Innovative Phase I Study of Concomitant and Consecutive Treatment with Dasatinib and MK-0457 in Refractory Ph+ CML and ALL Patients.

MK-0457 is a pan-aurora kinase inhibitor with demonstrated activity against wild-type and mutated BCR-ABL, including the T315I form, as well as FLT3 and JAK-2. It is a promising molecule for the management of Ph+ leukemias, in which the emergence of mutations in the ABL kinase domain still represents the main mechanism of resistance to TK inhibitors. In CML and ALL patients treated with a 5-day continuous infusion of MK-0457 at doses of 24-40 mg/m2/hr every 14 days, an increased incidence of related adverse events was shown.

In our Institution, an innovative Phase I clinical study of sequential and concomitant treatment with Dasatinib, previously administered for three months, and MK-0457 has been conducted. This combined activity suggests that MK-0457, in association with Dasatinib, would suppress the emergence of T315I and other resistant clone, improving upon the response rate for Dasatinib and the durability of response. The trial investigated two schedules of therapy: patients who achieved and maintained a major hematologic response after three months of therapy with Dasatinib (70 mg twice daily) received a 6-hour biweekly infusion of MK-0457 at 64 mg/m2/hr, whereas patients who failed to achieve a major hematologic response received a 5-days continuous infusion of MK-0457 at 10 mg/m2/hr, every 4 weeks. Biologically, the first schedule was demonstrated to suppress the emergence of Dasatinib-resistant clones, through a stronger inhibition of BCR-ABL, whereas the second one was showed to inhibit more potently Aurora Kinase activity.

Two patients with Ph+ ALL and one patient with CML in myeloid blast crisis, previously unsuccessfully treated with imatinib, were enrolled in the protocol. The first two patients, both in hematologic response after three months of treatment with Dasatinib, subsequently received the 6-hour biweekly schedule, maintaining the haematological response. No haematological toxicity was described. The third patient, enrolled in progression disease, received the 5 days MK-0457 schedule of treatment. His peripheral blood count was consistent with a severe pancytopenia, which required frequent platelets and red blood cells transfusions. His bad clinical performance status was compromised by a severe hemorrhagic pleural effusion, responsible for moderate dyspnoea and severe asthenia. After one cycle of MK-0457, a complete recovery of the pulmonary disease and a complete hematologic response were obtained.

The sequential and concomitant innovative administration of Dasatinib and MK-0457 represents a promising therapeutic strategy for refractory Ph+ CML and ALL, showing a relevant haematological activity in a limited number of patients. Assessment of the benefit risk profile for this combination remains to be determined.

Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Merck Sharp & Dohme.

No relevant conflicts of interest to declare.