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BackgroundTreatment options in older acute myeloid leukaemia (AML) patients include intensive chemotherapy, best supportive care (BSC), and hypomethylating agents. Currently, limited data is available on hypomethylating agents in older AML patients in unselected patient populations.MethodsTo compare the effectiveness of azacitidine with conventional therapy, we collected data of 227 consecutive AML patients (≥60 years) who were treated with azacitidine (N = 26), intensive chemotherapy (N = 90), or BSC (N = 97).ResultsAzacitidine-treated patients were older and had more comorbidities, but lower white blood cell- and bone marrow blast counts compared with intensive chemotherapy patients. Complete or partial response was achieved in 42% of azacitidine-treated patients and in 73% of intensive chemotherapy patients (P = 0.005). However, the overall survival (OS) was similar (1-year-OS 57% versus 56%, P = 0.93; 2-year-OS 35% versus 35%, P = 0.92), and remained similar after correction for risk factors in a multivariate analysis. Patients treated with BSC had an inferior OS (1-year- and 2-year-OS 16% and 2%, P < 0.001). Compared to intensive chemotherapy, azacitidine-treated patients spent less days in the hospital (median in first three months 0.5 versus 56, P < 0.001), and needed less red blood cell and platelet transfusions (median per month 2.7 versus 7, P < 0.001 and 0.3 versus 5, P < 0.001) in the first three months.ConclusionsAzacitidine treatment is associated with a comparable OS but higher tolerability in a subgroup of older AML patients compared with intensive chemotherapy. Patients receiving BSC had a poor prognosis.

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Epidermal growth factor receptor (EGFR) inhibitor erlotinib, has been shown to induce complete remission of acute myeloid leukemia (AML) in two patients with concurrent lung cancer, suggesting a prominent role for EGFR in AML. However, EGFR expression analysis in AML is poorly defined and the role of EGFR in AML is still unclear. In this study, we determined the EGFR protein expression in different human AML cell lines and studied the impact of EGFR inhibition by canertinib on the AML cell survival, proliferation, apoptosis and their downstream signaling routes. Using flowcytometry, we have shown that total EGFR as well as the phosphorylated residue Tyr1068 is expressed in five out of the eight AML cell lines (range of 4.9-46.6% for total and phosphorylated EGFR). EGFR phosphorylation was found to be induced by EGF stimulation, which could be prevented by canertinib treatment, showing functional activity and specificity of the EGFR phosphorylation site. Canertinib was shown to decrease the AML cell survival sufficiently (at a median IC50 of 6.2 μM, range: 0.9 - 15.2 μM canertinib in n=8 AML cell lines) as measured by WST-1 assays. The lower cell survival was the net result of lower numbers of mitotic phospho-histone H3 positive cells and an increase in the number of Annexin V positive cells. Immunoblot analysis revealed that canertinib treatment (5uM) reduced the phosphorylation of Akt and Erk intracellular proteins downstream of the EGFR signaling pathway in AML cells. Long-term canertinib treatment (5uM) showed that downstream targets were re-activated after 24 hours, which suggest kinomic reprogramming by alternative escape mechanisms compensating for the loss of EGFR activity. These findings suggest encouraging possibilities for targeting EGFR as a therapeutic strategy in AML. Future studies are necessary to determine the exact mechanism through which EGFR activity might contribute to AML progression, relapses as well as to interact with possible escape mechanisms of AML cells. Citation Format: Ellen R. Scheepers, Kim R. Kampen, Eveline SJM de Bont. Inhibition of EGFR activity reduces AML cell survival via inhibition of downstream Akt and Erk signaling pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2772. doi:10.1158/1538-7445.AM2013-2772

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