Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms

Abstract

Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21-81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m²/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m² was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRD^neg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRD^neg) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRD^neg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m²/day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

Figure 1

Kaplan-Meier estimates of (a) overall survival and (b) relapse-free survival of the 121 patients who received GCLAM on this phase 1/2 study. Kaplan-Meier estimates of (c) overall survival and (d) relapse-free survival of the 94 patients who received GCLAM at the RP2D. Comparative Kaplan-Meier estimates of (e) overall survival and (f) relapse-free survival of the 54 patients age <65 years and the 40 patents age ≥65 years who received GCLAM at the RP2D.

Figure 2

Kaplan-Meier estimates of (a) overall survival and (b) relapse-free survival of the 94 patients who received GCLAM at the RP2D and 100 matched patients who received “7+3” at our institution.