Monitoring Response & Resistance to Therapy in CML
Leukemia Insights - Fall 2008
Several monitoring methods are available to assess response and resistance to therapy in CML: 1) cytogenetics, 2) FISH, 3) qualitative PCR, and 4) mutational studies. Advantages and disadvantages of each are detailed in a recent review.25
A simple way of monitoring patients outside the context of a protocol is as follows;
Bone marrow for morphology and cytogenetics should be done pretreatment then at 6 and 12 months (to assess imatinib response), then every 1-2 years if stable complete cytogenetic response. Cytogenetic karyotyping is the only routinely available assessment of all chromosomes.
FISH can help assess the cytogenetic response and can be done in peripheral blood. It can be easily used for long-term monitoring (e.g. every 6-12 months) although it would not allow for detection of chromosomal abnormalities in Ph-negative metaphases.
In cytogenetic CR, monitor with QPCR every 6 months. Aim for a BCR-ABL/ABL ratio of <0.1% in the international scale (i.e., 3-log reduction from standardized baseline). In a patient in cytogenetic CR, do not react drastically to rises in transcript levels unless consistent with loss of major molecular response (BCR-ABL/ABL ratio >0.1% in the international scale) and with a 1-log increase. Still, resort to lower-risk treatment changes, (e.g. increase imatinib dose), but not to higher-risk ones (e.g. allogeneic transplant).
In standard practice, do not do mutational analysis pretreatment or in patients responding to imatinib. Mutational studies are best done only in patients with cytogenetic or hematologic relapse on imatinib. About 50% will show mutations. A T315I mutation should lead to consideration of allogeneic stem cell transplant. The mutation IC50 to a particular agent is a better guide to select therapy. For example, most P-loop mutations respond well to dasatinib, while mutations V299L and F317L respond well to nilotinib. Please consult with a CML expert in such situations.
For QPCR and mutational studies, you may contact the M. D. Anderson Molecular laboratory at 713-794-4780, Dr. Luthra Raja.