Phase II Study of Bortezomib Added to Standard Daunorubicin and Cytarabine Induction and Dose Escalation of Bortezomib with Intermediate-Dose Cytarabine Consolidation Therapy for Patients with Previously Untreated Acute Myeloid Leukemia Age 60–75 Years: Cancer and Leukemia Group B (CALGB) Study 10502

Abstract 331

We previously demonstrated that bortezomib can be safely added to induction chemotherapy in patients with AML. We conducted a clinical trial in order to determine (a) the complete remission (CR) frequency in older patients treated with bortezomib plus daunorubicin and cytarabine induction chemotherapy and (b) the maximal tolerated dose (MTD) of bortezomib added to intermediate-dose cytarabine consolidation chemotherapy.

Adults ages 60–75 with previously untreated, including therapy-related, AML received bortezomib 1.3 mg/m² on days 1, 4, 8 and 11 with daunorubicin 60 mg/m²/day on days 1–3 and cytarabine100 mg/m²/day by continuous IV infusion on days 1–7. A bone marrow biopsy was conducted on day 18. For patients with residual disease, reinduction, consisting of identical doses of daunorubicin on days 1 and 2, cytarabine days 1–5, and bortezomib days 1 and 4, was administered. The phase II induction portion of this trial was designed to discriminate between true CR rates of no more than 45% versus at least 65%. If at least 25 CRs (at least 56%) were observed among the 45 evaluable patients, the regimen was to be considered worthy of further testing. A two-stage design was employed, which yielded greater than 90% power to detect a true response rate of at least 65%. There was at least a 0.91 probability of a negative result if the true response rate was no more than 45%, with at least 0.69 probability of early negative stopping.

Patients who achieved a CR or partial remission received consolidation chemotherapy consisting of cytarabine 2 gm/m²/day over 3 hours on days 1–5 (Int-DAC). Bortezomib was administered on days 1, 4, 8 and 11. Three cohorts of escalating dose levels of bortezomib were tested (0.7, 1.0, and 1.3 mg/m²). Patients could receive up to two courses of consolidation. Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation and were defined as grade 3 or 4 neurotoxicity, prolonged grade 4 myelosuppression, or any ≥ grade 3 toxicity that did not resolve to at least grade 2 by day 42.

A total of 98 patients were enrolled. Of the first 45 patients, 30 (67%) patients achieved CR, thereby excluding a true CR incidence of < 45%. Thirteen patients required reinduction. There were 7 deaths during induction among the first 45 (16%) patients of which two were considered treatment-related, caused by infection. Grade 3 and 4 non-hematologic and non-infectious toxicities observed in at least 10% of patients consisted of rash (18%), anorexia (16%), diarrhea (13%), nausea (13%), sensory neuropathy (13%), fatigue (11%), and systolic dysfunction (11%). Of the 98 patients, there were 13 (13%) deaths during induction of which 6 were considered treatment-related.

In consolidation, there were no DLTs within the first two 3-person cohorts treated with bortezomib 0.7 and 1.0 mg/m². One of the first 3 patients treated with Int-DAC and bortezomib at 1.3 mg/m² sustained a DLT consisting of grade 3 sensory neuropathy. There were no DLTs in the second cohort of 3 patients treated with bortezomib at 1.3 mg/m² and Int-DAC. Thus, an additional 11 patients were treated with 1.3 mg/m² in consolidation. Grade 3 and 4 non-hematologic and non-infectious toxicities observed in at least 10% of patients consisted of rash (14%), diarrhea (13%), and pain (13%).

Among the first 45 patients treated with induction and the 23 patients assessed for DLT in consolidation, overall grade 3 and 4 neurotoxicities were sensory neuropathy (13%), motor neuropathy (7%), confusion (2%), mood alteration (2%), cranial neuropathy (2%), somnolence (2%), and syncope (2%). There were no grade 3 or 4 pulmonary toxicities observed and no deaths during consolidation within the patient cohorts assessed for DLT.

In conclusion, the addition of bortezomib 1.3 mg/m² on days 1, 4, 8, and 11 to standard “3+7” daunorubicin and cytarabine induction chemotherapy for AML is tolerable and results in a remission rate at least as high as would be expected with “3+7” alone in older patients. The maximum tested dose of bortezomib given for consolidation chemotherapy was 1.3 mg/m² which proved to be tolerable in combination with Int-DAC. All patients have now completed treatment, and final response and toxicity data are being analyzed. CR data within clinically important subsets will be presented. The duration of relapse-free survival among patients in CR will influence planning a possible phase III trial.