in AML patients treated with azacitidine.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Bories P.
      • Bertoli S.
      • Huguet F.
      • Dobbelstein S.
      • Fornecker L.
      • Rauzy O.B.
      • et al.
      Efficacy of frontline 5-azacytidine in older AML patients unfit for chemotherapy [abstract].
      The median age of the patients in these studies was ~75 years old, which reflects the typical AML population. Similarly, the median age in the DACO-016 trial was 73 years.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      Most patients in this age range would be deemed ineligible for IC. Furthermore, even in those patients deemed eligible, IC will only benefit approximately a third of those who receive it.
      • Kantarjian H.
      • Ravandi F.
      • O'Brien S.
      • Cortes J.
      • Faderl S.
      • Garcia-Manero G.
      • et al.
      Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia.
      These observations, in addition to disappointing OS in elderly patients treated with LDAC,
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      indicate that HMA could become a promising future treatment option in very elderly patients.

      5.2 Comorbidities

      Comorbidities are highly prevalent in elderly patients and influence treatment decisions.
      • Pollyea D.A.
      • Kohrt H.E.
      • Medeiros B.C.
      Acute myeloid leukaemia in the elderly: a review.
      In AML management, the impact of comorbidities is poorly defined and often complicates treatment decisions. While many comorbidity indices have emerged in oncology, none have been validated on a large scale in the management of elderly patients with AML. Comorbidity scoring could be helpful in identifying subgroups of elderly patients who are likely to tolerate or benefit from IC.
      • Sorror M.L.
      • Maris M.B.
      • Storb R.
      • Baron F.
      • Sandmaier B.M.
      • Maloney D.G.
      • et al.
      Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
      It is encouraging to note that azacitidine appears to be active in elderly patients regardless of comorbidity burden. Pleyer et al. demonstrated that the absolute number of comorbidities had no effect on OS. Furthermore, OS in patients according to low-, intermediate- and high-risk comorbidity scores (based on hematopoietic cell transplantation comorbidity index) was 10.2, 9.0 and 9.7 months, respectively.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      These data suggest that the presence of comorbidities should not lead to a decision to withhold treatment with HMA in favor of BSC in elderly patients with AML.

      5.3 Performance Status

      Performance status (PS) is a frequently used parameter to quantify a patient's activities of daily life, and determine whether the patient is eligible for IC. Patients with PS >2 are often excluded from clinical trials in which patients are to be treated with IC; according to ECOG, it is generally plausible to include patients up to 75 years old with no comorbidities and a PS of 0–1 in such trials.
      • Oken M.M.
      • Creech R.H.
      • Tormey D.C.
      • Horton J.
      • Davis T.E.
      • McFadden E.T.
      • et al.
      Toxicity and response criteria of the Eastern Cooperative Oncology Group.
      HMA might be an option for patients with poor PS. As expected, most studies demonstrated that elevated ECOG-PS was associated with poorer OS in patients treated with azacitidine.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Ramos F.
      • Martinez-Robles V.
      • Bargay J.
      • Deben G.
      • Garrido A.
      • Serrano J.
      • et al.
      Azacitidine as front-line therapy in AML: results from the Spanish National Registry. Alma Study Investigators [abstract].
      Importantly, however, the AZA-AML-001 trial will be stratified according to ECOG-PS and this will determine whether azacitidine offers a survival advantage over conventional treatment options in patients with high ECOG-PS. In the DACO-016 trial, the subgroup of patients with an ECOG-PS of 2, but not 0–1, had significantly improved survival when treated with decitabine versus TC.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.

      6. Impact of Disease-Related Factors on Treatment Choice in Elderly Patients with AML

      6.1 Cytogenetics

      Adverse cytogenetics are associated with poor response rates and shorter survival in patients treated with IC
      • Knipp S.
      • Hildebrand B.
      • Kundgen A.
      • Giagounidis A.
      • Kobbe G.
      • Haas R.
      • et al.
      Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes.
      • Farag S.S.
      • Archer K.J.
      • Mrozek K.
      • Ruppert A.S.
      • Carroll A.J.
      • Vardiman J.W.
      • et al.
      Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461.
      • Frohling S.
      • Schlenk R.F.
      • Kayser S.
      • Morhardt M.
      • Benner A.
      • Dohner K.
      • et al.
      Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B.
      • Grimwade D.
      • Walker H.
      • Harrison G.
      • Oliver F.
      • Chatters S.
      • Harrison C.J.
      • et al.
      The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial.
      and LDAC.
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      With HMA, survival is also superior in patients with intermediate- compared to high-risk cytogenetics.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Bories P.
      • Bertoli S.
      • Huguet F.
      • Dobbelstein S.
      • Fornecker L.
      • Rauzy O.B.
      • et al.
      Efficacy of frontline 5-azacytidine in older AML patients unfit for chemotherapy [abstract].
      Nevertheless, in patients with unfavorable cytogenetics included in the AZA-001 trial, median OS was 12.3 and 5.3 months, respectively, in the azacitidine and CCR arms (p = 0.38). The 2-year OS rate was 38% and 16%, respectively (p = 0.001).
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      In the DACO-016 trial, the survival data were in favor of decitabine compared with TC for patients with poor-risk cytogenetics.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.

