Azacitidine in patients with WHO-defined AML – Results of 155 patients from the Austrian Azacitidine Registry of the AGMT-Study Group

Acute myeloid leukemia (AML) is an aggressive disease with an unfavorable prognosis [1, 2]. Only approximately 1/3 of elderly AML-patients are eligible for intensive chemotherapeutic approaches. Results remain poor and unsatisfactory, even for those who do meet inclusion criteria for such treatment (induction mortality of up to 29%; 2 year OS 6-11%) [3‐5]. Patients not suitable for intensive chemotherapy due to high age, comorbidities, poor performance status and/or adverse cytogenetics, or who have failed these treatment options, are frequently offered best supportive care (BSC) only [6], and the prognosis is dismal [7]. Other treatment options such as low-dose cytarabine, topotecan, gemtuzumab ozogamicin, clofarabine, cloretazine, or tipifarnib have not been promising [8‐14]. Treatment options for AML-patients with >30% BM-blasts unfit/ineligible for intensive chemotherapeutic approaches are particularly limited, as hypomethylating agents were not approved for this patient group. Only very recently has decitabine been granted EMA-, but not FDA-approval for the treatment of WHO-AML patients aged 65 or older who are not candidates for standard induction chemotherapy (http://​www.​ema.​europa.​eu/​ema/​index.​jsp?​curl=​pages/​medicines/​human/​medicines/​002221/​human_​med_​001589.​jsp%26;mid=​WC0b01ac058001d1​24).

Azacitidine (Vidaza®) received FDA-approval for MDS and AML with 20-30% BM-blasts in 2004 based on the results of several CALGB-trials [15]. EMA-approval for HR-MDS and AML with 20-30% BM-blasts was granted in 2008 following the pivotal AZA-001 trial [16]. In a subset-analysis, azacitidine was shown to prolong OS in elderly AML-patients with 20-30% BM-blasts [17].

The Austrian Azacitidine Registry (AAR) (ClinicalTrials.gov: NCT01595295) comprises 155 AML-patients who did not qualify for intensive chemotherapeutic approaches in most cases, and is currently the largest cohort of AML-patients treated with azacitidine published to date, with the highest per capita coverage of AML-patients in a nationwide registry, suggesting limited selection (Additional file 1: Tables S1 and S2). The aim was to include most AML-patients treated with azacitidine in Austria, and to gain a comprehensive view of the use, safety and efficacy of the drug in a broad range of WHO-defined AML, including patients with >30% bone marrow blasts, who have limited other therapeutic options, and for whom the drug has not been approved yet.

With 155 AML-patients included in the AAR and 8.4 million inhabitants, this is the highest per capita coverage of AML-patients in a nationwide registry, suggesting limited selection. The per capita inclusion of AML-patients into our national registry (18.9 per million inhabitants) is the largest as compared to data from other countries that has so far been published (0.06-6.58 per million inhabitants) (Additional file 1: Table S1) [15, 17, 21‐26]. The number of AML diagnoses per year, as well as the number of AML-patients included in the respective year for Austria in general and Salzburg in particular, is presented in Additional file 1: Table S2 (data obtained from Statistics Austria, personal communication 14.03.13). The percentage of patients in the MRC cytogenetic high-risk category is 17% in our AML cohort, which seems less than the proportion of cytogenetic high-risk AML-patients reported in several, but not all previously published smaller AML-cohorts treated with azacitidine (Additional file 1: Table S1). Cumulating evidence suggests that patients with high-risk cytogenetics respond poorly to conventional chemotherapeutic approaches, and that these patients especially may be candidates for hypomethylating treatment. Therefore, according to our understanding, patients with high-risk cytogenetics should be overrepresented, -rather than underrepresented-, in underrepresented-, in our registry, if an explicit selection bias concerning cytogenetic risk categories were present.

Median age, age range, pretreatment cytogenetic risk groups, azacitidine schedule and median azacitidine cycles are comparable to those documented in much smaller AML-patient-subsets (n = 20-82) in almost all previously published clinical trials and observational data so far (Additional file 1: Table S1) Therefore we believe that selection bias is minimized, both with respect to the choice of AML-patients for azacitidine treatment, as well as for the decision to include the patients in the registry (Additional file 2: Figure S2A).

The most common hematologic and non-hematologic adverse events, and the rates thereof are almost identical to previously published data from controlled trials as well as retrospective analyses [16, 27]. CR/mCR-, as well as HI-rates are comparable to, -and PR-rates slightly higher than-, the rates obtained in smaller series (n = 20-82) of AML-patients treated with azacitidine by others [15, 17, 21‐25]. Due to higher PR-rates, the overall response rate (Table 2) is one of the highest documented for AML-patients treated with azacitidine so far.

