Clinical Education Center
Chronic Myelogenous Leukemia: Testing to Detect and Treat Imatinib Resistance
The introduction of imatinib (Gleevec®) in 2001 dramatically improved the prognosis of patients with Chronic Myelogenous Leukemia (CML). An important aspect of therapy is the regular monitoring of patient response to identify those patients who are resistant, or become resistant, to imatinib.
Dr. Dan Jones, Medical Director, Cancer Diagnostics Services and Hematopathology, Quest Diagnostics Nichols Institute, discusses how recent developments in testing are enabling precise monitoring of response to imatinib and helping guide CML therapy.
Clinical Background–BCR/ABL1 Gene Rearrangement
The BCR/ABL fusion gene is formed by the rearrangement of the breakpoint cluster region (BCR) on chromosome 22 with the ABL1 proto-oncogene on chromosome 9. The translocation, which produces the BCR/ABL fusion protein, leads to a cytogenetic abnormality known as the Philadelphia chromosome, which is present in virtually all CML patients.
The presence of the Philadelphia chromosome can be detected by routine chromosome analysis (karyotype), fluorescent in situ hybridization (FISH) or quantitative reverse transcription polymerase chain reaction (PCR). Following a positive result, the stage of CML is based on the level of basophils and blasts in the blood or bone marrow.
The usefulness of each of the tests above for diagnosis as opposed to patient monitoring varies, notes Dr. Jones. “While each of these tests are adequate for diagnosis, PCR is the only technique sensitive enough to use as a routine monitoring tool once therapy has begun. So, it’s critical when the diagnosis is made that a PCR study is performed to provide a baseline.”1, 2
In addition to providing a basis for initial diagnosis, the PCR test plays an important role in monitoring therapy, since its high sensitivity can detect even very low levels of BCR/ABL1 transcript, indicative of residual CML1, 2 “Since the introduction of imatinib the primary goal of testing, and of therapy optimization, has been to identify the subset of patients who are not optimal responders,” says Dr. Jones. “This approach is now completely dependent on the PCRtest, which is the standard diagnostic test to monitor patients on treatment every 3 to 6 months, the frequency recommended in the National Comprehensive Cancer Network (NCCN) practice guidelines.” 1
The utility of the PCR test for monitoring therapy has been supported by the establishment of the International Scale (IS), a calibration system for BCR-ABL1 PCR assays. IS-compliant assays utilize secondary reference materials that are calibrated against the values obtained from a primary reference laboratory.3 “IS-complaint PCR assays enable comparisons to be made across the patient’s treatment regardless of the performing laboratory and are thus critical to patient management,” notes Dr. Jones. “They are the basis for assessing a patient’s response to therapy, and determining whether or not there needs to be a change in treatment.”
The clear presentation of these data across time periods can be a helpful tool to guide treatment decisions. “We can now help clinicians see the course of the disease in a graphical format,” says Dr. Jones. “We offer a longitudinal trending report, so clinicians can track a patient’s BCR/ABL1 transcript values in relation to treatment targets and to assess whether additional measures, such as dose escalation, or alternative therapies, such as other inhibitors, should be considered.”4 This is particularly significant, following the FDA approval in 2010 of dasatinib (Sprycel®) and nilotinib (Tasigna®) as alternative therapies for primary treatment as well as for patients with resistance to imatinib.
Once therapy with imatinib has started, initial response is critical. “We have evidence that achieving a very good initial response, as assessed by PCR, has an effect on the long term outcome,” continues Dr. Jones. “Data published in recent years show that having an optimal response, defined by PCR levels that drop approximately 3 logs over the first year of treatment, actually does prolong survival. Effective treatment early in the course of the disease impacts outcome.”5
A key goal of patient monitoring is, therefore, to determine primary or secondary resistance to imatinib. “In secondary resistance,” explains Dr. Jones, “values go down initially to the low levels you want to achieve, but subsequently come back up. This often occurs due to the leukemia developing ABL1 mutations which block imatinib or reduce the drug’s effectiveness. Matching a new drug with the particular mutation observed can improved outcomes”6
Once the PCR test has detected secondary resistance, studies can be performed to locate and identify the mutation.1, 2 Based on the results of these mutation studies, the clinician can determine which additional therapy to deploy to circumvent the particular mutation detected.“Our experience on the value of detecting the type of secondary resistance has evolved over the last 6 to 7 years. Now we have a number of drugs available to treat refractory cases of CML, enabling us to tailor therapy as needed.”
Primary resistance, whereby values do not decline sufficiently with initial therapy, remains “something of a puzzle” notes Dr. Jones. “One simple explanation in some cases is lack of patient compliance. Another is that the amount of drug isn’t sufficient to block the target. Data has shown that doubling the dose of imatinib could overcome many cases of apparent primary resistance.4 But there are a small number of patients, less than 5%, who still don’t have an optimal response even with such dose escalation. We think this could be due to an interplay between the patient’s genes related to the metabolism of drugs, as well as to the genetics of leukemia itself. We have published some initial studies identifying one of those leukemia-associated genes, PTGS1, influencing primary resistance whose effects could potentially be overcome by a combination of drugs.” 7
The availability of a precise testing modality has enabled clinicians to adjust therapy to effectively treat CML patients who develop secondary resistance to imatinib. It is hoped that continuing research will also lead to more effective options for patients with primary resistance.
National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: chronic myelogenous leukemia, version 1.2013. Available at
http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed August 8, 2012.
- Hughes T, Deininger M, Hochhaus A et al.Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1): 28–37.
- White H, Matejtschuk P, Rigsby P, et al.Establishment of the 1st World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL mRNA. BloodPrepublished online August 18, 2010; doi:10.1182/blood-2010-06-291641
- Jabbour E, Kantarjian M, Jones D, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia post cytogenetic failure on standard-dose imatinib therapy. Blood 2009.113:2154-2160.
- Hughes T,Hochhaus A,Branford S.Long-term prognostic significance of early molecular response to imatinib in newly diagnosed chronic myeloid leukemia: an analysis from the International Randomized Study of Interferon and STI571 (IRIS). Blood 2010 116: 3758-3765
- Jabbour E, Jones D, Kantarjian H, et al. Long-term outcome of patients with chronic myeloid leukemia treated with second generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood 2009.114(10):2037-2043
- Zhang W, Cortes J, Yao H, et al. Predictors of Primary Imatinib Resistance in ChronicMyelogenous Leukemia Are Distinct From Those inSecondary Imatinib Resistance. JCO. 2009; 27(22) 3642 - 3649