Chronic myeloid leukemia – CML – is a relatively rare blood cancer that’s diagnosed in about 5,000 Americans every year. It used to be a dire diagnosis with a poor outlook. Not anymore, though.
Today, it is believed that most CML patients can expect to live a normal lifespan. Why? The introduction of a number of different targeted medications has dramatically changed the treatment of the disease and the lives of people living with it.
dailyRx News spoke with a nationally known CML expert, Neil Shah, MD, PhD, who is Associate Professor of Medicine at the University of California, San Francisco. He is also Leader of the Hematopoietic Malignancies Program within the UCSF Helen Diller Family Comprehensive Cancer Center.
Dr. Shah had recently conducted a webinar for the Leukemia and Lymphoma Society. His presentation, CML Diagnosis and Treatment Update, covered everything from the basics of the disease to the latest treatment advances.
What is CML?
CML is a cancer of the bone marrow and blood. In addition to chronic myeloid leukemia, the disease has been referred to as chronic myelogenous leukemia, chronic granulocytic leukemia and chronic myelocytic leukemia.
Virtually all CML patients have what’s called the Philadelphia chromosome, which is formed when parts of two different chromosomes – 9 and 22 – exchange places with each other.
The Philadelphia chromosome then causes the fusion of two genes – BCR and ABL. The resultant BCR-ABL gene produces a protein (the BCR-ABL tyrosine kinase) that doesn’t function properly. And it’s the BCR-ABL tyrosine kinase that’s responsible for the development of CML.
There are two different phases of the disease: chronic and advanced (comprised of accelerated and blast phases). The vast majority – 85 percent – of CML patients are diagnosed in the chronic phase.
Dr. Shah explained that the median age of CML diagnosis is 53, and 60 percent of patients are men. The most common symptom is fatigue, but 40 percent of patients have no symptoms.
Dr. Shah says a bone marrow biopsy should be performed to diagnose and properly stage CML. The presence of the Philadelphia chromosome or other convincing evidence of the BCR-ABL fusion are used to make the diagnosis.
CML was the first disease to be treated with so-called targeted therapy - medicines that target specific genetic mutations.
Gleevec (imatinib) is what’s known as a tyrosine kinase inhibitor (TKI). It targets and then blocks the BCR-ABL tyrosine kinase.
This drug, approved to treat CML in 2001, essentially transformed CML from a fatal disease to one that can be successfully managed over many years in most patients.
Gleevec has dramatically extended lifespan – overall survival – of those living with CML. The 8-year survival rate is now 85 percent for CML patients, according to Dr. Shah, or 93 percent when only CML-related deaths are counted.
Not always therapeutic
Despite this outstanding record, some patients have to stop taking Gleevec.
Dr. Shah told us, “Slightly more than half of people who started imatinib were still on study drug [used in original clinical trials] and in a deep remission after 8 years.
“We anticipate that the new treatment milestone at 3 months means that about 35 percent of patients will need to switch at this time point for lack of achieving the desired milestone response, and another small percentage may need to change due to side effects,” Dr. Shah said.
The treatment milestone Dr. Shah is referring to is the National Comprehensive Cancer Network (NCCN) guideline that CML patients should achieve a complete cytogenetic response (CCyR) by 3 months. This means there are no Philadelphia chromosome-containing cells in at least 20 analyzed bone marrow cells.
And Gleevec sometimes stops working over time. “There is a small proportion of patients who respond well and tolerate imatinib well initially, but eventually lose response,” Dr. Shah said.
Resistance may occur because new mutations form. Up to 100 drug-resistant alterations have been identified so far. The disease can also progress when high levels of BCR-ABL are produced.
Finally, not taking the medication as prescribed can also result in failure.
Dr. Shah said, “A study showed that patients who missed 10 percent [3 pills a month] or more of prescribed doses had a much lower probability of achieving major or complete molecular responses compared with those who missed less than 10 percent.
Three medications can be used as second-line therapies should Gleevec fail. Sprycel (dasatinib), Tasigna (nilotinib), and Bosulif (bosutinib) are also TKIs. Sprycel and Tasigna can also be used as first-line therapies.
We asked Dr. Shah how doctors and newly diagnosed patients make a treatment decision. “Nilotinib and dasatinib both are superior to imatinib at effecting rapid deep cytogenetic and molecular responses, and both are tolerated reasonably well,” he said.
“I tell patients that my preference is that they take one of these agents rather than imatinib. In the absence of a contraindication, describe the main distinguishing side effects, monitoring requirements and the difference in the dosing regimens, and let the patient decide which one he/she prefers to initiate,” Dr. Shah explained.
Latest treatment advances
Two drugs have recently been approved for CML that no longer responds to other therapies. The US Food and Drug Administration approved Bosutinib, sold under the brand name Bosulif, and omacetaxine (Synribo) in late 2012.
We asked Dr. Shah to describe these.
“Bosulif is a second-generation TKI that is approved for CML patients of all phases who are resistant or intolerant to prior therapy, and is probably equivalent to dasatinib and nilotinib in the second-line setting,” Dr. Shah told us.
“It is not approved for frontline treatment. It is similar to dasatinib in terms of which mutations it is effective against. Diarrhea is a common side effect, although it tends to improve after a few weeks.”
“Omacetaxine is a protein synthesis inhibitor that is approved for chronic or accelerated phase CML patients with resistance and/or intolerance to two or more TKIs. Response rates to date have been modest, and typically of short duration, but clinical trial experience was rather limited,” Dr. Shah said.
He added, “Myelosuppression [suppression of bone marrow’s ability to produce blood cells] is common, and can be severe.”
We asked Dr. Shah what he thinks is the most important thing for CML patients to remember.
“This disease is relatively uncommon, yet is the subject of a great deal of study. I encourage patients to check in with a CML specialist from time to time to ensure that their disease is being adequately managed,” Dr. Shah said.
“There are many effective treatments available, and in most cases, we can achieve both effective disease control and preserve quality of life.”