Azacitidine in Patients with Relapsed/Refractory Acute Myeloid Leukemia : Retrospective Analysis of the Austrian Azacitidine Registry
Authors: Pleyer Lisa , Burgstaller Sonja , Stauder Reinhard , Girschikofsky Michael , Linkesch Werner , Pfeilstöcker Michael , Autzinger Eva Maria , Tinchon Christoph , Sliwa Thamer , Lang Alois , Sperr Wolfgang R. , Geissler Dietmar , Krippl Peter , Voskova Daniela , Rossmann Dieter H. , Schlick Konstantin , Thaler Josef , Halter Britta , Machherndl-Spandl Sigrid , Theiler Georg , Valent Peter , Eckmüllner Otto , Greil Richard 
Published: October 2019

Abstract
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 1st line) vs patients with relapsed/refractory AML following IC and/or low-dose chemotherapy/other disease-modifying therapy (AZA ≥2nd line).
Results
Baseline characteristics were generally comparable between patients treated with AZA 1st line (n=170) and AZA after IC (n=127), or AZA ≥2nd 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 ≥2nd line vs AZA 1st 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 ≥2nd line vs AZA 1st line [p=0.048], respectively; Figure 1) than patients treated with AZA 1st line.
Median time from initial diagnosis to AZA treatment was shorter for patients treated with AZA 1st line than AZA after IC or ≥2nd line (0.5, 9.2 and 7.8 months, respectively). Median number of cycles was higher for patients who received AZA 1st line than AZA after IC or ≥2nd 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 1st line and ≥2nd 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 1st line compared with pre-treated patients (24.4 and 22.2 vs 35.9% for AZA after IC [p=0.139] and AZA ≥2nd line vs AZA 1st 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 ≥2nd line vs AZA 1st 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 1st line than AZA after IC (12.8 vs 7.6 months, p=0.005) or ≥2nd 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 1st line, AZA after IC and ≥2nd line, respectively. In univariate analyses, baseline factors that significantly affected OS in patients who received AZA as ≥2nd 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 ≥2nd line therapy were encouragingly high and similar to response rates of AZA 1st 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.
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<7. Roboz G, et al. J Clin Oncol 2014;32:1919–26
Figure 1 Figure 1.
Figure 2 Figure 2.

Disclosures
Pleyer: Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Celgene: Consultancy, Honoraria. Off Label Use: Vidaza (azacitidine) is indicated for the treatment of adult AML patients who are not eligible for haematopoietic stem cell transplantation with 20–30 % blasts and multi-lineage dysplasia, according to WHO classification. This cohort also includes AML-patients with >30% bone marrow blasts.. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Celgene: Consultancy. Stauder:Novartis: Research Funding; Ratiopharm: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Girschikofsky:Pfizer: Honoraria, Research Funding; Mundipharm: Consultancy, Honoraria. Pfeilstöcker:Novartis: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Phadia: Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Valent:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Greil:Sanofi Aventis: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Janssen-Cilag: Honoraria; Merck: Honoraria; Mundipharma: Honoraria, Research Funding; Eisai: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; GSK: Research Funding; Ratiopharm: Research Funding.