Gleevec Resistance
- Gleevec has a high level of efficacy, tolerability and
durability in CML treatments. The 5 year data from the newly
diagnosed patients Gleevec trial showed disease progression rate
falling with time. Discontinuation of Gleevec due to side-effects
occurs in less than 5% of patients in all phases of disease so that
Gleevec intolerance is not common.
- For early chronic phase patients,
the rate of remission over 5 years on Gleevec first-line has been a 98%
of complete hematologic response (CHR), 92% rate of major cytogenetic
response (Ph+ less than 35%) and a 87% rate of complete cytogenetic
response (0%Ph+). In late phase CML patients who took Gleevec 2nd line
after Interferon failure, the MCR rate is 66% with the CCR rate being
55%. Gleevec could salvage these patients but the results showed that
early Gleevec initiation would have better benefit and Gleevec is now
standard first-line therapy.
- Gleevec resistance has occurred to a few patients in chronic
phase and more in the advanced phases of disease. Those who do not
reach milestones in therapy, comprising of the 2% who do not reach a CHR
and 8-13% who fail to achieve a major or complete cytogenetic remission,
are deemed patients who have primary resistance to Gleevec.
- Secondary resistance is easier to define-those who do achieve a response to
Gleevec and then lose it and those who progress from chronic to advanced
phases. From the IRIS trials, the rate of all types of progression of
disease is 18% at the 5 year follow-up. Most who progressed did so
within the first 3 years of Gleevec treatment. Within the first 3
years, the progression to advanced phases was 2% per year and relapse
within the chronic phase was 5% per year. In year 5 of Gleevec, the
risk rates for both progression to advanced phases and relapse within
chronic phase dropped to less than 1%.
- For late chronic phase patients or 2nd line Gleevec patients, 69% have remained
free from progression in 5 years. However, in this group, patients who achieved
a MCR and CCR within 3 months of Gleevec have a 87% and 94% rate of
freedom from disease progression versus 55% of the rest of the patients. In late
chronic phase 2nd line Gleevec patients, early MCR and CCR result in
more durable remission. The relapse rate of 2nd line Gleevec patients
is fixed at 7% per year. For patients who took Gleevec in accelerated
phase, the resistance/relapse rate is high at 75% with a 95% relapse
rate in myeloid blast crisis patients.
The Basis of Resistance
- Clinical resistance to Gleevec is defined as persistence or
re-emergence of the Ph chromosome from testing and in ABL kinase
inhibitors, the major mechanism for resistance occurs through the
acquisition of ABL point mutations. Other resistance mechanisms include
BCR-ABL overexpression, Lyn kinase overexpression, variability in the
amount and function of the drug influx protein. There is also CML stem
cell resistance where the CML progenitors are quiescent cells associated
with minimal residual disease and insensitive to the kinase inhibitor
drugs.
- Point mutations are amino acid substitutions in BCR-ABL
reactivating the kinase. There are over 40 BCR-ABL point mutations
discovered by doctors. Mutations interrupt critical drug contact points
to the oncoprotein or favor a conformation of the ABL kinase where drug
binding is reduced. The T315I mutation confers resistance to Gleevec as
well as ABL kinase inhibitors, Dasatinib and Nilotinib and overcoming
this resistance is a current area of CML research.
- Although it is accepted that mutations in the kinase domain
can give rise to Gleevec resistance and progression of disease, the fact
that mutations have been identified before Gleevec therapy was started
and do not always correlate to clinical resistance show that other
mechanisms and markers of resistance may be present. One of these is
cytogenetic clonal evolution (emergence of additional chromosomal
changes in the marrow) which has been correlated to detection of
mutations before Gleevec therapy and emergence of additional chromosomal
abnormalities do continue to play a role in both resistant and
progressive disease.
