After a person is diagnosed with chronic myelogenous leukemia, or CML, the first goal of treatment is to normalize blood counts. This means taking a drug to reduce the number of white blood cells in the body and to increase the number of red blood cells and platelets. The next treatment goal for drug therapy is to attack the underlying disease and to delay or prevent its progression.
For most patients with CML, standard treatment is the use of imatinib, a drug also known as Gleevec. Imatinib will usually normalize blood counts, bringing about what is called a hematologic remission. Imatinib is especially important because in most cases it also reduces the percentage of leukemic cells in the body. These are cells containing the Philadelphia chromosome, the genetic error that underlies CML. Sometimes doctors will prescribe a drug known as hydroxyurea before using imatinib, to normalize the blood counts more quickly.
Previously, interferon alpha had been a standard treatment for CML. Interferon has side effects that are difficult to tolerate and it is less effective than imatinib in reducing the number of leukemic cells in a patient's body. Some patients who were diagnosed before imatinib became available achieved good results with interferon and may still be treated with the drug.
Imatinib is a targeted anti-cancer drug. It's known as a tyrosine kinase inhibitor and it blocks the action of an abnormal enzyme called BCR-ABL. A major clinical trial shows imatinib brings about a complete hematologic response in 97 percent of patients who are in the chronic phase of CML. The drug brings about a complete cytogenetic response in 76 percent of patients. In almost 40 percent of patients, imatinib also brings about a significant reduction in the number of cells containing the Philadelphia chromosome when measured by the sensitive PCR molecular technique.
Most patients find side effects from imatinib mild and generally manageable. One common side effect is fluid buildup, often experienced as puffiness around the eyes. Other side effects can include bleeding, skin rash, diarrhea, nausea, muscle pain and fatigue. More serious side effects can include liver problems and abnormally low blood counts. There has been a report of rare, but serious, heart problems.
The effectiveness of imatinib can decrease rapidly if not taken as prescribed. Patients are at risk of relapse if they do not take their full dose on schedule. Imatinib can be expensive, which may be one reason patients may fail to take the drug as recommended. Patients may also falsely believe that if they experience good control of their blood counts (hematological response) their continued use of imatinib is not important.
Some patients taking imatinib may demonstrate an initial resistance to the drug (primary resistance) or they may develop resistance over time (secondary resistance). Sometimes a response can be restored by increasing the dosage. Side effects, however, are more likely with higher doses of imatinib, and may become intolerable.
If resistance occurs, patients may progress quickly to the accelerated or blast phase of CML. One treatment that may be appropriate following resistance is a stem cell transplant. Another option in cases of resistance is the use of a newer generation of tyrosine kinase inhibitor drugs. One drug, known as dasatinib, or Sprycel®. Another drug is known as nilotinib, or Tasigna®. These drugs are available by prescription in the US, and may be available in other countries either by prescription or through a clinical trial. Sometimes a person with CML develops a resistance that can not be overcome with either of these new tyrosine kinase inhibitors. These patients may benefit from participation in clinical trials using other drugs or combinations of drugs that may overcome resistance to imatinib, dasatinib or nilotinib.
Stem Cell Transplant
Drug therapy can help people live with CML for many years, possibly decades. The only proven cure for CML, however, is a stem cell transplant. This treatment uses large doses of chemotherapy, often combined with radiation, followed by a stem cell transplant. This procedure is also known as bone marrow transplant. Stem cell transplants are risky, and are usually an option only for younger patients who have a suitable donor. However, a stem cell transplant might be reconsidered in a patient who has failed drug therapies.
In a stem cell transplant, a patient's bone marrow is destroyed with the chemotherapy or chemotherapy plus radiation. The marrow is where blood stem cells harboring the Philadelphia chromosome reproduce. The aggressive treatment destroys all of the leukemic cells. However, normal blood stem cells die as well. Following the high dose therapy, healthy stem cells from a donor are infused into the blood of the person with CML. These stem cells migrate into the bone, and restore the patient's ability to manufacture new blood cells.
Good results depend on a close match between the patient's and donor's tissue. Identical twins often make excellent donors. Other brothers and sisters may also make good matches. A possible donor will be carefully tested to make sure that his or her stem cells have the best chance for a successful transplant. Transplant techniques using lower doses of chemotherapy and radiation are being tested in clinical trials, and may be appropriate for older patients.
Because of the risks involved with a stem cell transplant, most doctors will begin treating a person with CML with drug therapy. At the same time, the patient may be added to a bone marrow transplant list to begin the search for a compatible donor. This way, the search for a match is already underway if a transplant is reconsidered due to failure of drug therapy.
Difficult to Treat Cases of Resistance
Secondary resistance in CML may be caused by a type of genetic change called a point mutation. A small minority of patients with drug resistance to CML experience a particular point mutation that leads to especially-difficult-to-treat disease. This is known as the T315I mutation. Neither dasatinib nor nilotinib are effective in these cases.
A stem cell transplant will be considered, or reconsidered, in cases with the T315I mutation. New drugs are being tested that show promising results. One is called MD-0457, in a class of drugs known as aurora kinaise inhibitors. This drug is only available in clinical trials.
Other Emerging Therapies
Other research is directed at the question of whether CML might be cured with drug therapy if techniques are perfected to rid the body of small amounts of disease that remain even after effective treatment with tyrosine kinaise inhibitors. This is called residual disease. Researchers note that in cases of stem cell transplant, residual leukemic cells are destroyed through what's called called graft-versus leukemia effect. Transplanted cells produce white blood cells that recognize leukemia cells as "foreign," and they mount an immunologic attack. This observation has led to research in immunotherapy, including vaccinations, that might mirror the graft-versus leukemia effect. Immunotherapy is being studied in clinical trials.
Treating Advanced Disease
Advanced CML is difficult to treat. Imatinib can be effective in many of these cases, especially in higher doses. The patient, however, is more likely to relapse than a patient whose disease never advanced beyond the chronic phase of the disease. Treatment in clinical trials remains an option for the patient with advanced disease.
Produced in collaboration with the Leukemia & Lymphoma Society and supported through an educational grant from Bristol-Myers Squibb Company