A Phase 2 study of the Combination of Omacetaxine and Imatinib in the Treatment of Patients with Chronic Myeloid Leukemia (CML) in Advanced Stages or After Failure to Imatinib.

Despite the success of imatinib mesylate in treating patients with CML, several pts develop resistance to therapy. In addition, response rate for pts in accelerated (AP) or blast (BP) phase is significantly lower than in chronic phase (cp) and responses are usually short-lived. Omacetaxine (homoharringtonine) is a plant alkaloid extracted from cephalotaxus fortunei, with in vitro and clinical activity in CML. In vitro experience has shown synergy of omacetaxine combined with imatinib (Ref).

Evaluate the safety and efficacy of intravenous omacetaxine combined with imatinib in the treatment of patients with CML in CP, AP, or BP.

Patients with CML were eligible if they had 1) CP resistant to single agent imatinib, or 2) AP or BP, regardless of prior exposure to imatinib. Pts received omacetaxine 2.5 mg/m² by 24-hour continuous infusion daily for 5 days (days 1-5 of each cycle) every 4 weeks and imatinib, 400 mg daily for pts in CP and 600 mg daily for pts in AP or BP.

Fifteen pts were enrolled: 9 in BP, 3 in AP, and 3 in CP. The median age is 55 years (range, 21-77); median time from diagnosis to treatment 35 months (range, 1 to 139). Twelve pts (80%) were imatinib resistant. Three pts had not received imatinib (all in BP; one had received prior interferon and stem cell transplant). Eight pts had received treatment with at least one other tyrosine kinase inhibitor beside imatinib. Mutation analysis was performed in 14 out of 15 pts and 7 had mutations (T315I in 3, F317L in 2, F359V and Q252H one each). Patients received a median of 3 cycles 4 (1-34). Eight (53%) pts responded. Hematologic response was achieved in 7 of 14 evaluable pts (1 started in CHR): 3 CHR (all BP), and 4 BCP (3 BP, 1 AP). Cytogenetic responses were achieved in 4 (of 14)pts(28%): 2 complete , 1 partial and 1 minor (BP) and one of the pt in CR later achieved complete molecular response. Responses were usually transient although one pt (BP) remains in complete molecular remission 42 months from the start of therapy. One pt died of unrelated causes while in major cytogenetic response 12 months after start of therapy, and one pt changed therapy with an ongoing minor cytogenetic response after 13 months. Therapy was overall well tolerated and administered on outpatient basis. Grade 3-4 non hematologic toxicity (regardless of causality) included fatigue (20%), nausea & vomiting (13%), dizziness (7%) and weight loss (6%). Grade 3-4 hematologic toxicity included thrombocytopenia (93%), anemia (80%), and neutropenia (80%). Transient treatment interruptions were required in 6 patients because of myelosuppression. The median survival is 4.7 months. Three patients are alive, 35, 41 and 42 months from start of therapy: 1 still on therapy with complete molecular response; 1 with complete cytogenetic remission on bosutinib, and one (T315I) on hydroxyurea.

Omacetaxine combined with imatinib is effective in patients with advanced stages of CML and has a favorable toxicity profile. Further studies with this combination are warranted, particularly in advanced phase CML.

Cortes-Franco:Chemgenex: Research Funding; Novartis: Research Funding.