Median OS of elderly AML-patients is still low, irrespective of treatment modality. Conventional chemotherapy and other treatment options such as low-dose cytarabine, topotecan, gemtuzumab ozogamicin, clofarabine, cloretazine, tipifarnib, or laromustine show median OS rates of 2.0-6.7 months [7‐13, 28‐31]. In comparison, AML-patients with 20-30% blasts (formerly RAEB-t) treated with BSC only (n = 223; median age 73a) had a median OS of 5.2 months in a recent update of the Düsseldorf MDS registry data (U.Germing, personal communication, 17/09/2012). This is similar to 5.0 months OS of AML-patients randomized to best supportive care or low-dose cytarabine in a recent phase-III trial of untreated AML [32]. Therapy-naïve AML-patients (n = 242) randomized to decitabine in the same trial had a median OS of 7.7 months, which led to a positive opinion by EMA, with formal approval expected soon [32]. Previous reports of much smaller series of AML-patients treated with azacitidine documented median OS rates of 3, 7–9, 2.5-15, 8, 6–16 and 8.8 months, respectively [21‐25, 30]. (The reports giving OS-ranges did not separate the OS of AML- and MDS-patients explicitly). In light of the above, our OS results of 9.8 months are encouraging. Only two subanalysis of randomized clinical trials (CALGB-9211 (n = 27), AZA-001 (n = 55)) reported longer OS than observed in our cohort [17, 33]. The authors of the latter stated that this is likely due to exclusion of patients with an estimated life expectancy <3 months, ECOG-PS >2, t-AML, prior treatment, or planned allogeneic SCT [16, 17]. Overall, 61% of our registry population would have been excluded from this trial due to these reasons alone; if BM-blast count >30% is also taken into account, 90% would have been excluded. We thus consider our OS data to be remarkable, particularly since they were observed in a real-life AML-patient cohort, not selected or restricted by stringent inclusion/exclusion-criteria, and in which most patients had no other treatment option than azacitidine.

Significantly longer OS was observed in patients achieving any kind of response, be it marrow response, achievement of RBC/PLT-TI, or HI (Figures 1 and 2c, Additional file 1: Table S5). Similar results have been shown in smaller AML-patient cohorts (n = 11) treated with azacitidine [34]. Others, who did not analyze the HI-rate in their AML-cohorts (n = 25-55, BM-blasts 20-30%), also noted, that azacitidine can provide survival benefit, despite a low CR-rate [17], a finding which is similar to that seen in high-risk MDS-patients [16]. However, it is for the first time shown in multivariate analysis, that response in terms of HI alone, without requirement of concomitant BM-blast reduction, seems sufficient to confer longer OS in AML-patients treated with azacitidine (18.9 vs. 6.0 months) (Figure 1). If the commonly used AML response criteria [20] were to be applied, patients who experience HI without simultaneous BM-blast reduction would be considered as having neither CR nor PR, and thus as non-responders, with the result that treatment with azacitidine would/might be discontinued. In our opinion these patients should be considered as responders, and should continue to receive azacitidine until unambiguous clinical progression (i.e. renewed transfusion dependence and/or stark reduction of general performance).

We show for the first time in AML-patients treated with azacitidine, that further deepening of response after first response, i.e. achievement of BM-blast reduction in terms of PR or (m)CR after HI, seems to translate into significantly longer OS, compared with patients for whom first response was best response (Figures 1 and 2d, Additional file 1: Table S5). Similar results have been shown for MDS-patients treated with azacitidine [16, 35]. Therefore, in analogy to recommendations for MDS [35, 36], these data support the continued use of azacitidine in responding AML-patients.

It is possible, that a larger percentage of AML-MRF and t-AML may be present in our registry-population (Table 1). However, very little recent data is available on the incidence of all WHO-AML-subgroups in adults in Europe [37], and the recently published phase-III trial comparing decitabine vs. conventional care regimen also had a high percentage (35%) of secondary-AML [30]. In any case, t-AML is known to be associated with dismal prognosis [38], and AML-patients with preceding MDS/MPN and/or MDS-related cytogenetics (MRC) were shown to have worse OS than AML-NOS [39].

Our registry population includes many elderly and very old patients: 22% aged 75–79, 15% aged 80–84 and 8% ≥ 85 years, respectively; many of these very old patients would previously have been treated with best supportive care only. Importantly, age had no adverse effect on OS, irrespective of whether a cut-off of </≥75 (Additional file 1: Table S4) or </≥80 years was chosen (Figure 2a). In addition, only 40% of patients were untreated prior to azacitidine, whereas 39%, 7% and 6% were pretreated with conventional chemotherapy, low-dose cytarabine or ‘imids’, respectively (Table 1). In light of all of the above, we consider our response and OS results particularly relevant.

