The Feasibility of Combining Daunorubicin, Clofarabine and Gemtuzumab Ozogamicin Is Feasible and Effective. A Pilot Study.

New treatment combinations are required for older patients with AML. Clofarabine is a novel nucleoside analogue which has been shown in several phase 2 studies in older patients to be active alone or in combination. Gemtuzumab Ozogamicin (GO) is also active in older patients and is currently undergoing evaluation in several randomised trials. As part of the proposed UK NCRI AML16 Trial for patients over 60 years we have undertaken a Pilot Trial to establish the feasibility combining standard dose Daunorubicin (D) (50mg/m² days 1,3,5), Clofarabine (Clo) and GO (3mg/m²) as a novel combination, with the intention to compare D+Clo vs D+Ara-C both +/− GO on day 1. Five treatment cohorts were planned. Daunorubicin at a dose of 50mg/m² is included in all cohorts. Cohorts 1–4 combine D with Clo at a dose level of 15mg/m², 20mg/m², 25mg/m² and 30mg/m² given on days 1–5 for 2 courses, to establish the feasible Clo dose in combination. Cohort 5 comprises D + feasible Clo dose given as above + GO 3mg/m² on day 1 of course 1. Each cohort initially comprised 6 patients, and cohorts were expanded based on toxicity scoring. If toxicity criteria were satisfied the next cohort was opened. Thirty-four patients have been recruited. Of 6 patients in cohort 1 (15mg) 5 achieved CR without toxicity with one having refractory disease; of 7 patients in cohort 2 (20mg) 6 achieved CR with 1 having refractory disease; of 10 patients in cohort 3 (25mg) 4 achieved CR, 3 had refractory disease and 3 had induction deaths; and of 9 patients in cohort 4 (30mg) 5 entered CR, 2 had RD and 2 ID. Based on this, a dose of 20mg/m² was chosen for clofarabine. So far cohort 5 has recruited 2 patients, both of whom have entered CR. This cohort will shortly be completed.

Toxicity: No toxicity of grade >2 in AST and ALT was seen in any cohort; one patient on Clo (30mg) had a transient grade 3 bilirubin elevation after courses 1 and 2. One patient (30mg) had grade 4 renal toxicity. The mean time on antibiotics was 13.1 days with no difference between the cohorts. The median time to recovery of ANC was 19 (17–24) days and platelets 19 (14–21) days.

Conclusion: The combination of Daunorubicin 50mg/m² on days1, 3 and 5 and Clofarabine 20mg/m² days 1–5 with Gemtuzumab Ozogamicin 3mg/m² on day 1 is an effective and feasible combination for prospective evaluation.