fonte: medscape

October 31, 2010 — The US Food and Drug Administration (FDA) has approved an expanded indication for dasatinib (Sprycel tablets; Bristol-Myers Squibb Co, Ltd) for the first-line treatment of chronic-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Dasatinib previously was reserved for use in patients with resistance or intolerance to prior therapy including imatinib.

"Patients now have an option that has both improved response over imatinib, the current standard of care, and offers a once-daily dosing convenience with no fasting requirements," said Elliott Sigal, MD, PhD, the executive vice president, chief scientific officer, and president, research and development, for Bristol-Myers Squibb, in a company news release.

FDA approval was based on a priority review of data from the Dasatinib versus Imatinib Study In Treatment-Naive CP-CML Patients (DASISION) open-label phase 3 head-to-head international trial (n = 519) of 100 mg dasatinib and 400 mg imatinib, taken once daily.

Results at 1 year showed that dasatinib yielded significantly greater confirmed complete cytogenetic response and major molecular response rates than imatinib (76.8% vs 66.2% [P = .007] and 52.1% vs 33.8% [P < .0001], respectively). Median time to respond was also more quickly achieved in the dasatinib compared with imatinib group (3.1 months vs 5.6 months for complete cytogenetic response and 6.3 months vs 9.2 months for major molecular response, respectively).

"Data from the DASISION trial demonstrated that newly diagnosed patients with Ph+ CML in chronic phase who received Sprycel attained higher and faster molecular and confirmed complete cytogenetic response rates by 12 months compared to imatinib," noted Dr. Sigal. As a condition of accelerated approval, the company is required to collect additional long-term safety and efficacy data.

The most commonly reported adverse events reported in 10% or more of dasatinib-treated study patients included myelosuppression, fluid retention, diarrhea, headache, musculoskeletal pain, and rash. Serious adverse events included pleural effusion (2%; grades 3/4, <1%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). Grade 3/4 laboratory abnormalities for newly diagnosed, treatment-naive patients with chronic CML receiving dasatinib vs imatinib included neutropenia (20% vs 22%), thrombocytopenia (19% vs 10%), anemia (11% vs 7%) , hypophosphatemia (5% vs 24%), and hypokalemia (0% vs 2%). There was no discontinuation of dasatinib resulting from laboratory abnormalities. Rates of laboratory abnormalities were higher for patients with chronic CML who were intolerant or resistant to imatinib and who received a starter dose of dasatinib.

The FDA notes that severe thrombocytopenia, neutropenia, and anemia occur less often in patients with chronic-phase CML than advanced-phase disease or Ph+ acute lymphoblastic leukemia. However, complete blood counts should still be performed weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression is generally reversible and usually managed via dose reductions or temporary interruption of therapy.

Dasatinib is also associated with potentially severe fluid retention that can manifest as pleural effusion, superficial localized edema, and generalized edema. Patients with symptoms suggestive of pleural effusion (eg, dyspnea or dry cough) should be evaluated by chest radiographs. Fluid retention is typically managed by supportive care measures that include diuretics or a short course of steroids. Severe pleural effusion may require thoracentesis and oxygen therapy.

Because of the potential for QT interval prolongation, dasatinib should be used with caution in patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and in those taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Hypomagnesimia and hypokalemia should be corrected before the start of dasatinib.

Dasatinib is metabolized hepatically by the cytochrome P 450 isoenzyme 3A4 (CYP 3A4), and concomitant use of strong enzyme inhibitors (eg, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole) can increase the risk for toxicity. Close monitoring and dasatinib dose reductions should be considered if systemic use of a potent CYP 3A4 inhibitor cannot be avoided. Grapefruit juice can also increase plasma concentrations of dasatinib and should be avoided.

Coadministration of strong inducers (dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, and phenobarbital) may necessitate dasatinib dose increases. St. John’s Wort has an unpredictable effect on dasatinib concentrations, including occasional decrease of plasma concentrations; this popular herb, used for depression and other conditions, should therefore be avoided.

Because dasatinib is also a time-dependent inhibitor of the enzyme, caution is advised with concomitant use of CYP 3A4 substrates having a narrow therapeutic index (eg, alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids [ergotamine and dihydroergotamine]).

Long-term suppression of gastric acid secretion by use of histamine 2 antagonists or proton-pump inhibitors is likely to decrease dasatinib exposure and is not recommended; antacids should be administered at least 2 hours before or 2 hours after dosing with dasatinib.

Dasatinib previously was approved for the treatment of chronic, accelerated, myeloid, or lymphoid blast Ph+ CML with resistance or intolerance to prior therapy including imatinib, and for the treatment of patients with Ph+ acute lymphoblastic leukemia with resistance or intolerance to previous therapy.