Azacitidine in Patients with Relapsed/Refractory Acute Myeloid Leukemia : Retrospective Analysis of the Austrian Azacitidine Registry

Background

The prognosis of patients with relapsed/refractory acute myeloid leukemia (AML) following intensive chemotherapy (IC) is poor; furthermore, treatment options for these patients are limited. Few studies have assessed outcomes of azacitidine (AZA) in a relapsed/refractory setting.^1–3 Response rates and survival in these studies have been variable.

Methods

The Austrian AZA Registry was initiated to gain a comprehensive view of the use, safety and efficacy of AZA in a broad range of ‘real-life’ AML patients. The sole inclusion criteria were the diagnosis of AML according to World Health Organization (WHO) criteria and treatment with ≥1 dose of AZA. Here, we assess clinical outcomes in patients with newly diagnosed AML (AZA 1^st line) vs patients with relapsed/refractory AML following IC and/or low-dose chemotherapy/other disease-modifying therapy (AZA ≥2^nd line).

Results

Baseline characteristics were generally comparable between patients treated with AZA 1^st line (n=170) and AZA after IC (n=127), or AZA ≥2^nd line (n=176), respectively (Figure 1). However, pre-treated patients had a significantly lower proportion of patients younger than 75 years (18.9 and 29.0 vs 59.4% for AZA after IC [p<0.001] and AZA ≥2^nd line vs AZA 1^st line [p=0.001], respectively; Figure 1), as well as a lower proportion of myelodysplastic syndrome (MDS)-related features (48.0 and 54.6 vs 71.2% for AZA after IC [p=0.003] and AZA ≥2^nd line vs AZA 1^st line [p=0.048], respectively; Figure 1) than patients treated with AZA 1^st line.

Median time from initial diagnosis to AZA treatment was shorter for patients treated with AZA 1^st line than AZA after IC or ≥2^nd line (0.5, 9.2 and 7.8 months, respectively). Median number of cycles was higher for patients who received AZA 1^st line than AZA after IC or ≥2^nd line (6 [range 1–46], 3 [range 1–27] and 3 [range 1–35], respectively). Time from AZA stop to death was 1.8 months for the AZA 1^st line and ≥2^nd line cohorts, and 2.1 months for patients receiving AZA after IC.

There was no significant difference in overall response rate (ORR) according to International Working Group (IWG) 2003 criteria⁴ (complete response [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR]) in patients treated with AZA 1^st line compared with pre-treated patients (24.4 and 22.2 vs 35.9% for AZA after IC [p=0.139] and AZA ≥2^nd line vs AZA 1^st line [p=0.072], respectively; Figure 1). Furthermore, rates of hematologic improvement (HI) according to IWG 2006 criteria⁵ were also similar (53.2 and 51.0 vs 63.3% for AZA after IC [p=0.349] and AZA ≥2^nd line vs AZA 1^st line [p=0.250], respectively; p=0.463; Figure 1). When ORR and rate of HI were combined, the difference remained non-significant (Figure 1).

Median overall survival (OS) was significantly higher with AZA 1^st line than AZA after IC (12.8 vs 7.6 months, p=0.005) or ≥2^nd line (12.8 vs 6.0 months, p<0.001; Figures 1, 2a and 2b). Relapse-free survival was 8.9, 9.1 and 9.0 months for AZA 1^st line, AZA after IC and ≥2^nd line, respectively. In univariate analyses, baseline factors that significantly affected OS in patients who received AZA as ≥2^nd line therapy were peripheral blood blast count >0% (p=0.01), lactate dehydrogenase >225IU/L (p=0.012), and poor-risk cytogenetics (according Medical Research Council [MRC] criteria; p=0.011).

Conclusion

This study represents the largest cohort of relapsed/refractory AML patients treated with AZA, comprising almost four times as many patients (n=176) than the largest cohorts reported to date (n=47). Despite a shorter OS than patients treated with AZA 1st line, response rates in patients who received AZA as a ≥2^nd line therapy were encouragingly high and similar to response rates of AZA 1^st line patients. Median OS of 7.6 months in relapsed patients or those who are refractory to IC, which generally confers a dismal prognosis (median OS: ~3 months),^6,7 is promising. Thus, salvage therapy with AZA is a treatment option for patients with relapsed/refractory AML, which should be further pursued in clinical trials.

<1. Maurillo L, et al. Cancer 2012;118:1014–22

<2. Al-Ali HK, et al. Leuk Lymphoma 2011;53:110–7

<3. Ivanoff S, et al. Am J Hematol 2013;88:601–5

<4. Cheson BD, et al. J Clin Oncol 2003;21:4642–9

<5. Cheson BD, et al. Blood 2006;108:419–25

<6. Ferrara F, et al. Haematologica 2004;89:998–1008

<7. Roboz G, et al. J Clin Oncol 2014;32:1919–26

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