      6.2 ‘Proliferative’ AML

      Based on available data it remains unclear whether HMA could potentially be effective in highly proliferative AML. Patients with a white blood cell (WBC) count of ≥15 × 109/L were excluded from AZA-AML-001. In contrast, patients with a WBC count of ≤40 × 109/L were eligible for DACO-016, although the median WBC count of enrolled patients was 3.4 × 109/L (range: 0.3–127.0);
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      only 24% of patients had a WBC count of ≥10 × 109/L. Some retrospective studies have suggested that patients with a WBC count of ≥10 × 109/L benefit less from azacitidine than those with lower WBC counts.
      • Maurillo L.
      • Venditti A.
      • Spagnoli A.
      • Gaidano G.
      • Ferrero D.
      • Oliva E.
      • et al.
      Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.
      Conversely, other studies have found that WBC count did not impact OS in patients with AML treated with azacitidine.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Bories P.
      • Bertoli S.
      • Huguet F.
      • Dobbelstein S.
      • Fornecker L.
      • Rauzy O.B.
      • et al.
      Efficacy of frontline 5-azacytidine in older AML patients unfit for chemotherapy [abstract].
      Furthermore, it is unclear whether a given BM blast threshold has any clinical significance. For example, in several studies, the OS of patients treated with IC was not significantly different in patients with 20–30% blasts compared with patients with >30% blasts.
      • Arber D.A.
      • Stein A.S.
      • Carter N.H.
      • Ikle D.
      • Forman S.J.
      • Slovak M.L.
      Prognostic impact of acute myeloid leukemia classification. Importance of detection of recurring cytogenetic abnormalities and multilineage dysplasia on survival.
      • Bernstein S.H.
      • Brunetto V.L.
      • Davey F.R.
      • Wurster-Hill D.
      • Mayer R.J.
      • Stone R.M.
      • et al.
      Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndrome as defined by French–American–British criteria: a Cancer and Leukemia Group B Study.
      • Estey E.
      • Thall P.
      • Beran M.
      • Kantarjian H.
      • Pierce S.
      • Keating M.
      Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy.
      Likewise, some emerging clinical trial data suggest that HMA are effective in patients with >30% blasts. In DACO-016, decitabine improved survival in patients with >30% blasts.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      Except one study,
      • Ramos F.
      • Martinez-Robles V.
      • Bargay J.
      • Deben G.
      • Garrido A.
      • Serrano J.
      • et al.
      Azacitidine as front-line therapy in AML: results from the Spanish National Registry. Alma Study Investigators [abstract].
      retrospective data have indicated that blast count (>30% vs ≤30%) at baseline did not predict OS in elderly patients treated with azacitidine.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Maurillo L.
      • Venditti A.
      • Spagnoli A.
      • Gaidano G.
      • Ferrero D.
      • Oliva E.
      • et al.
      Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.

      6.3 Type of AML

      Incidence of secondary AML from an antecedent hematological disorder (AHD) or previous exposure to chemotherapy and/or radiation (therapy-related AML), increases with age and is associated with poor outcomes irrespective of age, cytogenetic risk, PS or whether patients receive IC. Even for patients <65 years old treated with IC, median OS is only 7–9 months.
      • Lehmann S.
      • Lazarevic V.
      • Horstedt A.S.
      • Hulegardh E.
      • Nilsson C.
      • Antunovic P.
      • et al.
      Poor outcome in secondary acute myeloid leukemia (AML): a first report from the population-based Swedish Acute Leukemia Registry [abstract].
      It is clear, therefore, that there is an unmet clinical need for new treatment options in secondary AML. Possibilities include HMA and allogeneic hematopoietic stem cell transplantation using reduced-intensity conditioning (HCT-RIC).
      Few data are available regarding the efficacy of HMA in secondary AML. In the DACO-016 trial, 36% of enrolled patients suffered from secondary AML. There was a trend towards improved survival in patients given decitabine versus TC which did not achieve statistical significance.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      In azacitidine studies, 20–51% of patients had secondary AML (Table 2). A recent retrospective study of 26 patients with AML secondary to Philadelphia-negative myeloproliferative neoplasms indicated that azacitidine was associated with a promising response rate of 38% and an OS of 8 months.
      • Thepot S.
      • Itzykson R.
      • Seegers V.
      • Raffoux E.
      • Quesnel B.
      • Chait Y.
      • et al.
      Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).

      7. Impact of Treatment-Related Factors in Elderly Patients with AML

      7.1 Achieving Complete Response

      Irrespective of age, long-term survival of patients with AML treated with IC depends on the ability to clear BM blasts at an early stage and induce a CR.
      • Kern W.
      • Haferlach T.
      • Schoch C.
      • Loffler H.
      • Gassmann W.
      • Heinecke A.
      • et al.
      Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: data from the German AML Cooperative Group (AMLCG) 1992 Trial.
      • Wheatley K.
      • Burnett A.K.
      • Goldstone A.H.
      • Gray R.G.
      • Hann I.M.
      • Harrison C.J.
      • et al.
      A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council's Adult and Childhood Leukaemia Working Parties.
      Similarly, in patients with AML treated with LDAC, OS is strongly associated with achievement of CR.
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      By contrast, one of the observations regarding azacitidine is its apparent ability to offer a survival advantage in elderly patients with AML who achieve any kind of hematological response, regardless of whether CR is achieved.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      In a palliative setting, the translation of any hematological response, not only CR, into improved survival might establish a new paradigm in the treatment of AML, especially in the elderly.

