Pilot Study Of Erlotinib In Patients With Acute Myeloid Leukemia

Preclinical data suggest “off-target” efficacy of EGFR tyrosine kinase inhibitor erlotinib in MDS and AML by inducing apoptosis and promoting differentiation in myeloblasts (Boehrer et al., Blood, 2008). The cytotoxic effect of erlotinib on leukemic myeloblasts ex vivo occurs at concentrations below the plasma levels achievable with regular dosing of this drug. Two case reports, in literature, of patients with concomitant AML and lung cancer, treated with erlotinib and demonstrated AML response, corroborate these findings. The exact targets of erlotinib in MDS/AML are unknown but inhibition of SRC family kinases, Syk, mTOR, and drug efflux system has been suggested. Since normal CD34+ bone marrow cells are not affected by this agent, and no myelosuppression is seen in patients taking erlotinib, clinical application of this drug for the treatment of MDS/AML seems attractive. Clinical studies testing efficacy of erlotinib in MDS are undergoing. We report a pilot study of administration of erlotinib in AML.

This was a single-institution pilot study. The study was approved by scientific review committee and IRB. All patients signed informed consent. Eligibility included a confirmed diagnosis of AML per WHO classification (>20% blasts), no pre-existing history of MDS, newly diagnosed disease in patients older than 70 or relapsed disease in younger patients unfit for chemotherapy or refractory disease at any age. All cytogenetics and molecular profile categories were eligible. An ECOG performance status of 0-3 was acceptable. WBC count had to be less than 20,000/cumm, and hydroxyurea or other therapies to be discontinued at least 14 days prior to treatment; therefore, patients with high proliferative rate disease were excluded. Smokers were excluded due to potential diminished erlotinib plasma concentration with cigarette smoking. Drugs with potential interaction with erlotinib metabolism were not allowed. Erlotinib was given orally at 150 mg per day continuously in 28-day cycles. Bone marrow at baseline was evaluated for morphology, cytogenetics, flow-cytometry, and molecular profile (FLT3, NPM1, CEBPA mutations). CD34+ cells were separated from bone marrow aspirates taken at baseline, day 3-4, and day 8+1 of treatment, and frozen/banked for future correlative studies. Response was evaluated by bone marrow examination after each cycle. A flow-cytometry was performed on the bone marrow aspirate after the first cycle to be compared with baseline, specifically for evidence of differentiation. Given possibility of “slow/delayed response” with erlotinib, patients were planned to continue at least 3 cycles of treatment in the absence of disease progression or toxicity. Assessment of overall response was the primary endpoint of the study.

Between August 2010 and August 2012, a total of 11 patients were treated on this study at Indiana University Simon Cancer Center. One patient had relapsed AML, and 1 had relapsed/refractory disease; 9 patients were older than 70 with newly diagnosed AML. Two patients with newly diagnosed AML demonstrated modest response with the first cycle of treatment, with reduction of bone marrow blasts from 89% and 88% to 71% and 73%, respectively, but both experienced disease progression subsequently. Nine other patients had progression of the disease without any response. Of these, 6 completed at least one cycle of treatment, and 3 were taken off study earlier due to disease progression (per peripheral blood blast count) and clinical deterioration. None of the patients with circulating blasts showed meaningful response by total WBC or absolute peripheral blood blast count. Flow-cytometry of bone marrow aspirate following the first cycle compared to pre-treatment sample did not show evidence of differentiation in any of the 8 patients who completed at least one cycle of therapy. None of the patients experienced drug-related toxicity.

This pilot study, which enrolled mostly older AML patients with newly diagnosed disease, did not demonstrate clinical response to erlotinib monotherapy when administered continuously at 150 mg per day. No evidence of differentiation was observed in AML blasts after 4 weeks of therapy. The treatment was well tolerated without drug-related adverse events.

No relevant conflicts of interest to declare.