Advances in Treatment of Previously Treated Ph+ Chronic Myeloid Leukemia - Episode 2
Shared insight on chromosomal abnormalities and genetic alterations that influence the disease course and management of CML.
Moshe Talpaz, MD: The classic CML [chronic myeloid leukemia] is associated with a well-known, well-described translocation between chromosomes 9 and 22. The gene known as ABL, coming from the Abelson leukemia virus, is relocated from chromosome 9 to 22, where it is a juxtaposition to another gene, which is broken and called BCR, or breakage cluster region. Collectively, they form a joint gene, the BCR-ABL, which is driving the disease known as chronic myeloid leukemia. It’s associated with a unique RNA transcript, the BCR-ABL transcript, and a unique protein product, the BCR-ABL protein.
There’s more than 1 mutation associated with BCR-ABL. There’s 1 of which the product is a protein known as p190, which is more common in Philadelphia-positive acute lymphoblastic leukemia. There is the protein p210, which is the common protein in the traditional Philadelphia-positive CML and p230, which is sometimes seen and commonly in some cases of CML. There are multiple types of tests that are available to study the disease and to follow up on the disease. The 1 most commonly used is a test known as polymerase chain reaction amplification, which amplifies the BCR-ABL transcripts specifically. Another test, which is available, is called FISH, or fluorescent in situ hybridization, test. We also have the standard cytogenetic test, which identifies the Philadelphia chromosome.
As far as sensitivity, the polymerase chain reaction test, the PCR test, for BCR-ABL is the most sensitive test and it has the ability to detect a low level of disease transcript, which makes it very useful in following the therapy for the disease, especially when the permission is established. The FISH test is moderately sensitive and has the capacity to detect disease at a level of about 0.5%. It’s useful at the beginning of the treatment, whereas standard cytogenetics typically study 20 cells on average. It’s not very sensitive, but it can be used initially for the diagnosis of the disease.
It should also be mentioned that standard cytogenetic testing can be done only on bone or cannot be done on blood because it requires dividing cells, whereas the FISH and PCR tests can be done on peripheral blood. So follow-up of the patient can be done by monitoring blood and doesn’t require repeated bone marrow tests for assessing the level of molecular disease.
For the purpose of diagnosis, we can use either the PCR test or the FISH test, or the standard cytogenetics. The follow-up can be based initially on the FISH test when the level of the disease is relatively high. But once we get to levels of 1% or less of the disease, we should use the PCR. The frequency of testing can vary from patient to patient, but in the initial phases, we like to test patients at least once every 3 months and assess the response, which will guide us to the type of treatment and dose of treatment. Subsequently, once a patient has established a stable remission, the frequency of testing, at least in my practice, can be reduced to once every 6 months. That usually occurs well into 1 or 2 years of therapy.
Let me address cytogenetic abnormalities. Standard cytogenetics is done at diagnosis and usually entails 20 analyzable cells, which show the typical translocation of chromosomes 9 and 22. However, sometimes at diagnosis, or during the disease course, we have findings of additional abnormal clones with additional mutations. Those usually represent the finding of transition to an accelerated phase of CML. Although it also depends on the frequency of this mutation, we expect a relatively high frequency to call it-accelerated disease. Some cytogenetic abnormalities are particularly indicative of high risks, such as trisomy of chromosome 8, the addition of chromosome 7, deletion of chromosome 7, and loss of chromosome 17.Also, partial or complete loss of an arm, which indicates a loss or mutation in TP53. Those represent high risk and are usually accompanying other disease features typical for accelerated phase CML.
Transcript edited for clarity.