Phase II Study of Bortezomib as a Single Agent In Patients with Relapsed/Refractory or De Novo Acute Myeloid Leukemia Unfit for Intensive Therapy

Abstract 4360

In spite of significant therapeutic improvements over the last 15–20 years approximately 20% of adult patients with acute myeloid leukemia (AML) is refractory and up to 60–70% relapses following front-line chemotherapy. Refractory/relapsed AML has a very unfavorable prognosis and novel agents are needed to improve outcome for these patients. Bortezomib is a potent inhibitor of the 26S proteasome which has been found to inhibit AML blast survival and interfere with the interaction between AML progenitors and microenviromental niche. The present study was designed to explore the safety and efficacy of Bortezomib given as single agent at the unconventional dose of 1.5 mg/m2, to patients with AML, unfit for conventional chemotherapy or with relapsed/refractory disease, after previous lines of therapy. Thirteen patients have been included in the study, being 10 evaluable. Nine males and 4 females, median age 70 (range 60–78), 4 and 1 cases were de novo and secondary AML, respectively. Six and 2 patients had refractory and relapsed disease, respectively. Bortezomib 1.5 mg/m2 was given on day 1,4,8 and 11 of each 21 day cycle, for a maximum of 8 cycles. Bone marrow samples were collected at baseline and, for response evaluation, on day 1 of each cycle. Three of 13 patients died early due to pulmonary infection. Among the remainder, we observed 5 haematological improvement (HI) defined as a reduction of peripheral blast count < 25% as compared to baseline and a Hb level increase by 2 gr/dL. One patient had a stable disease lasting for 3 months, the remaining 4 patients had a rapid progressive disease. Median number of delivered cycles until progression was 3 for patients with HI, whereas patients with progression were able to receive no more than 1 course of bortezomib. Median overall survival of patients with HI/stable disease was 4 months (range 3–8) versus 2 (range 1–2) of those with progression. Of 10 evaluable patients, 6 developed peripheral neuropathy which was NCI-CTC grade 4 in 2 (neurological bladder, requiring permanent catheterization in 1 instance) and grade 1–2 in 4. In the last, neuropathy resolved promptly after bortezomib discontinuation. In conclusion, bortezomib does have anti-leukemic activity and future clinical trials should focus on its combination with conventional chemotherapy. In this context, a dose reduction would be desirable due to neurologic complications observed in our study.