Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia

Abstract

We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75 mg/m² daily on days 1–7. Bortezomib was dose escalated from 0.7 mg/m² on days 2 and 5 to 1.3 mg/m² on days 2, 5, 9 and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1–12+). Five of 23 patients achieved remission, including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously treated patients with AML.

Keywords::

• Relapsed AML
• bortezomib
• azacitidine

Acknowledgements

The authors thank all of the patients who participated in this trial as well as the dedicated nurses and nurse practitioners who cared for them in the James Cancer Hospital inpatient/outpatient Leukemia Units and the Clinical Treatment Unit. This work was supported by: NIH/NCI K23CA120708 (W.B.), K12CA133250 (J.C.B. and A.W.), CA102031 (G.M.). A.W. is a Paul Calabresi Clinical Scholar and a scholar of the American Society of Hematology-Harold Amos Medical Faculty Development Program. Support was also provided by Celgene Corporation and Millennium, Inc.

Potential conflict of interest:

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