      7.2 Maintenance or Post-Remission Therapy

      Controversies exist regarding the role of post-remission chemotherapy in improving long-term survival in elderly patients with AML. Several studies have indicated that subsequent cycles of induction chemotherapy following achievement of CR offered no benefit to patients.
      • Juliusson G.
      • Antunovic P.
      • Derolf A.
      • Lehmann S.
      • Mollgard L.
      • Stockelberg D.
      • et al.
      Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry.
      • Goldstone A.H.
      • Burnett A.K.
      • Wheatley K.
      • Smith A.G.
      • Hutchinson R.M.
      • Clark R.E.
      Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial.
      • Stone R.M.
      • Berg D.T.
      • George S.L.
      • Dodge R.K.
      • Paciucci P.A.
      • Schulman P.P.
      • et al.
      Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine.
      By contrast, early clinical data suggest that maintenance therapy with azacitidine may benefit some patients with AML, MDS or chronic myelomonocytic leukemia (CMML).
      • Grovdal M.
      • Karimi M.
      • Khan R.
      • Aggerholm A.
      • Antunovic P.
      • Astermark J.
      • et al.
      Maintenance treatment with azacitidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy.
      In a phase II study, 23 patients with AML/MDS/CMML who had reached CR with induction chemotherapy received azacitidine as maintenance therapy; median duration of CR was 13.5 months. Of particular interest was a subgroup of 4 patients with a karyotype including trisomy 8, who all achieved CR with durations of 18–30.5 months. Furthermore, as with MDS,
      • Silverman L.R.
      • Fenaux P.
      • Mufti G.J.
      • Santini V.
      • Hellstrom-Lindberg E.
      • Gattermann N.
      • et al.
      Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes.
      evidence suggests that a proportion of AML patients who respond to azacitidine go on to achieve a better response with continued treatment.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      Also, it is likely that termination of treatment with azacitidine following a response could lead to rapid relapse as has recently been observed in patients with MDS.
      • Voso M.T.
      • Breccia M.
      • Lunghi M.
      • Poloni A.
      • Niscola P.
      • Finelli C.
      • et al.
      Rapid loss of response after withdrawal of treatment with azacitidine: a case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia.
      Indeed, given the reversible nature of epigenetic modifications, it is likely that continuous treatment with azacitidine is required in patients with AML, though this assertion requires substantiation in prospective clinical trials.

      7.3 Relapsed or Refractory AML

      There is no standard of care for relapsed/refractory AML following chemotherapy. The prognosis is generally very poor.
      • Estey E.
      • Dohner H.
      Acute myeloid leukaemia.
      • Breems D.A.
      • van Putten W.L.
      • Huijgens P.C.
      • Ossenkoppele G.J.
      • Verhoef G.E.
      • Verdonck L.F.
      • et al.
      Prognostic index for adult patients with acute myeloid leukemia in first relapse.
      Several retrospective studies have assessed azacitidine in this setting. Some studies have reported superior outcomes in first-line versus relapsed/refractory patients. For example, Maurillo et al. reported an overall response rate (ORR) of 48% vs 19%, respectively, in the two groups (p = 0.006) which translated into an OS of 9 months vs 7 months.
      • Maurillo L.
      • Venditti A.
      • Spagnoli A.
      • Gaidano G.
      • Ferrero D.
      • Oliva E.
      • et al.
      Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program.
      Other studies have demonstrated similar outcomes in first-line versus relapsed/refractory patients treated with azacitidine.
      • Gavillet M.
      • Noetzli J.
      • Blum S.
      • Duchosal M.A.
      • Spertini O.
      • Lambert J.F.
      Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine.
      Results from retrospective studies suggest that decitabine may have limited clinical activity in patients with relapsed/refractory AML. In a study of 47 patients treated with decitabine in a salvage setting, only 4 patients achieved a CR.
      • Ganetsky A.
      • Adel N.G.
      • Frattini M.G.
      • Maslak P.G.
      • Heaney M.L.
      • Jurcic J.G.
      • et al.
      Decitabine for the treatment of acute myeloid leukemia (AML): Memorial Sloan-Kettering Cancer Center experience [abstract].
      Similarly, in a retrospective study of 19 patients with relapsed/refractory AML, no patients achieved CR/CRi and OS was only 3.1 months.
      • George T.J.
      • Woolery J.E.
      • Wetzstein G.A.
      • Ho V.Q.
      • Lancet J.E.
      • List A.F.
      • et al.
      A Retrospective Study of Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia: Lack of Response Observed In a Heavily Pretreated Population [abstract].
      Whether the preclinical observation of cross resistance between decitabine, but not azacitidine, and cytarabine is clinically meaningful is not yet known.
      • Qin T.
      • Jelinek J.
      • Si J.
      • Shu J.
      • Issa J.P.
      Mechanisms of resistance to 5-aza-2′-deoxycytidine in human cancer cell lines.
      In general, the available data suggest that HMA might only have limited activity in the setting of relapsed/refractory AML after chemotherapy. Novel salvage therapies within clinical trials are urgently required.

