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Brand name(s): Sprycel™

• Approved for chronic myeloid leukemia

Full prescribing information ³ 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.

Glossary Terms

A drug that is used to decrease the number of platelets in the blood in order to prevent blood clotting.

An abnormal loss of the appetite for food. Anorexia can be caused by cancer, AIDS, a mental disorder (i.e., anorexia nervosa), or other diseases.

Weakness; lack of energy and strength.

An immature blood cell.

A procedure to replace bone marrow that has been destroyed by treatment with high doses of anticancer drugs or radiation. Transplantation may be autologous (an individual's own marrow saved before treatment), allogeneic (marrow donated by someone else), or syngeneic (marrow donated by an identical twin).

Refers to the early stages of chronic myelogenous leukemia or chronic lymphocytic leukemia. The number of mature and immature abnormal white blood cells in the bone marrow and blood is higher than normal, but lower than in the accelerated or blast phase.

A type of research study that tests how well new medical approaches work in people. These studies test new methods of screening, prevention, diagnosis, or treatment of a disease. Also called clinical study.

The brain and spinal cord. Also called central nervous system.

The study of chromosomes and chromosomal abnormalities.

Difficult, painful breathing or shortness of breath.

Swelling caused by excess fluid in body tissues.

Effectiveness. In medicine, the ability of an intervention (for example, a drug or surgery) to produce the desired beneficial effect.

In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

A condition marked by fever and a lower-than-normal number of neutrophils in the blood. A neutrophil is a type of white blood cell that helps fight infection. Having too few neutrophils increases the risk of infection.

Tissue in which new blood cells are formed.

In medicine, loss of blood from damaged blood vessels. A hemorrhage may be internal or external, and usually involves a lot of bleeding in a short time.

An anticancer drug that belongs to the family of drugs called antimetabolites.

A drug used to treat different types of leukemia and other cancers of the blood, gastrointestinal stromal tumors, skin tumors called dermatofibrosarcoma protuberans, and a rare condition called systemic mastocytosis. It is also being studied in the treatment of other types of cancer. Imatinib mesylate blocks the protein made by the bcr/abl oncogene. It is a type of tyrosine kinase inhibitor. Also called Gleevec and STI571.

A biological response modifier (a substance that can improve the body's natural response to infections and other diseases). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. The body normally produces these substances. They are also made in the laboratory to treat cancer and other diseases.

Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop.

A statistics term. The middle value in a set of measurements.

Having to do with or resembling the bone marrow. May also refer to certain types of hematopoietic (blood-forming) cells found in the bone marrow. Sometimes used as a synonym for myelogenous; for example, acute myeloid leukemia and acute myelogenous leukemia are the same disease.

A condition in which there is a lower-than-normal number of neutrophils (a type of white blood cell).

An abnormality of chromosome 22 in which part of chromosome 9 is transferred to it. Bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia.

An abnormal collection of fluid between the thin layers of tissue (pleura) lining the lung and the wall of the chest cavity.

A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.

The percentage of patients whose cancer shrinks or disappears after treatment.

In statistics, describes a mathematical measure of difference between groups. The difference is said to be significant if it is greater than what might be expected to happen by chance alone. Also called statistically significant.

A condition in which there is a lower-than-normal number of platelets in the blood. It may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues.