Dasatinib in Patients with Imatinib-Resistant Chronic Myeloid Leukemia: Experience from a Cancer Centre in Northern India

INTRODUCTION: Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. It is structurally unrelated to imatinib, binding to the oncologically relevant catalytically active conformation of BCR ABL. It is active against all tested BCR ABL mutations except T315I that confer Imatinib resistance.

AIM:

Primary Aim: Survival with Dasatinib.

Secondary Aim: Toxicity profile of Dasatinib.

MATERIALS AND METHODS: A total number of 12 patients were included in this study with a median age of 40 years. Five patients were male and seven female. The median duration, since starting therapy for CML was 58.9 months. The median duration since start of treatment with dasatinib was 9.5 months. Out of the 12 patients, 9 were in chronic phase (75%) and 3 were in myeloid blast crisis (25%). Amongst these, 8 patients (66.7%) had taken prior imatinib therapy for more than 3 years. The dose of prior imatinib therapy ranged from 400 mg in patients of chronic phase to upto 800mg in blast crisis patients. For inclusion in the study, patients were required to have adequate hepatic and renal function and eastern co-operative oncology group (ECOG) performance score of 2 or lower. Exclusion criteria included previous dasatinib therapy, significant cardiovascular disease or significant bleeding disorder unrelated to CML. Imatinib failure was defined as progression from chronic phase to blast crisis while receiving 400mg/day or more imatinib or from accelerated phase to blast crisis while receiving 600mg/day or more imatinib. The hematology and cytogenetic responses were accessed as per standard criteria.

RESULTS: A total number of 12 patients were enrolled in this pilot study out of which 7 are still on therapy. 5 patients discontinued therapy due to death. The median duration of dasatinib therapy was 7.5 months. The longest follow up patient on therapy being 20 months. The median daily dasatinib dose was 100mg. Nine patients (75%) had a major hematologic response and three patients (25%) had minor hematologic response. Dasatinib induced a major cytogenetic response in 5 (41.7%) patients, minor cytogenetic response in 1 (8.5%) patients, and minimal cytogenetic response in 4 (33.3%) patients. No cytogenetic response was seen in 2 patients of blast crisis. The median duration of survival was not achieved till August 2008. The one year survival by Kaplan-Meier method is 64% (1 month – 19 months). Dasatinib had a favorable toxicity profile. Among the non hematologic events, the most frequent adverse events were diarrhea (3/12), vomiting (3/12), peripheral edema (4/12), arthralgia (3/12), fatigue (5/12), rash (3/12), epistaxis (2/12), fever (1/12) and headache (2/12). Dose interruption was required for one patient with pleural effusion which was reversible with diuretics and steroids. No patients had grade 4 toxicity. The cytopenias were generally reversible and could be managed effectively by dose interruption or reduction. Since these patients had prior therapy with imatinib, assessment of relative contribution of therapy to myelosuppression could be a confounding factor.

CONCLUSION: Dasatinib induced hematologic and cytogenetic response in majority of patients who had progressed on imatinib therapy. Dasatinib has a favorable toxicity profile. The hematologic and non hematologic adverse events could be managed with dose alterations. It presents a potentially new therapeutic option for patients with imatinib failure or intolerance.