      7.4 Allogeneic Hematopoietic Cell Transplant (HCT)

      Allogeneic HCT is a potentially curative treatment for some patients with AML.
      • Bacher U.
      • Talano J.A.
      • Bishop M.R.
      Monitoring and prevention of relapse after allogeneic hematopoietic cell transplantation for myeloid malignancies.
      Following the introduction of RIC-HCT, an increasing number of elderly patients is offered such a treatment modality.
      • Aoudjhane M.
      • Labopin M.
      • Gorin N.C.
      • Shimoni A.
      • Ruutu T.
      • Kolb H.J.
      • et al.
      Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT).
      • de Lima M.
      • Giralt S.
      Allogeneic transplantation for the elderly patient with acute myelogenous leukemia or myelodysplastic syndrome.
      • Estey E.
      • de Lima M.
      • Tibes R.
      • Pierce S.
      • Kantarjian H.
      • Champlin R.
      • et al.
      Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
      • Hegenbart U.
      • Niederwieser D.
      • Sandmaier B.M.
      • Maris M.B.
      • Shizuru J.A.
      • Greinix H.
      • et al.
      Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors.
      • Schetelig J.
      • Bornhauser M.
      • Schmid C.
      • Hertenstein B.
      • Schwerdtfeger R.
      • Martin H.
      • et al.
      Matched unrelated or matched sibling donors result in comparable survival after allogeneic stem-cell transplantation in elderly patients with acute myeloid leukemia: a report from the cooperative German Transplant Study Group.
      • Wong R.
      • Giralt S.A.
      • Martin T.
      • Couriel D.R.
      • Anagnostopoulos A.
      • Hosing C.
      • et al.
      Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years.
      Nevertheless, relapse remains an issue.
      • Bacher U.
      • Talano J.A.
      • Bishop M.R.
      Monitoring and prevention of relapse after allogeneic hematopoietic cell transplantation for myeloid malignancies.
      Several studies have shown azacitidine to benefit patients in a post-allogeneic HCT setting as either a maintenance
      • Craddock C.
      • Jilani N.
      • Siddique S.
      • Vyas P.
      • Goodyear O.
      • Dennis M.
      • et al.
      Azacitidine is well tolerated after allogeneic stem cell transplantation and its administration is associated with a reduced risk of acute graft-versus-host disease [abstract].
      • De Lima M.
      • Giralt S.
      • Thall P.F.
      • de Padua S.L.
      • Jones R.B.
      • Komanduri K.
      • et al.
      Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study.
      • Jabbour E.
      • Giralt S.
      • Kantarjian H.
      • Garcia-Manero G.
      • Jagasia M.
      • Kebriaei P.
      • et al.
      Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia.
      • Platzbecker U.
      • Wermke M.
      • Radke J.
      • Oelschlaegel U.
      • Seltmann F.
      • Kiani A.
      • et al.
      Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial.
      or a salvage
      • Jabbour E.
      • Giralt S.
      • Kantarjian H.
      • Garcia-Manero G.
      • Jagasia M.
      • Kebriaei P.
      • et al.
      Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia.
      • Bolaños-Meade J.
      • Smith B.D.
      • Gore S.D.
      • McDevitt M.A.
      • Luznik L.
      • Fuchs E.J.
      • et al.
      5-Azacytidine as salvage treatment in relapsed myeloid tumors after allogeneic bone marrow transplantation.
      • Czibere A.
      • Bruns I.
      • Kroger N.
      • Platzbecker U.
      • Lind J.
      • Zohren F.
      • et al.
      5-Azacytidine for the treatment of patients with acute myeloid leukemia or myelodysplastic syndrome who relapse after allo-SCT: a retrospective analysis.
      • Graef T.
      • Kuendgen A.
      • Fenk R.
      • Zohren F.
      • Haas R.
      • Kobbe G.
      Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine.
      • Lubbert M.
      • Bertz H.
      • Wasch R.
      • Marks R.
      • Ruter B.
      • Claus R.
      • et al.
      Efficacy of a 3-day, low-dose treatment with 5-azacytidine followed by donor lymphocyte infusions in older patients with acute myeloid leukemia or chronic myelomonocytic leukemia relapsed after allografting.
      • Schroeder T.
      • Czibere A.
      • Kroger N.
      • Platzbecker U.
      • Bug G.
      • Uharek L.
      • et al.
      Phase II study of azacitidine and donor lymphocyte infusions as first salvage therapy in patients with acute myeloid leukemia or myelodysplastic syndromes relapsing after allogeneic HSCT: final results of the AZARELA study [abstract].
      therapy. Through an observed expansion of regulatory T-cells, azacitidine might augment the graft-versus-leukemia (GvL) effect without increasing the risk of graft-versus-host disease (GVHD).
      • Goodyear O.C.
      • Dennis M.
      • Jilani N.Y.
      • Loke J.
      • Siddique S.
      • Ryan G.
      • et al.
      Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

      7.5 Quality of Life and Tolerability Considerations

      In a palliative setting, it is essential that a treatment is well tolerated, feasible in an outpatient setting and maintains, or improves, quality of life. Both azacitidine and decitabine have similar safety profiles, which are comparable to that known for LDAC.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Finelli C.
      • Giagounidis A.
      • et al.
      Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.
      The most predominant grade 3/4 AEs are hematological toxicities that are generally manageable by dose delays and/or supportive measures. Pleyer et al. found that the majority of hematological toxicities with azacitidine were documented during early treatment cycles, as is the case in MDS.
      • Pleyer L.
      • Stauder R.
      • Burgstaller S.
      • Schreder M.
      • Tinchon C.
      • Pfeilstocker M.
      • et al.
      Azacitidine in patients with WHO-defined AML: results of 155 patients from the Austrian Azacitidine Registry (AAR) of the AGMT study group.
      • Santini V.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Silverman L.R.
      • List A.
      • et al.
      Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*.
      As expected, the most predominant non-hematological toxicities were gastrointestinal events and injection site reactions. These events were generally mild and managed with standard supportive measures.
      Furthermore, a recent retrospective analysis indicated that azacitidine can induce transfusion independence in ~50% of previously transfusion-dependent patients with AML.
      • Gavillet M.
      • Noetzli J.
      • Blum S.
      • Duchosal M.A.
      • Spertini O.
      • Lambert J.F.
      Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine.
      As well as being a strong prognostic factor for prolonged survival, transfusion independence is likely to improve quality of life.
      • Gavillet M.
      • Noetzli J.
      • Blum S.
      • Duchosal M.A.
      • Spertini O.
      • Lambert J.F.
      Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine.
      Generally, quality of life must be considered a key goal of treatment. Unfortunately, there is a universal paucity in research evaluating quality of life in both curative and non-curative treatment options in elderly patients with AML. For HMA, patient-reported outcomes were studied in patients with MDS treated with azacitidine. Encouragingly, patients in a phase III study experienced significantly improved quality of life parameters (fatigue, dyspnea, physical functioning, positive affect and psychological distress) than patients receiving BSC.
      • Kornblith A.B.
      • Herndon J.E.
      • Silverman L.R.
      • Demakos E.P.
      • Odchimar-Reissig R.
      • Holland J.F.
      • et al.
      Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study.
      Patient-reported outcomes and quality of life assessments are an important endpoint in the AZA-AML-001 study. Thus, these results will help define the exact impact of azacitidine on the quality of life in elderly patients.