The absolute number of comorbidities had no adverse effect on OS. Accordingly, the HCT-CI [40], which is based on the number and weighting of comorbidities, could not discriminate patient-groups with different OS (Additional file 1: Table S4), whereas the ECOG-PS [41], which is based on the patient’s ability to cope with activities of everyday life, could (Figure 1, Additional file 1: Table S5). In our opinion, high age and presence of comorbidities should not lead to a decision to withhold treatment of azacitidine in favor of BSC, if the patient has an ECOG-PS < 2.

Azacitidine seems effective in AML, irrespective of BM-blast count (Additional file 1: Table S4, Figure 2b). Lack of correlation between survival and median pre-treatment BM-blast count has previously been reported in WHO-AML-patients (n = 40) [21]. We believe, that AML-patients with >30% BM-blasts should not be precluded from treatment with azacitidine.

Interestingly, patients experiencing hematologic toxicity grade 3–4 in any, one, several, or all cell lineages had significantly better OS (Figure 1). In clinical practice it is important to note that AML-patients may develop a worsening of cytopenia(s) during the first two months prior to azacitidine response, but this does not seem to be associated with an increased rate of infection or hemorrhage [14, 15]. In fact, even when occurring, these events did not negatively impact OS in our cohort, and neither did non-hematologic toxicity, nor duration of adverse events (Additional file 1: Table S4). The majority of grade 3-4 hematologic adverse events were documented during early treatment cycles, suggesting that (a) patient tolerance to azacitidine increases as treatment continues, (b) a certain amount of aplasia-induction seems necessary before response occurs, and (c) likely reflects the fact that most patients respond after cycle 3. Patients in whom azacitidine dose had to be reduced due to an adverse event even had improved OS in univariate analyses. This effect was however lost in multivariate analysis. It seems fair to state that dose reductions were possible without negative impact on OS. We deduct that the occurrence of adverse events should not lead to permanent treatment discontinuation with azacitidine in most cases. Azacitidine should be continued as planned whenever possible, if necessary with dose reduction or treatment pause.

Achievement of the FDA-approved target-dose of 75 mg/m²×7 days did not have a significant effect on OS, and neither did the predominantly applied schedule (Additional file 1: Table S4). Similar results have been shown by others for MDS [27, 40]. Concerning OS of responding patients only (n = 70), it made no relevant difference which regimen or dose was used in the first cycle, or which regimen or dose was predominantly used over all cycles (Additional file 1: Table S4). The 5-2-2 regimen and/or dose reductions, be it in days (d1-5) and/or dose per day (100 mg flat), seem feasible, safe, and without loss of efficacy. In spite of the impression of non-inferiority of alternative schedules and dosages demonstrated by our data, we still recommend initiation of azacitidine in the FDA-approved dosage and regimen.

We acknowledge the limitations of data obtained from a registry and are fully aware, that clinical trials may not be substituted, but only complemented by these. If adequate in size and analyzed carefully, registry data can be of value in supplementing or extending data from trials. The strength of this manuscript lies in the size of the documented patient group, that allows statistical generation of hypothesis, which may be assessed by clinical trials in due time. It was our explicit intention and the design of the registry not to select patients, but in contrast to obtain a widespread view of the use, toxicity and effects of azacitidine in a real-world clinical setting. We believe this is substantiated by the following facts:

We moderately hypothesize and suggest, that our rather ‘aggressive’ initiation of treatment, irrespective of comorbidities, bone marrow blast count, age or pre-treatment, as well as the ‘persistent’ continuation of treatment with azacitidine once the drug was commenced (i.e. treatment until overt clinical progression, rather than mere laboratory signs of progression such as stable or slightly rising blast counts in blood or bone marrow) might play a part in our results, although this cannot directly be proven by the data as presented.

In conclusion, azacitidine seems to be well tolerated and efficacious in WHO-AML-patients in a real-world non-trial clinical setting. The observed median OS of 9.8 months in this largely pretreated cohort including 66% of patients with bone marrow blasts >30% is encouraging. We confirm the previously reported non-essentiallity of CR for prolongation of OS in our cohort of AML-patients treated with azacitidine. In our opinion, age >80, number of comorbidities, and/or bone marrow blasts >30% should not preclude patients from treatment with this drug, which should be continued as long as response is durable, and onset of overt clinical progression occurs.