Research Papers:

The mTOR inhibitor everolimus in combination with azacitidine in patients with relapsed/refractory acute myeloid leukemia: a phase Ib/II study

Peter Tan, Ing Soo Tiong, Shaun Fleming, Giovanna Pomilio, Nik Cummings, Mark Droogleever, Julie McManus, Anthony Schwarer, John Catalano, Sushrut Patil, Sharon Avery, Andrew Spencer and Andrew Wei _

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Oncotarget. 2017; 8:52269-52280. https://doi.org/10.18632/oncotarget.13699

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Peter Tan1, Ing Soo Tiong1,2, Shaun Fleming1, Giovanna Pomilio2, Nik Cummings3, Mark Droogleever4, Julie McManus3, Anthony Schwarer5, John Catalano6, Sushrut Patil1, Sharon Avery1, Andrew Spencer1,2 and Andrew Wei1,2

1Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia

2Australian Centre for Blood Diseases, Monash University, Melbourne, Australia

3Department of Pathology, Alfred Hospital, Melbourne, Australia

4Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands

5Eastern Health Clinical School, Monash University, Box Hill, Australia

6Clinical Haematology, Frankston Hospital, Frankston, Australia

Correspondence to:

Andrew Wei, email: andrew.wei@monash.edu

Keywords: acute myeloid leukemia, everolimus, azacitidine, mTOR, clinical trial

Received: October 21, 2016     Accepted: November 20, 2016     Published: November 29, 2016


Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5–21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1–5 and 8–9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21). Major adverse events (grade > 2) were mostly disease-related: neutropenia (73%), thrombocytopenia (67%), mucositis (24%) and febrile neutropenia (19%). Overall survival (OS) of the entire cohort was 8.5 months, and overall response rate (ORR; including CR/CRi/PR/MLFS) was 22.5%. Furthermore, a landmark analysis beyond cycle 1 revealed superior OS and ORR in patients receiving 2.5 mg everolimus with azoles, compared to those without azoles (median OS 12.8 vs. 6.0 months, P = 0.049, and ORR 50% vs. 16%, P = 0.056), potentially due to achievement of higher everolimus blood levels. This study demonstrates that everolimus in combination with azacitidine is tolerable, with promising clinical activity in advanced AML.

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