Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care

Abstract

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51–0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31–46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

“…Treatment of patients with TP53-mutated AML remains challenging. Non-intensive therapies with hypomethylating agents-azacitidine and decitabine-are frequently offered, especially to elderly patients [48,49]. These drugs show acceptable response rates and favorable toxicity profiles.…”

Clonal selection in therapy‐related myelodysplastic syndromes and acute myeloid leukemia under azacitidine treatment

“…Median number of cycle was 10 (range 3-15). Median OS was 15 months (range, [12][13][14][15][16][17][18][19][20][21][22].…”

“…11,12 Response rates for AZA treatment of t-MN are similar to de novo MDS but were associated with shorter survival. [13][14][15][16] The genetic landscape of MDS/AML has been extensively studied with driver mutations involving transcription factors, signal transduction proteins, epigenetic modifiers, and components of RNA splicing. [17][18][19] Notably, the molecular architecture in patients with therapy-related disease is distinct from de novo myeloid neoplasms.…”

Clinical update on hypomethylating agents

“…A subgroup analysis of the AZA-001 trial focusing on low-blast count AML [19], and a large randomized phase III trial in elderly AML patients with bone marrow blast counts > 30% showed that AZA improved survival compared to conventional care in older AML patients deemed ineligible for intensive chemotherapy [20]. The survival benefit was particularly apparent in high-risk subgroups with adverse cytogenetics or myelodysplasia-related changes [21]. DAC showed activity in older patients with poor/intermediate risk, but failed to improve survival when compared to best supportive care or low-dose AraC [22].…”