Azacitidine in Acute Myeloid Leukemia: Comparison of Patients with AML-MRF Vs AML-NOS Enrolled in 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

Background

Few data exist reporting the incidence of World Health Organization (WHO)-defined acute myeloid leukemia (AML) subgroups in adults in Europe,1 but the incidence of AML with myelodysplastic-related features (MRF) may be higher than initially reported.2–4 Whether the presence of multilineage dysplasia has an independent prognostic impact in AML is still controversial.5,6 However, AML patients with preceding myelodysplastic syndrome (MDS)/myeloproliferative neoplasm and/or MDS-related cytogenetics (Medical Research Council [MRC]) have been shown to have poorer survival than AML-not otherwise specified (NOS).7 Previous studies of AML patients treated with azacitidine (AZA) included AML-MRF patients, but did not report on outcomes separately.3,4, 8–12

Methods

Due to the lack of data assessing the prognostic impact of AML-MRF in elderly AML patients treated with AZA, we analyzed patients with AML-MRF from the Austrian AZA Registry, which was initiated to gain a comprehensive view of the safety and efficacy of AZA in ‘real-life’ patients. Similar to the approach taken by others who assessed the effect of AML-MRF irrespective of treatment modality,7 patients with AML and recurrent cytogenetic abnormalities (RCA), and treatment-related AML (tAML) based on the WHO 2008 classification13 were excluded, as these subsets have particularly good (AML-RCA) or dismal prognosis (tAML), respectively.

Results

The AML-MRF group comprised 217 patients (AZA 1st line, n=121; AZA ≥2nd line, n=96) and the AML-NOS group comprised 90 patients (AZA 1st line, n=33; AZA ≥2nd line, n=57). Baseline characteristics were comparable except AML-MRF patients had worse Hematopoietic Cell Transplant Comorbidity Index (HCT-CI) scores and a higher proportion of high-risk cytogenetics (Figure 1). The latter is expected as most high-risk cytogenetic abnormalities are defined as MDS-related.13 Median time from diagnosis to AZA start was <1 month for AZA 1st line and >6 months for AZA ≥2nd line.

The median number of AZA cycles was 4 (range 1–35) for AML-MRF patients and 4.5 (range 1–46) for AML-NOS patients.

The overall response rate (ORR)14 was similar for AML-MRF vs AML-NOS patients (complete response [CR] + CR with incomplete blood count recovery [CRi] + partial response [PR]: 29.0 vs 33.3%, respectively; p=0.586). Rates of hematologic improvement15 were similar for AML-MRF vs AML-NOS patients (57.9 vs 57.4%; p=0.964). Median duration of response was 7.0 vs 5.5 mo, respectively. ORR was similar for AML-MRF and AML-NOS patients irrespective of AZA treatment line (Figure 1).

Median overall survival (OS) for AML-MRF vs AML-NOS patients was 9.4 vs 9.7 mo for the total cohort (p=0.490; Figure 2), and 13.1 vs 10.8 mo for patients treated with AZA 1st line. For responding patients, median OS, response duration and relapse-free survival were numerically longer for AML-MRF than AML-NOS patients within the total cohort (17.1 vs 12.6; 7.0 vs 5.5; and 9.8 vs 8.5 mo), and even more so in the AZA 1st line cohort (19.7 vs 12.6; 7.4 vs 3.9; and 10.5 vs 7.9 mo). In univariate analyses, baseline factors that significantly negatively impacted OS in AML-MRF patients treated with AZA were peripheral blood blasts >0% (p=0.025), Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 (p=0.004), >3 comorbidities (p=0.004), and poor cytogenetics (p=0.001). Notably, none of these factors showed statistical significance for AML-NOS patients.

Conclusions

This represents the first and largest report comparing outcomes of AML-MRF vs AML-NOS patients treated with AZA. Outcomes of AML-MRF patients were similar to patients with other AML-NOS subgroups. AZA seems a feasible treatment option for these patients despite the reported poor prognostic impact of MRF.

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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:Janssen-Cilag: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Lang:Celgene: Consultancy. Sperr:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Phadia: Research Funding. Valent:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, 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.