Medical CML Monitoring Approaches
Recommended Monitoring Approaches for CML in Chronic Phase Patients
Since there was partial consensus among CML experts regarding monitoring techniques, the
doctors in the Blood article recommend several monitoring approaches:
1. The Conservative Approach
• Cytogenetic analysis is the central element of monitoring.
• Monitor patients with a BMA cytogenetic analysis every 6 months until a CCR is reached .
• Once a CCR reached, BMA CA monitoring can be done every 6-12 months.
2. The “FISHer” Approach
• Marrow aspirations are painful so some physicians rely on peripheral blood FISH to follow
response and avoid doing marrows.
• Some of these physicians also use FISH to monitor molecular response, either erroneously
thinking that FISH is sensitive enough to evaluate molecular response or not convinced that
molecular response may add information to patients already FISH negative.
3. The ‘Molecular Enthusiast’ Approach
• Some CML experts believe in the PCR molecular analysis to the extent that they substitute
it for cytogenetics monitoring.
• PCR studies are performed at diagnosis, then every 3 months in the first year and every 3-
6 months subsequently.
• The aim of this type of monitoring is that it relies purely on peripheral blood monitoring
with the aim of achieving and maintaining QPCR levels at a major molecular response or better.
• Cytogenetic responses may not be related, instead a PCR 2-log response is equivalent to
such a response.
Disadvantages:
• Wide variation of PCR tests from 0.5 log or 2-5 fold fluctuations in commercial and even
some reference laboratories.
• Disregard of any information from looking at the marrow like percentage of basophils and
blasts, presence of myelofibrosis and cytogenetic abnormalities in Ph positive or Ph negative cells.
• False negatives in labs using low PCR sensitivity.
• Unfamiliarity with the fluctuations of results which may not reflect a major change in CML
burden.
• Physicians are seldom provided with the baseline for the laboratory reporting the result
making interpretation difficult.
4. The “I don’t care about any such studies’ Approach
• Interestingly, some physicians do not use any of the tests, especially for elderly patients
since they believe the benefit/cost ratio is this case to be low. One of the reasons for this is that
for such patients, no therapeutic intervention is planned until hematologic relapse which can be
evaluated from complete blood counts.
• Many doctors do not believe in this approach since beneficial interventional therapy may
be left until too late when the patient advances in disease and at this stage, therapies are less
effective.
4. The ‘Hybrid’ Approach
• This is the recommended approach by CML Experts from MD Anderson Cancer Center.
• Pretreatment bone marrow CA is favored as it can aid prognosis since it can measure the
percent of blasts, basophils and clonal evolution in the marrow.
• Although FISH and PCR are not recommended at diagnosis unless physicians wish to
routinely monitor by these techniques and rely on them before CCR, these techniques do reveal
to the physician that the disease is measurable by FISH and PCR and a baseline established.
• BMA CA are recommended at 6 and 12 months, then once every 1-2 years after CCR.
• If Ph negative chromosomal abnormalities prove to be clinically insignificant by further
studies, then marrow analysis can be performed at more than 2 years interval after a CCR.
• FISH is recommended every 3 months from the blood until the test is negative. FISH
studies should be omitted when a marrow CA is performed. After CCR, FISH should not be
done, only serial monitoring by QPCR studies.
• Patients can be monitored by PCR every 3 months in the first 12 months, then every 6
months once a stable complete cytogenetic response is achieved.
• If a PCR shows a patient to be out of MMR or show a rising PCR trend, there should be a
repeat PCR, more frequent monitoring like every 3 months and repetition of a bone marrow
cytogenetics, especially if the PCR is above 1%.
• Variations in PCR of a CCR patients should not dictate a change of therapy to allogeneic
transplant.
• In a patient who is in CCR but the PCR has risen consistently to more than 5-fold or has
gone out of MMR, it may be reasonable to increase Gleevec dose or switch to a 2nd generation
tyrosine kinase inhibitor if the Gleevec dose increase is not effective.
Recommendations for mutational analysis:
• Mutational studies should be performed when there is cytogenetic or hematologic
resistance or relapse.
• Mutational studies performed when there is a PCR rise must be interpreted with caution
especially if change of therapy based on that is contemplated.
• When a change of therapy is considered, it may be helpful to do a mutations test as there is
differing sensitivities of the new drugs to different mutations. For example, if a T315I mutation
is identified, an allogeneic transplant or a specific T315I inhibitor should be considered.