      8. Treatment Schedules of Hypomethylating Agents in AML

      It is accepted that the treatment schedule of a drug in a phase III study provides guidance to practitioners in treating patients when this agent is approved later. However, this does not necessarily mean that the issue of dosing is finally settled. For HMA, treatment approaches used in clinical trials for patients with AML have largely been extrapolated from the experience in MDS. This is particularly true for decitabine. In the DACO-016 trial, decitabine was applied at a dose of 20 mg/m2/day for 5 days every 4 weeks,
      • Kantarjian H.M.
      • Thomas X.G.
      • Dmoszynska A.
      • Wierzbowska A.
      • Mazur G.
      • Mayer J.
      • et al.
      Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia.
      Yet, results from a phase II trial with decitabine in elderly patients with AML support the likelihood that a 10 day schedule, with subsequent cycles abbreviated based on response and toxicity could be more effective than the 5 day regimen used in the DACO-016 trial.
      • Blum W.
      • Garzon R.
      • Klisovic R.B.
      • Schwind S.
      • Walker A.
      • Geyer S.
      • et al.
      Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine.
      This issue requires substantiation in prospective clinical trials comparing the two regimens.

      9. Differences in Mechanism of Action Between Azacitidine and Decitabine

      Phase II data and retrospective studies hint that azacitidine and decitabine may have different activities in some AML populations e.g. WHO–AML (20–30%) and relapsed/refractory AML. Mechanisms of action that might underlie possible differences in clinical activities of azacitidine and decitabine have not been defined; however, preclinical comparisons of the two drugs suggest that they have different activities and are non-equivalent agents.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      Based on available data, it is currently unclear whether there is any correlation between the extent of hypomethylation elicited by azacitidine and subsequent clinical response. The evidence from our study
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      and others
      • Fandy T.E.
      • Herman J.G.
      • Kerns P.
      • Jiemjit A.
      • Sugar E.A.
      • Choi S.H.
      • et al.
      Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies.
      • Raj K.
      • John A.
      • Ho A.
      • Chronis C.
      • Khan S.
      • Samuel J.
      • et al.
      CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.
      indicate that changes in methylation with azacitidine therapy do not correlate with clinical response. We found that although treatment with azacitidine rapidly reduced LINE-1 DNA methylation levels (a surrogate of global methylation) within the first cycle, it was the initial degree of methylation, rather than treatment-associated changes, which was found to be indicative of subsequent response.
      • Cross M.
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      • et al.
      Pretreatment Long interspersed element (LINE)-1 methylation levels, not early hypomethylation under treatment, predict hematological response to azacitidine in elderly patients with acute myeloid leukemia.
      Similarly, reduction in the methylation at the p15CDKN2B locus following azacitidine treatment did not correlate with response in patients with MDS.
      • Raj K.
      • John A.
      • Ho A.
      • Chronis C.
      • Khan S.
      • Samuel J.
      • et al.
      CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.
      Conversely, a recent phase I study assessing oral azacitidine in patients with MDS,
      • Garcia-Manero G.
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      • Kambhampati S.
      • Scott B.L.
      • Tefferi A.
      • Cogle C.R.
      • et al.
      Safety and Efficacy of Oral Azacitidine (CC-486) Administered in Extended Treatment Schedules to Patients with Lower-Risk Myelodysplastic Syndromes.
      indicated that extent of hypomethylation correlated with response.
      Currently, it is also unclear whether response to decitabine correlates with changes in methylation. Some studies suggest that early epigenetic changes predict clinical response in patients with AML treated with decitabine. For example, Yang et al. demonstrated that methylation levels of Alu repeats, LINE-1 and total genomic DNA were significantly decreased within 5 days of treatment with decitabine in patients with AML; reduced methylation correlated with response.
      • Yang A.S.
      • Doshi K.D.
      • Choi S.W.
      • Mason J.B.
      • Mannari R.K.
      • Gharybian V.
      • et al.
      DNA methylation changes after 5-aza-2′-deoxycytidine therapy in patients with leukemia.
      Similarly, in a recent study, decitabine-mediated hypomethylation of several tumor-suppressor genes, including p15CDKN2B, correlated with subsequent clinical response within the first cycle of treatment.
      • Yan P.
      • Frankhouser D.
      • Murphy M.
      • Tam H.H.
      • Rodriguez B.
      • Curfman J.
      • et al.
      Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia.
      Overall, however, it is not yet clear whether decitabine and azacitidine have different effects on DNA hypomethylation in clinical studies which could reflect functional differences between the two agents.
      A key difference between azacitidine and decitabine is that the former, being a ribonucleoside, is incorporated into both RNA and DNA; decitabine, on the other hand, is a deoxyribonucleoside and is only incorporated into DNA.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      In preclinical studies in mice, it was estimated that 80–90% of azacitidine becomes incorporated into RNA; the remaining 10–20% is incorporated into DNA.
      • Li L.H.
      • Olin E.J.
      • Buskirk H.H.
      • Reineke L.M.
      Cytotoxicity and mode of action of 5-azacytidine on L1210 leukemia.
      In human AML cell lines, approximately 65% of azacitidine appears to incorporate into RNA.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      Therefore, the conventional description of azacitidine as a DNA hypomethylating agent may be an oversimplification, overlooking potential additional mechanisms of activity mediated via incorporation into newly synthesized RNA, including ribosomal RNA (rRNA), transfer RNA (tRNA), messenger RNA (mRNA) and microRNAs. Studies performed in the 1970s and 1980s demonstrated that azacitidine may alter the processing of tRNAs and rRNAs, leading to inhibition of protein synthesis.
