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Brand name(s): Sprycel™

• Approved for chronic myeloid leukemia

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

On June 28, 2006, the U.S. Food and Drug Administration (FDA) granted accelerated approval to dasatinib (Sprycel™, made by 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 (Gleevec®). 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 percent of patients because of resistance; 18 percent discontinued imatinib because of drug intolerance. The maximum imatinib dose was 400 – 600 mg/day in approximately 50 percent 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 percent) of Ph+ hematopoietic cells. The major cytogenetic response rate in CP patients was 45 percent (95 percent CI: 37 percent, 52 percent).

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 percent (95 percent CI: 49 percent, 68 percent) in AP, 32 percent (95 percent CI: 22 percent, 44 percent) in MB, 31 percent (95 percent CI: 18 percent, 47 percent) in LB, and 42 percent (95 percent CI: 26 percent, 59 percent) 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 percent CI: 2.79, upper limit not reached) for LB patients and 4.8 months (95 percent 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 percent of patients; the most common events included superficial edema (36 percent) and pleural effusion (22 percent). Bleeding occurred in 40 percent of all patients; 14 percent of patients experienced gastrointestinal bleeding.

Hematological toxicities were the most common grade 3/4 adverse events. Neutropenia and thrombocytopenia occurred in approximately 48-83 percent of patients and anemia in 18-70 percent. 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 percent), fluid retention (9 percent), febrile neutropenia (8 percent), dyspnea (6 percent), pyrexia (5 percent), pleural effusion (5 percent), and diarrhea (5 percent). Grade 3/4 CNS hemorrhage occurred in 1 percent of patients. Fatal CNS hemorrhage was observed in six patients.

On November 8, 2007, the FDA granted accelerated approval of a new dosing regimen of dasatinib for the treatment of adults with chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate.

The new dosing regimen is 100 mg taken orally once daily. The FDA had previously granted accelerated approval to dasatinib in June 2006 for the treatment of adults with CP, accelerated phase, or myeloid or lymphoid blast phases of CML with resistance to or intolerance to prior therapy, including imatinib mesylate. In June 2006, the FDA also granted regular approval for the treatment of patients with Philadelphia positive acute lymphoblastic leukemia. The recommended dosing regimen in the 2006 approval was 70 mg twice daily.

A randomized, 2x2, open-label study evaluated the safety and efficacy of four dosing regimens of dasatinib in patients with CP CML. Dasatinib was administered at a dose of 100 mg once daily, 140 mg once daily, 50 mg twice daily or 70 mg twice daily. Patients with significant cardiac disease were excluded from the study. A total of 670 patients were randomized. The primary endpoint was major cytogenetic response (MCyR), defined as elimination or substantial diminution (by at least 65 percent) of Ph+ hematopoietic cells.

The primary analysis showed comparable efficacy for the 100 mg once daily schedule (MCyR=53 percent, 95 percent CI: 44 percent-62 percent) and the 70 mg twice daily schedule (MCyR=51 percent, 95 percent CI: 42 percent-60 percent).

Safety analyses revealed a reduction in adverse reactions with the 100 mg once daily dose regimen compared with the previously approved 70 mg twice daily regimen. These adverse events included fluid retention all grades (24 percent vs. 32 percent), pleural effusion all grades (10 percent vs. 18 percent), and grade 3/4 hematologic toxicities, including neutropenia (34 percent vs. 43 percent), thrombocytopenia (22 percent vs. 38 percent), and anemia (10 percent vs. 17 percent).

Submission of further follow-up data from ongoing studies will convert this accelerated approval to regular approval.

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