Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 22 de julio del 2004
I) Imatinib mesylate (GleevecTM, STI-571)
Bone marrow is the spongy tissue located inside the large bones of the body that makes red blood cells (to carry oxygen and other materials to all tissues of the body), white blood cells (to fight infection), and platelets (to make the blood clot). Chronic myelogenous leukemia, or CML, is a blood cancer where too many white blood cells are made in the bone marrow. The white blood cells keep growing in number and do not develop normally. As a result, immature white blood cells are found in the blood and the bone marrow.
CML is diagnosed in about 4,500 Americans each year. The typical patient is usually middle-aged or older, although the cancer can occur in children also. There are three phases of CML that a patient passes through, each one more advanced than the previous: the chronic phase, the accelerated phase, and the blast crisis phase. The more advanced the phase, the more progressive the disease, and thus the more likely to cause physical symptoms. Although chemotherapy and drug therapy with interferon-alpha are available, the only known curative treatment is bone marrow transplantation, for which only a small percentage of patients are eligible.
Most people with CML have a gene mutation (change) called the Philadelphia chromosome. Remember that every cell in the body contains DNA (genetic code) that tells the cell what to do. DNA is packaged into structures called chromosomes. CML occurs when part of the DNA from one chromosome accidentally moves to another chromosome. This newly created abnormal chromosome is called the Philadelphia chromosome, named after the city in which scientists first discovered it. The Philadelphia chromosome results in the bone marrow making a new enzyme called the bcr-abl tyrosine kinase. This enzyme in turn causes the continual development of too many white blood cells.
(Note: The Philadelphia chromosome is not a mutation that can be passed from parent to child, meaning it is not a hereditary disease.)
Imatinib is a drug that was designed in the laboratory to target the abnormal bcr-abl protein, thus killing the leukemia cells. In other words, imatinib works in CML as a type of tyrosine kinase inhibitor, but not part of the EGFR-inhibitor family (see gefitinib, erlotinib). However, scientists quickly discovered that imatinib does not have only one function and one target. The efficacy of imatinib in advanced gastrointestinal stromal tumors (GIST) was established after its approval for CML patients, based on imatinib's "multipurpose" nature. Rather than tyrosine kinase inhibition, as in CML, imatinib fights GIST via inhibition of something called the "KIT signal-transduction pathway". The ability of imatinib to block this pathway involved in tumor growth makes it a promising treatment for GIST patients who have failed conventional chemotherapy.
Imatinib received accelerated approval for patients with chronic myeloid leukemia (CML) in May 2001. Imatinib is indicated for the treatment of patients with Philadelphia chromosome–positive CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy.
Imatinib is also indicated for the treatment of pediatric patients with Philadelphia chromosome-positive chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy.
In February 2002, it was approved for the treatment of a rare form of abdominal cancer called gastrointestinal stromal tumor (GIST). In GIST, imatinib mesylate works by blocking a different abnormal enzyme found on the tumor cells.
In December 2003, the FDA granted regular approval to Imatinib as a second line treatment for refractory CML.
The recommended dosage of Imatinib depends on the phase of CML:
Patients with CML in the chronic phase = 400 mg/day
Patients with CML in the accelerated or blast crisis phase = 600 mg/day taken as six 100 mg tablets
Patients with GIST = 400 mg/day
Side effects frequently reported in trials include:
Imatinib mesylate has been found to produce a complete cytogenetic response in more than 60% of previously untreated patients. However, there are no controlled trials to date demonstrating an actual clinical benefit, such as improvement in disease-related symptoms or increased survival. Furthermore, there are no long-term data at present on the durability of this response, nor is there information on the usefulness of salvage therapies (interferon-alpha or allogeneic stem cell transplantation) after failure of imatinib mesylate.
Nonetheless, many clinical trials are ongoing in an effort to address these important questions, and they are fueled by the promising results of already completed studies, such as the ones below:
1) CML study: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia O'Brien SG, et al. University of Newcastle, Newcastle, United Kingdom. N Engl J Med. 2003 Mar 13;348(11):994-1004.
Materials and Methods
Imatinib is superior to interferon-alpha plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML in terms of hematologic and cytogenetic responses, drug tolerability, and likelihood of disease progression to accelerated-phase or blast-crisis CML.
2) GIST study: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors, Demetri GD, et al. Dana-Farber Cancer Institute and Harvard Cancer Center, USA. N Engl J Med. 2002 Aug 15;347(7):472-80.
Materials and Methods
Imatinib gave a durable objective response in over 50% of patients with advanced unresectable or metastatic gastrointestinal stromal tumor.
Numerous studies of imatinib in CML and GIST are ongoing. In addition, imatinib is currently being investigated for its effectiveness against other kinds of cancer, as well, including acute lymphocytic leukemia and hypereosinophilic syndrome (HES).
For further information, please see Targeted Therapy Basics.