On June 28, 2006, the U. S. Food and Drug Administration granted accelerated approval to dasatinib (Sprycel, Bristol-Myers Squibb) for use in the treatment of adults with chronic phase (CP), accelerated phase (AP), or myeloid or lymphoid blast (MB or LB) phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate. Submission of further follow-up data from ongoing studies will convert this accelerated approval to regular approval. In addition, the FDA granted regular approval to dasatinib for use in the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
Efficacy was demonstrated in four single-arm studies. A total of 445 patients were treated with dasatinib at a starting dose of 70 mg twice daily. Median times from initial diagnosis were 64, 91, and 49 months in CP, AP, and MB patients, respectively, and 28 and 20 months in LB and Ph+ ALL patients, respectively. The patient population was extensively pre-treated. Prior treatment included imatinib, chemotherapy, interferon, hydroxyurea and/or anagrelide, and bone marrow transplantation. Imatinib was discontinued in 82% of patients because of resistance; 18% discontinued imatinib because of drug intolerance. The maximum imatinib dose was 400 – 600 mg/day in approximately 50% of patients and > 600 mg/day in the remaining patients.
The primary efficacy endpoint in CP studies was major cytogenetic response, defined as elimination or substantial diminution (by at least 65%) of Ph+ hematopoietic cells. The major cytogenetic response rate in CP patients was 45% (95% CI: 37%, 52%). Primary endpoints in AP, MB, and LB /Ph+ ALL studies were hematologic responses. Major hematologic response was defined as either a complete hematologic response or no evidence of leukemia. Major hematological response rates were 59% (95% CI: 49%, 68%) in AP, 32% (95% CI: 22%, 44%) in MB, 31% (95% CI: 18%, 47%) in LB, and 42% (95% CI: 26%, 59%) in Ph+ ALL.
At the time of data cutoff, the median response duration for CP, AP, or MB phase patients could not be determined since most responding patients had remained in response. The median response duration was 3.7 months (95% CI: 2.79, upper limit not reached) for LB patients and 4.8 months (95% CI: 2.89, upper limit not reached) for Ph+ ALL patients.
The safety population included 911 patients with CML and Ph+ ALL. Gastrointestinal (diarrhea, nausea, abdominal pain, and vomiting) and constitutional (pyrexia, headache, fatigue, asthenia, and anorexia) events were the most common adverse events. Fluid retention occurred in 50% of patients; the most common events included superficial edema (36%) and pleural effusion (22%). Bleeding occurred in 40% of all patients; 14% of patients experienced gastrointestinal bleeding.
Hematological toxicities were the most common grade 3/4 adverse events. Neutropenia and thrombocytopenia occurred in approximately 48-83% of patients and anemia in 18-70%. These events were less common in CP patients than in advanced-stage CML or Ph+ ALL patients. Other common grade 3/4 events included bleeding (10%), fluid retention (9%), febrile neutropenia (8%), dyspnea (6%), pyrexia (5%), pleural effusion (5%), and diarrhea (5%). Grade 3/4 CNS hemorrhage occurred in 1% of patients. Fatal CNS hemorrhage was observed in six patients.
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