Three novel regimens for relapsed/refractory acute myeloid leukemia – a randomized phase II trial

Mark R. Litzow from  Mayo Clinic, Rochester, MN, USA, and colleagues conducted a randomized phase II trial to evaluate three novel regimens in patients with acute myeloid leukemia (AML) who were in first relapse or were refractory to induction/re-induction chemotherapy. Patients were randomized to receive carboplatin-topotecan (CT), each by continuous infusion for five days, alvocidib, cytarabine, and mitoxantrone (FLAM) in a timed sequential regimen, or sirolimus in combination with mitoxantrone, etoposide, and cytarabine (S-MEC). 

Ninety eligible patients with relapsed/refractory AML with >10% bone marrow blasts within two weeks prior to induction randomization were enrolled. Thirty-five patients were enrolled in the CT cohort, 36 in the FLAM cohort, and 19 in the S-MEC cohort. Simon two-stage design was implemented for each of the three treatment cohorts. The median age in the FLAM group was 62 years in comparison with 55 years for the CT and the S-MEC cohort.

The primary objective of the study was the achievement of a complete remission (CR) or a CR with incomplete blood count recovery (CRi).

Key findings:

• Median follow-up for the 11 patients still alive: 37.1 months (range, 23.8–49.0 months)
• Median OS in the CT, FLAM and S-MEC arms: 5.9 months (95% CI, 4.3–12.2) vs 4.4 months (95% CI, 2.5–7.1) vs 8.3 months (95% CI, 5.1 months–not reached)
• Overall response rate of achieving CR or CRi in the CT, FLAM, and S-MEC arms: 14% (5/35; 90% CI, 7–35) vs 28% (10/36; 90% CI, 16–43) vs 16% (3/19; 90% CI, 4–36)
• Nine treatment-related deaths occurred, seven (four elderly patients) in the FLAM arm
• The most common hematologic adverse events included cytopenias of one to three cell lines
• Non-hematologic adverse events were infections, gastrointestinal toxicities, and metabolic abnormalities

This study demonstrated that patients with high-risk AML receiving alvocidib, cytarabine, and mitoxantrone regimen had superior CR rate. In addition, the findings of this study demonstrate that  FLAM regimen had an "encouraging response rate" in patients with R/R AML. The authors added that the FLAM regimen should be further evaluated in larger clinical trials but should be administered with caution in elderly patients.