      • Cihak A.
      • Weiss J.W.
      • Pitot H.C.
      Characterization of polyribosomes and maturation of ribosomal RNA in hepatoma cells treated with 5-azacytidine.
      • Lu L.J.
      • Randerath K.
      Mechanism of 5-azacytidine-induced transfer RNA cytosine-5-methyltransferase deficiency.
      • Reichman M.
      • Penman S.
      The mechanism of inhibition of protein synthesis by 5-azacytidine in HeLa cells.
      However, this is a largely understudied area of research. Nevertheless, possibly due to dual effects on DNA hypomethylation and protein synthesis, azacitidine appears to have multiple effects on cells.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      • Qiu X.
      • Hother C.
      • Ralfkiaer U.M.
      • Sogaard A.
      • Lu Q.
      • Workman C.T.
      • et al.
      Equitoxic doses of 5-azacytidine and 5-aza-2′deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome.
      • Schaefer M.
      • Hagemann S.
      • Hanna K.
      • Lyko F.
      Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines.
      In fact, previous studies have indicated that azacitidine rapidly (within 4–8 h) elicits cell death in AML cell lines, and this predominantly occurs during the G-1 phase of the cell cycle (when cells are not actively dividing).
      • Gorczyca W.
      • Gong J.
      • Ardelt B.
      • Traganos F.
      • Darzynkiewicz Z.
      The cell cycle related differences in susceptibility of HL-60 cells to apoptosis induced by various antitumor agents.
      • Murakami T.
      • Li X.
      • Gong J.
      • Bhatia U.
      • Traganos F.
      • Darzynkiewicz Z.
      Induction of apoptosis by 5-azacytidine: drug concentration-dependent differences in cell cycle specificity.
      These observations indicate that the cytotoxic effects of azacitidine are not restricted to actively dividing cells (S phase) and, therefore, may be related to RNA-mediated mechanisms. Decitabine also leads to cell cycle arrest and cell death.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      However, incorporation of decitabine into DNA is restricted to cells in S-phase (Fig. 3). Azacitidine's potential to kill cells independently of the cell cycle may be important because only a proportion of hematopoietic stem cells in the BM are actively dividing at any given time.
      • Silverman L.R.
      • Fenaux P.
      • Mufti G.J.
      • Santini V.
      • Hellstrom-Lindberg E.
      • Gattermann N.
      • et al.
      Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes.
      Furthermore, RNA-mediated effects on cell viability may occur more rapidly than DNA-mediated effects, which require cell division for passive reduction of DNA methylation to occur. For example, azacitidine-mediated inhibition of protein synthesis in vitro occurred within 24 h in human AML cell lines (which is within the doubling time of these cells).
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      These rapid changes could potentially explain the rapid anti-leukemia activity of azacitidine that has been observed in some trials.
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      Decitabine-mediated re-expression of tumor suppressor genes, such as p15INK4b, takes up to 72 h in culture.
      • Paul T.A.
      • Bies J.
      • Small D.
      • Wolff L.
      Signatures of polycomb repression and reduced H3K4 trimethylation are associated with p15INK4b DNA methylation in AML.
      Another difference between azacitidine and decitabine is that azacitidine has a greater effect on global gene expression.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      At this point, it is worth mentioning that several caveats remain to be considered in interpreting these results. The sometimes conflicting data might reflect differences in treatment schedules, loci assessed, the techniques used to quantify methylation and time-points at which samples were taken in relation to treatment. The target cells under investigation represent a further critical point. Most of the studies were conducted on relatively heterogeneous populations of blood or bone marrow cells. Thus, dynamic methylation changes under treatment with HMA at a cellular level could not be distinguished from those occurring at the population level as a result of selective death of cells with a particularly high or low level of methylation.
      Figure thumbnail gr3
      Fig. 3Impact of azacitidine and decitabine on the cell cycle. Both incorporate into replicating DNA during the S phase. However, it is thought that azacitidine is also incorporated into RNA which can occur at any stage of the cell cycle.
      Adapted from Morgan DO. The cell cycle: principles of control. New Science Press, Sunderland, MA; 2007.
      Finally, the effects of HMA on cell viability cannot be accounted for solely by epigenetic mechanisms. Evidence suggests that a dose-dependent mechanism of action for both HMA exist. The hypomethylation-mediated effect on gene re-expression is demonstrated at low doses while inhibition of cell proliferation (decitabine) and cytotoxicity (azacitidine) is observed at high doses.
      • Hollenbach P.W.
      • Nguyen A.N.
      • Brady H.
      • Williams M.
      • Ning Y.
      • Richard N.
      • et al.
      A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines.
      Currently, there is no direct clinical evidence to confirm whether differences in mechanism of action translate into differences in clinical activity. This could only be addressed by translational studies and head-to-head prospective trials. However, as the RNA-mediated effects of azacitidine are beginning to be unraveled, specific molecular pathways that underlie possible differences between the two drugs in the clinic are being identified. For example, recent work has demonstrated that azacitidine reduces levels of ribonuclease reductase (RR), a rate-limiting enzyme in DNA synthesis. Although not fully understood, it is thought that this phenomenon may be the result of azacitidine destabilizing the mRNA of one the of RR's subunits. It is possible that this mechanism underlies the activity of the azacitidine in patients with AML.
      • Aimiuwu J.
      • Wang H.
      • Chen P.
      • Xie Z.
      • Wang J.
      • Liu S.
      • et al.
      RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia.
      Characterization of differences in the mechanism of action of azacitidine and decitabine at the molecular level may, ultimately, guide treatment decisions in individual patients.