- There is controversy over the time when mutations are
acquired. If a mutation is found before Gleevec is started and the same
mutation is detected at the time of relapse, this suggests the resistant
clone proliferating under selective pressure. However, this is not
always the case and mutations have been found before Gleevec is started
and a different mutation is responsible for clinical relapse. Therefore
screening for mutations at diagnosis or in patients with stable residual
disease may not be a good idea.
- Instead, quantitative PCR monitoring can be used to predict
which patients need mutations screening at the time of a rise in PCR
values. However, this area is also not clear since many PCR assays are
not sensitive enough and it is common to have PCR fluctuations in
patient results. Some labs suggest mutations screening at a 2-fold PCR
rise, some a 5-fold PCR rise and some a 10-fold PCR rise. Patients who
lose a major molecular response by going to less than 3-log PCR
reduction and if this is linked to a BCR-ABL mutation from mutations
screening, these patients may be in need of a change in therapy.
Defining Gleevec Failure/Suboptimal Response
- No hematologic response at 3 months of Gleevec is termed
failure and a no complete hematologic response at 3 months is termed a
suboptimal response. An optimal response to Gleevec therapy in 3 months
is a 1-2 log PCR reduction.
- Having greater than 95%Ph+ at 6 months of Gleevec is Gleevec
failure with a 35-95%Ph+ at 6 months being a suboptimal response. An
optimal response to Gleevec at 6 months is achieving a Ph percentage
less than 35%.
- Not reaching a MCR or less than 35%Ph+ at 12 months of Gleevec
is termed failure with a 1-35%Ph+ at 12 months being a suboptimal
response. An optimal response at 12 months is 0%Ph+ and a PCR 3-log
reduction.
- No CCR at 18 months is termed Gleevec failure. A CCR but no
PCR 3-log reduction at 18 months is termed a suboptimal response to
Gleevec. An optimal response to Gleevec at 18 months is being in CCR
and having a greater than 3-log PCR reduction.
- No cytogenetic response to Gleevec at 6 months and inability
to achieve a MCR at 12 months leaves the patient with only a 20% chance
of ever achieving a CCR at a later time. A PCR 3-log reduction, also
termed a major molecular response (MMR) is accepted by doctors as a
milestone in Gleevec therapy which if the patient achieves, there is
minimal risk of relapse and 100% protection from disease progression as
seen from the IRIS trials 5 year follow-up. The desirable timeframe for
achieving a PCR 3-log reduction is in the first 12-24 months of Gleevec
therapy.
REFERENCE:
Defining and Managing Imatinib Resistance
Defining and Managing Imatinib Resistance
Michael J. Mauro
Correspondence: Michael J. Mauro MD, Associate Professor, Center for
Hematologic Malignancies, Oregon Cancer Institute, Oregon Health &
Science University, 3181 SW Sam Jackson Park Road, UHN-73C, Portland, OR
97239 USA; Email: maurom@ohsu.edu <mailto:maurom@ohsu.edu>
Abstract
While imatinib is highly effective therapy, with improving prospects
over time for sustained remission and potential to severely limit or
eliminate disease progression and transformation, a minority of patients
either fail or respond suboptimally to imatinib; as well, disease
eradication may not be possible with imatinib. Distinct patterns of
resistance have evolved with the use of imatinib, and Abl kinase
mutations, which alter imatinib binding or favor kinase conformations
inaccessible to imatinib, are a common finding associated with clinical
resistance. Dasatinib and nilotinib, alternate Abl kinase inhibitors,
restore hematologic and cytogenetic remission in the majority of
patients with primary failure or acquired resistance in chronic phase
disease; in advanced disease and Philadelphia chromosome (Ph)+ ALL,
responses are more limited and relapse is common. Future studies with
these agents will focus on further optimizing imatinib response,
reduction of minimal residual disease, and prevention of resistance.
Still newer inhibitors active against T315I mutant BCR-ABL may overcome
primary and secondary resistance to dasatinib and nilotinib.
http://www.asheducationbook.org/cgi/content/full/2006/1/219