Combination of Gleevec (Imatinib) and Sprycel (Dasatinib) May Decrease Relapse Rate Against Cml
Chronic myeloid leukemia (CML or chronic myelogenous leukemia) is a disease in which too many white blood cells are made in the bone marrow.Chronic myelogenous leukemia (also called CML or chronic granulocytic leukemia) is a slowly progressing blood and bone marrow disease that usually occurs during or after middle age, and rarely occurs in children. Normally, the body produces bone marrow stem cells (immature cells) that develop into mature blood cells.
CML can occur in adults (usually middle-aged) and children. The disease affects 1 to 2 people per 100,000 and accounts for 7 - 20% cases of leukemia. It is usually associated with a chromosome abnormality called the Philadelphia chromosome. CML is a relatively rare disorder that affects about 5,000 people a year in the United States.
In CML, the body tells too many bone marrow stem cells to develop into a type of white blood cell called granulocytes. Some of these bone marrow stem cells never become mature white blood cells. These are called blasts. Over time, the granulocytes and blasts crowd out the red blood cells and platelets in the bone marrow.
As with many types of cancer, the treatment of chronic myelogenous leukemia can be challenging.The goal of chronic myelogenous leukemia treatment is to eliminate the blood cells that contain the abnormal BCR-ABL gene because this is the gene that causes CML. For most people, treatment won't cure CML but it can help them achieve long-term remission of their disease. This often allows them to live a relatively normal life, even though they may have to cope with medication side effects and frequent medical visits.
The answer requires careful attention to all the factors known to influence survival after high-dose chemotherapy and bone marrow transplantation, including the patient's age, the interval since diagnosis, the presence or absence of histocompatibility with the donor, and the patient's status with respect to cytomegalovirus, because transplantation-related mortality remains appreciable.
Drug developers zeroed in on this very defect to create Gleevec, one of the most novel cancer treatments developed in the last two decades. Gleevec knocks out this protein, helping to keep these abnormal white blood cells in check and improve the lives of many people with CML. But doctors have to make sure Gleevec is working by monitoring patients with periodic blood and DNA tests, particularly because certain patients may become resistant to the drug.
The development of the tyrosine kinase inhibitor imatinib revolutionized the treatment of chronic myeloid leukemia (CML).The high response rate associated with imatinib, coupled with its tolerability, have led to its adoption as frontline medical therapy in CML. However, some patients are intolerant or resistant to this agent, and much of the latest research in CML has focused on this area. The recent US Food and Drug Administration (FDA) approval of the multi-kinase inhibitor dasatinib provides a viable alternative for patients who can't tolerate or are resistant to imatinib.
"Many Ph+ ALL cells lack a tumor-suppressor gene called Arf, which is normally present in CML cells at the time the disease is first diagnosed," said Sherr. Stripped of the anti-tumor effects of Arf and nurtured by growth factors produced in the bone marrow, these ALL cells become less responsive to imatinib and more difficult to eliminate. Sherr reasons that the cells' survival advantage increases their opportunity to develop mutations in the BCR-ABL protein, which prompt imatinib resistance.
Patients taking dasatinib (Sprycel) achieve complete cytogenetic response - absence of the mutated protein that drives this disease - more rapidly than we've observed historically using the current front-line therapy,also side effects are very manageable ;according to a study.
Development of Gleevec, which inhibits a biological switch called a tyrosine kinase that is abnormally activated in CML. This activation, triggered by an abnormal breakage and rearrangement of a chromosome, drives uncontrolled proliferation of white blood cells.
Resistance to imatinib mesylate has prompted the development of newer generation inhibitors, such as a compound known as dasatinib, which are not only considerably more potent than imatinib mesylate, but also are active against cells expressing many of the mutations that make them resistant to the latter agent. Dasatinib also inhibits another important survival protein known as Src. However not all patients respond to dasatinib, and the risk remains that patients will develop resistance to this agent as well.
A new product named AMN107 (under trial by Novertis), a half-new, half-old hybrid. Half of AMN107's chemical makeup is identical to a portion of Gleevec, the remainder is completely different.In experiments with laboratory samples of CML cells, AMN107 killed the cells more effectively than Gleevec. AMN107, is about 20 times more potent than Gleevec and is effective in treating Gleevec-resistant disease in model systems. In follow-up studies with mice with a human form of CML, AMN107 produced lengthier remissions than Gleevec and triggered remissions in animals in which the disease had become resistant to Gleevec. Side effects in the animals were minimal.
Imatinib now seems to be the initial treatment of choice for patients with CML who do not have a suitable bone marrow donor or who are not candidates for transplantation. A large challenge is to consider how this drug might be incorporated into
the treatment of patients who are candidates for transplantation.
Simultaneous treatment of chronic myeloid leukemia (CML) patients with a combination of the drugs Gleevec (imatinib) and Sprycel (dasatinib) may decrease the chance of cancer's return or at least increase the length of time before relapse, U.S. researchers report.
Both drugs target a protein called BCR-ABL, which is known to cause CML.
Normally, CML patients are first treated with Gleevec. If the cancer develops resistance to Gleevec and returns, it's treated with Sprycel. But it's now known that BCR-ABL can also develop resistance to Sprycel.
Based on their study of 12 CML patients, a team at Memorial Sloan-Kettering Cancer Center, New York City, recommend that rather than sequential treatment with Gleevec and Sprycel, CML patients should be treated with both drugs when they're first diagnosed in order to prevent, or delay, the emergence of drug-resistant forms of BCR-ABL.
In this case, the target of both Gleevec and dasatinib is the Abelson tyrosine kinase (ABL), an enzyme that becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML. Dasatinib differs from Gleevec in that it is a “sloppier inhibitor” that does not hold its target to such tight structural constraints.
The researchers also noted that a new drug that targets Gleevec- and Sprycel-resistant BCR-ABL is currently in clinical trials.