Addition of Bortezomib (Velcade) to AML Induction Chemotherapy Is Well Tolerated and Results in a High Complete Remission Rate.

In vitro experiments have shown that the addition of a proteasome inhibitor to an anthracycline results in synergistic cytotoxicity to leukemia cells and, specifically, the leukemia stem cell. Hence, we initiated this phase I study to determine if the proteasome inhibitor, bortezomib, could be safely added to conventional treatment for acute myeloid leukemia (AML). Eligibility was restricted to patients ≥ 18 with relapsed disease after a remission of at least 3 months and patients ≥ 60 without prior treatment for AML. All patients were required to have an ECOG performance status of 0–3 and adequate cardiac, renal, and hepatic function. Patients with ≥ grade 2 peripheral neuropathy prior to enrollment were excluded. All patients received idarubicin 12 mg/m² on days 1–3 and cytarabine 100 mg/m² by continuous infusion days 1–7. Bortezomib was added to this regimen on days 1, 4, 8, and 11 by IV bolus. Cohorts of 3–6 patients were treated with the following doses of bortezomib: 0.7, 1.0, 1.3, and 1.5 mg/m². An additional 6 patients were to be treated at the candidate maximally tolerated dose (MTD). Dose limiting toxicities (DLTs) were defined as prolonged myelosuppression, severe neuropathy, and other grade 3 or 4 toxicities. Dose escalation was permitted if < 2 DLTs were experienced in 3–6 patients at a given dose level. The study is now closed, with 30 patients entered and 24 patients evaluable at this time. The age range was 42–75 years, with a median of 65. There were 13 males and 11 females. Of these patients, 16 were ≥ 60 with previously untreated AML, of whom 4 had a prior history of MDS or MPD, 4 were ≥ 60 with relapsed AML, and 4 < 60 with relapsed AML. Among the first 6 patients treated at 0.7 mg/m², there was 1 DLT consisting of prolonged neutropenia. In the second cohort of 6 patients treated with 1.0 mg/m² bortezomib, there was 1 DLT consisting of prolonged thrombocytopenia. No DLTs were encountered in 9 patients treated with 1.3 mg/m² bortezomib. Because the MTD had not been reached, an additional cohort assessing 1.5 mg/m² bortezomib was added. Three patients have completed treatment at this dose and no DLTs were experienced; a final 6 patients are currently undergoing treatment. There have been no significant neurologic or cardiac toxicities. There was one death within the first 45 days of protocol treatment. This occurred in the setting of febrile neutropenia in a patient previously transplanted for AML who received 1.5 mg/m² bortezomib. Of the first 24 patients, 14 (58%) achieved complete remission (CR), 3 achieved remission without complete recovery of platelet count (CRp), 3 achieved a partial remission (6–24% BM blasts), and 4 patients failed to respond. In conclusion, bortezomib was well tolerated up to 1.3 mg/m² in this regimen and this combination produced an encouraging remission frequency in this population of patients. A phase II study of this combination will proceed in the cooperative group setting.