Azacitidine in Older Patients with Acute Myeloid Leukemia (AML) and Adverse Karyotype. Subanalisis from the Alma Study
Authors: Falantes Jose , Deben Guillermo , Martinez Robles Violeta , Bargay Joan , Salamero Olga , Pedro Carmen , Redondo Santiago , Garrido Ana , Bergua Juan Miguel , Tormo Mar , Xicoy Blanca , Font Patricia , González-López Tomás José , Ramos Fernando 
Published: October 2019

Background

Adverse karyotype and age are associated with poor prognosis in older AML patients (pts). Although complete remission (CR) can be achieved with intensive chemotherapy (IC) in pts with adverse cytogenetics, overall survival (OS) and leukemia free-survival (LFS) are poor (Knipp S, et al. Cancer 2007). In addition, low doses of ARA-C (LDAC) did not offer survival benefit in older pts with poor cytogenetics as compared to hydroxyurea and best supportive care (BSC) (Burnett A, et al. Cancer 2007). Azacitidine has shown a survival advantage in older pts with newly diagnosed AML in a recent phase 3 trial, as compared to conventional care regimens (BSC/LDAC/IC)(Dombret H, et al. EHA 2014).

Aim

To evaluate the role of azacitidine and factors associated with OS in pts with newly diagnosed AML and adverse karyotype from the ALMA study (Ramos F, et al. Blood 2012;120:abstract 3593).

Methods

Retrospective, multicenter study, of pts with newly diagnosed AML and adverse karyotype who received front-line azacitidine in Spain. Response to azacitidine was evaluated by ELN-2010 criteria. Overall survival was evaluated by Kaplan-Meier method and log-rank test.

Results

Thirty-nine pts were identified. Median age: 71y (52-83). Baseline characteristics are shown in table 1. All pts received azacitidine (75 mg/m2 sc x7 days) as first line treatment. Median time from AML diagnosis to therapy was 16 days (1-88). 56% of pts had bone marrow (BM) blasts >30% at diagnosis (median: 32%; range: 20-90). Five out of 39 (13%) pts had leucocyte count (WBC) >15x109/L and 20/39 (51%) had ECOG performance status >1. Complex karyotype (CK) and monosomal karyotype (MK) was present in 18/39 pts each (46%). Within the subset showing CK, 14/18 (78%) had MK. Complete remission (CR) and CRi was 23.1% and 5.1% respectively (ORR=28.2%). Median courses of therapy to best response: 3 (1-11). After 17m median follow-up, median OS (95% CI) was 7m (3.1-8.8). Estimated 1-year survival was 29.8%. There were no differences in median OS in pts with MK vs. rest of pts with CK (median OS 9m [95% CI: 5.3-12.6] vs. 6.5m [3.1-8.8], respectively; p=0.854). Monosomal karyotype, CK with >5 abnormalities, BM blasts >30% and ECOG status >1 did not achieve statistically significance in multivariate analysis. Only WBC at baseline (>10x109/L or >15x109/L; threshold not relevant) had an impact on OS in both univariate (3m [95% CI: 4.9-13] vs. 9m [4.9-13] if WBC <10x10e /L; p=0.014) and multivariate analysis (HR=3.3, [95% CI 1.1-9.5], p=0.025; Table 2). Most frequent causes of death were disease progression and infection (82%).Table 2Multivariate analysis for survivalParameterHR95% CIp-valueWBC >10x109/L3.341.17-9.580.025BM blast >30%1.080.46-2.540.855MK0.950.33-2.740.919CK1.610.58-4.510.361ECOG >11.840.81-4.170.144

Conclusion

Albeit retrospective and non-comparative, azacitidine seems to improve median and 1y survival as compared to historic AML data in pts with adverse cytogenetics. An elevated WBC >10x109/L at diagnosis was the only parameter associated to adverse outcome in this set of pts.Table 1Baseline characteristicsAge, median (range)71 (52-83)ECOG performance status 0-1 2-319 (48.7%) 20 (51.3%)WBC (x109/L), median (range) WBC >10x109/L, N (%)2.2 (0.9-89.2) 5 (12.8%)BM blasts, median; (range) BM blasts >30%, N (%)32 (20-90) 22(56.4%)Complex karyotype (CK), N (%)18 (46.2)Monosomal karyotype (MK), N (%)18 (46.2%)Both CK and MK, N (%)14/18 (77.8%)Prior MDS, N (%)11 (28.2%)Karyotype, N (%) Complex >3 Complex >5 Chrom 7 abn Chrom 3 abn -7 only Chrom 5 and 7 abn Chrom 5 abn Other6 (15.4%) 11 (28.2%) 4 (10.3%) 4 (10.3%) 8 (20.5%) 2 (5.1%) 2 (5.1%) 2 (5.1%)*Excludes pts with chromosome 5 and 7 abnormality

Disclosures

Falantes: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count >30% This paper deals with both on-label and off-label use of azacitidine in AML. Xicoy:Celgene: Honoraria. Ramos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.