      10. Summary and Future Perspectives

      Given that the incidence of AML (and indeed secondary AML) increases with age,
      • National Cancer Institute SEER Cancer Statistics Review 1975–2009
      most patients are deemed unsuitable for, or decline, intensive treatment options,
      • Menzin J.
      • Lang K.
      • Earle C.C.
      • Kerney D.
      • Mallick R.
      The outcomes and costs of acute myeloid leukemia among the elderly.
      and outcomes following intensive treatment are poor,
      • Jabbour E.J.
      • Estey E.
      • Kantarjian H.M.
      Adult acute myeloid leukemia.
      there is a major unmet medical need for well-tolerated treatment options that can improve survival and quality of life in elderly patients with AML.
      Owing to their acceptable tolerability profiles, and emerging evidence of clinical efficacy, HMA may provide an exciting new approach to the treatment of elderly patients, either as monotherapy or in combination regimens with other agents/approaches including histone deacetylase inhibitors, immunomodulatory drugs like lenalidomide, cytotoxics or allogeneic HCT. In the European Union (EU), the recent approval of decitabine for the treatment of elderly patients (≥65 years old) with AML will certainly provide a much needed treatment option for patients who are not candidates for IC. However, the phase III DACO-016 data need to be interpreted with caution, given that the trial did not achieve its primary endpoint and it was not designed as a non-inferiority trial. On the other hand, concerns regarding the efficacy of decitabine are, in part, mitigated by its favorable tolerability profile and the dearth of other treatment options in this setting.
      Clinical evidence demonstrates that azacitidine has promising activity in patients with AML. It is already licensed for patients with 20–30% blasts (for whom it confers a survival benefit)
      • Fenaux P.
      • Mufti G.J.
      • Hellstrom-Lindberg E.
      • Santini V.
      • Gattermann N.
      • Germing U.
      • et al.
      Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia.
      and phase II data/retrospective studies suggest that it is active and well tolerated in patients with >30% BM blasts,
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      including those with relapsed/refractory AML.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      • Thepot S.
      • Itzykson R.
      • Seegers V.
      • Raffoux E.
      • Quesnel B.
      • Chait Y.
      • et al.
      Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM).
      • Gavillet M.
      • Noetzli J.
      • Blum S.
      • Duchosal M.A.
      • Spertini O.
      • Lambert J.F.
      Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine.
      Furthermore, azacitidine appears to prolong survival in patients with AML without the achievement of CR.
      • Al-Ali H.K.
      • Jaekel N.
      • Junghanss C.
      • Maschmeyer G.
      • Krahl R.
      • Cross M.
      • et al.
      Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study.
      Owing to these findings, data from the AZA-AML-001 trial are eagerly awaited to define the role of azacitidine in the treatment of AML in the elderly.
      How does the accumulating evidence of the clinical activity of HMA change the treatment landscape for elderly patients with AML? Indeed, these developments do not render intensive treatment options obsolete. The previously discussed survival data and limitations of HMA must be considered carefully (the DACO-016 study did not meet its primary end point of improved survival with decitabine and the results of the phase III AZA-AML-001 trial are yet unavailable).
      Thus, wherever possible, both curative and non-curative treatment options should be offered within clinical trials. If this is not feasible, patients and care-givers need to be made absolutely clear of the risk–benefit profiles of (where applicable) IC, LDAC, HCT and HMA. Evidence suggests that elderly patients often confuse curative and non-curative approaches, highlighting the need for thorough counseling between physician and patient, so that the latter can make an informed choice on their preferable approach.
      • Sekeres M.A.
      • Steensma D.P.
      Boulevard of broken dreams: drug approval for older adults with acute myeloid leukemia.
      Therefore, before embarking on a HMA-based treatment regimen, it is essential that goals of therapy are clearly elucidated. Both patient- and disease-related prognostic factors that may indicate, or preclude, IC or LDAC such as age, comorbidity burden, PS, cytogenetics and likelihood of CR need to be considered in decision making.
      • Burnett A.K.
      • Milligan D.
      • Prentice A.G.
      • Goldstone A.H.
      • McMullin M.F.
      • Hills R.K.
      • et al.
      A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment.
      • Knipp S.
      • Hildebrand B.
      • Kundgen A.
      • Giagounidis A.
      • Kobbe G.
      • Haas R.
      • et al.
      Intensive chemotherapy is not recommended for patients aged >60 years who have myelodysplastic syndromes or acute myeloid leukemia with high-risk karyotypes.
      • Farag S.S.
      • Archer K.J.
      • Mrozek K.
      • Ruppert A.S.
      • Carroll A.J.
      • Vardiman J.W.
      • et al.
      Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461.
      • Frohling S.
      • Schlenk R.F.
      • Kayser S.
      • Morhardt M.
