FDA Okays Sprycel for CML Resistant or Intolerant to Gleevec

ROCKVILLE, Md., June 29 - The FDA today granted accelerated approval to Sprycel (dasatinib) for adults with chronic myeloid leukemia who are intolerant to Gleevec (imatinib) or become resistant to it.

The FDA also gave standard approved to the agent for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) with resistance or intolerance to prior therapy.

Sprycel will be available nationwide within days, according to Bristol-Myers Squibb, the drug maker.

Known mechanisms of resistance to Gleevec, which was approved in 2001, include mutations in the protein sequence of the BCR-ABL tyrosine kinase, multidrug resistance gene overexpression, and the activation of alternate signaling pathways involving the SRC family kinases.

For many patients with CML, the risk of developing resistance increases with the number of years of prior treatment and severity of disease. Patients with advanced Ph+ALL generally develop resistance more rapidly than CML patients, including those in blast phase (an average of two months versus 10 months, respectively).

The drug maker said Sprycel is the first approved oral tyrosine kinase inhibitor predicted to bind to multiple conformations of the ABL kinase based on modeling studies.

Earlier this month the FDA's Oncologic Drugs Advisory Committee (ODAC) unanimously recommended accelerated approval for Sprycel.

The company submitted one phase I trial and five phase II trials for review that enrolled a total of 94 Gleevec-intolerant patients and 457 Gleevec-resistant patients. In the data reported Sprycel demonstrated hematologic and cytogenic responses in 31% to 59% of patients who were resistant or intolerant to Gleevec.

Most responses occurred within the first three months.

The drug is associated with grade 3 or 4 thrombocytopenia, neutropenia and anemia, which are more frequent in patients with advanced CML or Ph+ALL than in chronic phase CML. Myelosuppression was also observed in patients with normal baseline laboratory values as well as in those with baseline abnormalities. Complete blood counts should be performed weekly for the first two months of treatment, and then monthly or as clinically indicated. Myelosuppression may respond to dose reduction or interruption.

Other side effects included hemorrhage, including fatal central nervous system hemorrhage in 1% of patients, edema in 9% of patients, and QTc prolongation in less than 1% of patients.