When you are first diagnosed with chronic myelogenous leukemia, the first goal is to reduce the very high number of white blood cells (WBC) in the blood stream. This abnormality is generally caused by a defective gene, called BCR-ABL, which drives WBCs to proliferate in number. The mainstay of treatment are tyrosine kinase inhibitor (TKI) medications (Gleevec, Tasigna, Sprycel, Bosulif), which will inhibit the leukemia gene.
TKIs are highly effective and most people with chronic-phase CML will respond to treatment. But it’s important to realize that “response” will mean different things at different times.
The first type of response is called a hematologic response, which means that the number and relative proportion (the differential) of the cells that make up blood (WBCs, red blood cells, platelets) start to go back to how they were before. Once the numbers have returned to the normal range, this is called a complete hematologic response (CHR).
However, the abnormally high number of WBCs is a sign of CML – it isn’t the cause. The underlying problem is the activity of the BCR-ABL gene, so the next goal is to destroy cells containing this gene and suppress the gene signals that are driving WBCs to proliferate. Abnormal cells are detected with cytogenetic testing. A major cytogenetic response (MCR) has occurred when fewer than one-third of cells in a sample are seen to have the CML abnormality. If no cells with the abnormality are detectable, this is called a complete cytogenetic response (CCyR).
Cytogenetic testing is limited by the limited number of cells in a given sample, so it’s important to zero in at the molecular level to determine if there’s any leukemia activity. This involves PCR (polymerase chain reaction) testing, which can infer the presence of BCR-ABL by the amount of signal proteins (called transcripts) that the gene is producing. This type of response is measured by the reduction in transcript number. If the number is reduced to one-tenth of what it had been, this is called a 1-log reduction. If reduced to 1/100th (i.e. 1%) of what it was, this is a two-log reduction, which roughly corresponds to CCyR. A three-log reduction is 1/1000th (i.e. 0.1%). This is called a major molecular response (MMR).
A common benchmark for treatment success is if a person can achieve CCyR or MMR within the first year of treatment. This means that the risk that CML will progress (or be fatal) is very low.
So “response” can viewed as a gradual deepening of the degree of suppression of leukemia – from CHR to CCyR to MMR, which corresponds to the control at the level of the blood, the cell, and the molecule.
With increasingly sensitive testing, labs can identify people who have reached a 4-log reduction (i.e. 0.01%), and even a 5-log reduction (0.001%) at some centres. People who have better than a 4-log reduction are considered to have a complete molecular response (CMR), also known as “molecularly undetectable leukemia”. As the name implies, no leukemia cells can be detected in any sample. “Free of detectable leukemia” means that CML is being completely suppressed. It’s not quite the same as being “leukemia-free” (although it may be in some cases), but it’s the next best thing – and it’s a powerful indication of how well the TKIs can work in controlling the disease process in CML.