      • Benner A.
      • Dohner K.
      • et al.
      Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B.
      • Grimwade D.
      • Walker H.
      • Harrison G.
      • Oliver F.
      • Chatters S.
      • Harrison C.J.
      • et al.
      The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial.
      Furthermore, recent developments suggest that molecular profiling of aberrations such as NPM1 and DNMT3A mutations, and MLL translocations, could identify patients who are most likely to benefit from a certain treatment or dose intensity.
      • Patel J.P.
      • Gonen M.
      • Figueroa M.E.
      • Fernandez H.
      • Sun Z.
      • Racevskis J.
      • et al.
      Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.
      • Schlenk R.F.
      • Dohner K.
      • Krauter J.
      • Frohling S.
      • Corbacioglu A.
      • Bullinger L.
      • et al.
      Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.
      • Itzykson R.
      • Thepot S.
      • Quesnel B.
      • Dreyfus F.
      • Beyne-Rauzy O.
      • Turlure P.
      • et al.
      Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine.
      Our approach is to discuss in depth with the patients the possibilities available. We suggest a curative treatment option (IC and/or HCT) in patients with no contraindications or a non-curative approach within a trial. If clinical studies are not feasible and based on our experience, we recommend azacitidine in patients with BM blasts 20–30%. If blasts are >30%, we advice either LDAC or decitabine based on cytogenetics. We must reiterate that there are no direct head-to-head data available at the moment to make objective comparisons between azacitidine and decitabine. Nevertheless, it may well be that further molecular and translational studies, aimed at fully understanding the mechanism of action of the two drugs, could drive treatment choices in specific subgroups of patients.
      One additional perspective merits mentioning. HMA and IC are not necessarily mutually exclusive. Indeed, in vitro data suggest a possible synergistic effect of cytarabine and azacitidine when azacitidine is administered before cytarabine probably through the induction of deoxycytidine kinase by azacitidine which phosphorylates cytarabine to its active compound, ara-CTP.
      • Neil G.L.
      • Berger A.E.
      • Bhuyan B.K.
      • DeSante D.C.
      Combination chemotherapy of L1210 leukemia with 1-beta-D-arabinofuranosylcytosine and 5-azacytidine.
      • Kong X.B.
      • Tong W.P.
      • Chou T.C.
      Induction of deoxycytidine kinase by 5-azacytidine in an HL-60 cell line resistant to arabinosylcytosine.
      Yet, clinical data to the safety, efficacy, and optimal scheduling of HMA and chemotherapy in acute leukemias are very limited. In 17 pediatric patients with relapsed acute lymphoblastic leukemia after high-dose cytarabine, treatment with azacitidine followed by another course of high-dose cytarabine yielded a complete remission in two of 9 evaluable patients in a phase I-study.
      • Avramis V.I.
      • Mecum R.A.
      • Nyce J.
      • Steele D.A.
      • Holcenberg J.S.
      Pharmacodynamic and DNA methylation studies of high-dose 1-beta-D-arabinofuranosyl cytosine before and after in vivo 5-azacytidine treatment in pediatric patients with refractory acute lymphocytic leukemia.
      Recently, a pilot trial in elderly patients with newly diagnosed AML which assessed the safety of azacitidine added to standard induction and consolidation therapy was published. The authors concluded that the combination of azacitidine 75 mg/m2 with standard induction therapy was feasible and this combination selected as an investigational arm in a randomized phase-II study, which is currently halted due to an increased cardiac toxicity in the experimental arm.
      • Krug U.
      • Koschmieder A.
      • Schwammbach D.
      • Gerss J.
      • Tidow N.
      • Steffen B.
      • et al.
      Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia — a randomised SAL pilot study.
      Another clinical trial is evaluating an initial priming with azacitidine and a sequential, response-adapted application of induction chemotherapy in elderly patients with AML (DRKS00004519). Thus, integrating both options in well-designed trials might further optimize outcome even in younger patients.
      In summary, there is strong preclinical rationale, and clinical data, to support the use of HMA in elderly patients with AML. The AZA-AML-001 trial will be instrumental in indicating azacitidine's role in this setting and will determine whether it can provide an additional option to decitabine in this area of unmet medical need.

      Disclosures and Conflict of Interest Statements

      H.K.A. has received research funding and honoraria from Celgene ; N.J. has nothing to declare; D.N. is a member of the Speakers Bureau of Celgene.

      Author Contributions

      Concept and Design: H.K. Al-Ali
      Data Collection: H.K. Al-Ali, N. Jaekel
      Analysis and Interpretation of Data: H.K. Al-Ali, D. Niederwieser
      Manuscript Writing and Approval: H.K. Al-Ali, N. Jaekel, D. Niederwieser

      Acknowledgments

      The authors would like to acknowledge the writing assistance of Lynn Pritchard of FireKite during the development of this manuscript. Medical writing support for this manuscript was funded by Celgene International.

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