In the last 15 years, treatments for CML have dramatically improved. Due to these advances, there are an increasing number of people with CML who are in remission (no signs or symptoms of cancer).
Tyrosine-Kinase Inhibitors (TKIs)
TKIs are oral medications designed to block the signals that tell cancer cells to grow and divide. TKIs are targeted treatments, which means that they focus on specific cell mechanisms thought to be important for cancer growth. Because of this focus, targeted treatments tend to spare healthy cells and cause less severe side effects than chemotherapy.
• Imatinib (Gleevec). This drug was the first TKI approved by the FDA for CML and dramatically changed the outlook for people with CML. Imatinib, taken as a pill every day, makes the cancer go into long term remission in most patients. It works by shutting down the function of BCR-ABL, the abnormal protein produced by the Ph chromosome. This altered protein permits CML cells to grow and divide in excess and prematurely leave the bone marrow. In eight out of ten people treated with imatinib, the Ph chromosome disappears completely (deep molecular remission).
Many of the earliest patients treated with imatinib have now been in remission for more than ten years, and research is ongoing to explore the possibility of a “treatment free remission”; however, indefinite treatment continues to be the standard. Despite its long safety and successful response record, imatinib is not effective for all patients, either due to resistance or intolerance, so doctors sometimes must turn to other treatments.
• Nilotinib (Tasigna) and dasatinib (Sprycel). Like imatinib, nilotinib and dasatinib are taken in pill form and treat CML by blocking the growth and division of cells. They target the same BCR-ABL protein, but with increased potency. When used as a first-time treatment, both drugs have been shown to be more effective than imatinib as measured by an increase in deep molecular remissions and protection against the progression to advanced phases of CML. These medications can also benefit people whose CML stops responding to imatinib and those who cannot continue on imatinib because of its side effects.
Both of these drugs have their own distinct side effects. Nilotinib is associated with liver enzyme elevation, changes in blood sugar, and increased risk of vascular problems. Dasatinib is associated with fluid retention in the lungs (pleural effusion) and elsewhere in the body (pericardial effusion). Rarely, there can be an increase in pressure in the blood flow between the heart and lungs (pulmonary hypertension). These side effects need to be weighed against the benefits for people considering treatment with nilotinib or dasatinib.
• Bosutinib (Bosulif). Similar to nilotinib and dasatinib, bosutinib was developed for people with CML who cannot benefit from taking imatinib. Like all targeted treatments, bosutinib causes side effects that must be carefully monitored by patients and their doctors; side effects can include liver function problems and GI symptoms, such as diarrhea. Despite these issues, bosutinib provides an alternative for patients with resistance to or intolerance of imatinib, nilotinib, or dasatinib.
• Ponatinib (Iclusig). Ponatinib was initially developed to be beneficial for CML with a specific gene mutation known as T315I. This mutation makes CML cells resist treatment with imatinib, nilotinib, dasatinib and bosutinib. However, ponatinib can also benefit patients with more advanced and more resistant CML, not just those with the T315I mutation. Ponatinib was initially approved as a treatment for patients with some forms of leukemia in December 2012; it was subsequently temporarily removed from the market to address safety concerns regarding vascular events. After 3 months, it returned to the market with several new safety measures added to the label. Although the side effects of ponatinib carry risk, it may be of benefit for patients with highly resistant CML, and can be an effective treatment strategy for patients who have only limited or higher-risk options.
The most important milestone reached with TKI treatments is called major molecular remission; it occurs when the amount of measurable CML is 1,000 times smaller than when it was first diagnosed. Doctors look for this level of remission within the first 12 to 18 months of continuous treatments. There are also interim milestones—blood cell counts returning to normal, the spleen enlargement resolving, an early (after three to six months of treatment) reduction in measurable CML, and no cells with the Ph chromosome found in the blood or bone marrow.
Other Treatment Options
• Omacetaxine (Synribo). Approved by the FDA in October 2012, Synribo is an injectable medicine used to treat adults with CML who are no longer responding to, or could not tolerate, two or more TKIs. It can stabilize CML for a period of time by bringing back blood remission and, in some patients, a deeper (cytogenetic) response; this includes patients with the T315I mutation. The most common side effects of Synribo include a low level of platelets in the blood (thrombocytopenia); low red blood cell count (anemia); a decrease in infection-fighting white blood cells (neutropenia), which may lead to infection and fever, diarrhea, nausea, weakness and fatigue; injection site reaction; and a decrease in the number of lymphocytes in the blood (lymphopenia).
• Chemotherapy. Older medications such as hydroxyurea can still be useful to control high blood cell counts. Doctors now mostly prescribe hydroxyurea very early in the diagnosis process (before Ph chromosome testing results are available) and subsequently only if all other treatments have stopped working. Often, the vitamin folic acid is taken with hydroxyurea. Common side effects of this drug include skin ulcers, nail changes, and low blood counts.
• Immune system modulators. Before imatinib was approved, the standard treatment for CML was interferon. Interferon may work by stimulating an immune response as well as by blocking the division of cancer cells and slowing tumor growth. Researchers continue to study ways of incorporating interferon and a number of other medications designed to strengthen the body’s immune response to CML, including vaccines. The ability to “reprogram” a patient’s or donor’s immune cells so they can recognize and destroy cancer cells has generated great interest as to whether this approach will work for other white blood cell (myeloid) disorders.
• Stem cell/bone marrow transplant. This treatment is usually recommended for younger patients who have already tried a number of other treatments that either did not work or caused side effects that could not be tolerated. It is also an option for any patient whose CML advances under treatment or presents in an advanced stage; in both cases, control of the CML prior to transplant is important. Also, to be eligible for a transplant, patients need a well-matched donor; this is usually a close relative, such as a brother or sister. Because the risks associated with bone marrow transplants increase with age, and TKI therapy can offer significant long term benefit for most, the number of patients going on to transplant is low.
No matter what treatment option is chosen, continual monitoring is essential. CML is a chronic disease, and patients will see their doctor and other members of their health care team many times—in the first several years after diagnosis, likely every 3 to 6 months. Monitoring may consist of complete blood count tests, EKGs to assess heart rhythms, liver function tests, and molecular testing (in particular, a test called quantitative Polymerase Chain Reaction, or qPCR). Patients should talk to their doctor to seek the best molecular testing available; they should also receive the test results and make sure they understand what the results mean.
While CML has become a chronic, highly treatable disease, there are still questions that can only be answered in clinical trials. For instance, the current guidance is that TKIs must be taken continuously, even if the patient is in major molecular remission. Investigations into whether it is ever safe to discontinue treatments should take place only in the well-monitored environment of a clinical trial.
Clinical trials will also be essential as new questions arise, and as new treatment approaches are being researched and developed. The search for newer targeted drugs and immune-based therapy is ongoing.
Patients who are interested in participating in clinical trials should talk to their doctor; availability of clinical trials can be found at www.clinicaltrials.gov, a service of the U.S. National Institutes of Health.