The FDA has approved imatinib for chronic myelogenous leukemia and alemtuzumab for B-cell chronic lymphocytic leukemia
For the almost 5,000 people diagnosed annually with chronic myelogenous leukemia (CML) the prognosis has been poor: Only 32% will be alive five years after their diagnosis. Now, with the Food & Drug Administration's rapid approval of Gleevec (imatinib mesylate, formerly STI-571, Novartis), these patients may have a more hopeful future.
The drug's positive clinical trial results led to a priority review by the FDA and an approval after only 2.5 months of review, making this the fastest time to market of any cancer treatment.
The FDA has approved imatinib as an oral therapy for the treatment of patients with CML in the blast-crisis, accelerated phase or in chronic phase after failure of interferon-alpha therapy. As the first oncology drug to be developed using rational drug design, imatinib specifically blocks the action of Bcr-Abl, a protein product of the Philadelphia chromosome, the well-known marker for CML and cause of the uncontrolled proliferation of white blood cells in CML.
"This drug targets only abnormal cells, and corrects the probleman abnormal enzymethat causes cancerous cells to grow out of control," said Ralph Vogler, M.D., scientific program director for extramural grants of the American Cancer Society. "This is another example of the emerging importance of this new class of drugsthe molecular target drugs."
Imatinib's approval was based on data from three phase II open-label, single-arm studies that showed a major cytogenetic response in patients with advanced stages of CML. Patients with chronic phase CML, after failure with interferon therapy, achieved an 88% hematologic response and a 49% overall cytogenetic response, both primary endpoints of the study. These clinical trials were not designed to determine whether imatinib improves survival, and follow-up studies are being done to confirm clinical effectiveness. Several clinical trials are also testing the possible effectiveness of imatinib in other cancers, including glioma, soft tissue sarcoma, and a rare gastrointestinal cancer called gastrointestinal stromal tumor (GIST).
The most frequently reported drug-related adverse events noted with imatinib were nausea, vomiting, edema, and muscle cramps. Edema was most often periorbital or in lower limbs and was managed with diuretics, other supportive measures, or by reducing the dosage of imatinib.
The recommended dosage of imatinib is 400 mg orally per day for patients in chronic phase CML and 600 mg orally per day for patients in accelerated phase or blast crisis. Novartis has instituted a comprehensive patient assistance program for the drug, which will cost about $2,000 per month.
Though seemingly overshadowed by the rapid approval of imatinib, Berlex Laboratories' alemtuzumab (Campath) also received accelerated FDA approval for leukemia. However, it's for use as third-line therapy to treat one of the most prevalent forms of adult leukemiaB-cell chronic lymphocytic leukemia (B-CLL). B-CLL affects approximately 60,000 people in the United States. The drug, developed through Mil-lennium Pharmaceutical's 50/50 joint
venture with Ilex Oncology, is indicated for the treatment of B-CLL in patients who have been treated with alkylating agents and who have failed fludarabine (Fludara, Berlex) therapy.
Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody that works by targeting the CD52 antigen on the malignant lymphocytes. The drug binds to CD52 and induces antibody-dependent lysis following binding. "Campath provides a new option for refractory patients who have no other approved therapeutic options available," acknowledged Kanti Rai, M.D., chief of the division of hematology and oncology, Long Island Jewish Medical Center, and a principal investigator.
The FDA approval was largely based on a 93-patient, single-arm phase II study demonstrating an overall response rate of 33%, with a complete remission rate of 2% and a 31% partial response.
Alemtuzumab will carry a boxed warning regarding the hematologic toxicity (pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia), infusion reactions (fever, rigors, dyspnea, hypotension), and infections (sometimes fatal bacterial, viral, fungal, and protozoan infections) that can be associated with therapy. The FDA's Oncologic Drugs Advisory Committee voted 14 to 1 that the benefit of alemtuzumab therapy outweighed its toxicity profile, despite concern over the 15% mortality rate that was possibly related to the drug's toxicities.
"The question that no one can answer is [whether B-CLL patients are] better off getting Campath or [whether the best option is] just leaving them alone and letting the disease take its natural course, which in most cases would be fatal," said Jeff Lattf, M.D., chief medical officer at Berlex.
Tammy Chernin. There's new hope for some leukemia patients. Drug Topics 2001;11:16.