Defining and Recognizing the Causes of Imatinib Resistance and the Importance of Adherence


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The 3-month point can be a very valuable time point at which to classify a patient as resistant in terms of primary response to a [tyrosine kinase inhibitor], such as in this case of imatinib unresponsiveness.

— John Goldman, DM, FRCP, FRCPath, FMedSci

Imatinib (Gleevec) is a highly effective therapy for the majority of patients with chronic myeloid leukemia (CML). In the IRIS study, only 30% of patients could be considered to have failed imatinib treatment after 6 years.1 However, these 30% of patients are a substantial minority. John Goldman, DM, FRCP, FRCPath, FMedSci, of Imperial College London, provided an example of a case of a 50-year-old female patient with chronic-phase CML who received initial therapy with standard-dose imatinib. Due to her lack of a complete hematologic response and BCR-ABL transcript level above 10% at 3 months, she would be considered to have failed imatinib based on both European LeukemiaNet and National Comprehensive Cancer Network (NCCN) criteria, respectively.

Two Scoring Systems

The basis for heterogeneity in response to imatinib is not known, and efforts have been made to classify patients at the time of diagnosis in order to determine prognosis. Until recently, assessment of the prognosis of patients treated with tyrosine kinase inhibitors has relied on risk stratification based on prognostic classifications developed for patients treated with conventional chemotherapy2 or interferon alfa.3 A slight discordance was demonstrated between these two scoring systems when used in the IRIS study. More recently, the EUTOS (European Treatment and Outcome Study for CML) score has been developed based on data from a registry of 2,060 patients enrolled in studies of first-line imatinib-based regimens.4 This scoring system is based on spleen size and percentage of basophils, and can discriminate between high- and low-risk patients with regard to probability of complete cytogenetic response and progression-free survival. However, the EUTOS scoring system remains to be independently confirmed and does not appear to correlate very well with data from Hammersmith Hospital in London, according to Dr. Goldman.

Benefit of 3-month Cutoff

So, is there a better way to determine prognosis? Assessment of BCR-ABL transcript level at 3 months appears to be the best way to identify patients destined to fare poorly. A recent analysis of 283 patients with chronic-phase CML at Hammersmith Hospital receiving imatinib (or a second-generation tyrosine kinase-inhibitor in case of failure) who were followed for up to 8 years was reported by Marin et al.5 Receiver operating characteristic analysis was conducted to determine the BCR-ABL transcript level cutoffs that would best predict patient outcome. Patients with transcript levels of more than 9.84% at 3 months had significantly lower 8-year probabilities of overall survival (56.9% vs 93.3%; P < .001) and progression-free survival, as well as complete cytogenetic response and complete molecular response, than those with higher transcript levels. Dr. Goldman pointed out the fact that a transcript level cutoff of 0.61 or lower at 3 months was able to define the probability that a patient would subsequently achieve a complete molecular response.

Based on this analysis and other published papers corroborating these results, particularly that of Hanfstein et al6 published this year, Dr. Goldman concluded that “the 3-month point can be a very valuable time point at which to classify a patient as resistant in terms of primary response to a [tyrosine kinase inhibitor], such as in this case of imatinib unresponsiveness.” However, there was some disagreement among panel members about changing therapy if a patient has a transcript level above this cutoff at 3 months. Jorge Cortes, MD, suggested waiting until 6 months to consider a change, whereas Dr. Goldman pointed out the lack of prognostic value of the 6-month time point. Interestingly, the NCCN Clinical Practice Guidelines do not provide a recommendation for assessing a response to therapy at 6 months, while the European LeukemiaNet recommendations do provide for such an assessment.

Three Patterns of Molecular Response

In continuation of his presentation, Dr. Goldman noted that three patterns of molecular response can be described in patients achieving complete cytogenetic response following imatinib therapy.7 In the first, transcript levels continue to decline, reaching a level below 0.01%, and the patient does well. In the second, transcripts decline up to a point, reaching a level between a major molecular response and a complete cytogenetic response, and then level off (plateau). In the third, transcript levels initially decline, but then increase and the initial complete cytogenetic response is lost (cytogenetic relapse). It is important to note that patients with each pattern can have different levels of responsiveness or sensitivity to a particular tyrosine kinase inhibitor.

Mechanisms of Resistance

What are the mechanisms that underlie resistance? Resistance can be primary or secondary (acquired), each of which may have a different molecular basis. Dr. Goldman has created a classification scheme for resistance that categorizes resistance as being pharmacologic, leukemia cell–related, or patient-related. Acquisition of ABL kinase domain mutations is an important acquired mechanism of resistance that can be categorized as being leukemia cell–related. For example, the mutation caused by replacement of threonine by isoleucine at 315 (T315I) interferes with the binding of imatinib and the second-generation tyrosine kinase inhibitors; this resistance may be overcome with third-generation investigational agents such as ponatinib.

Patient-related resistance is particularly related to poor adherence and refers primarily to patients who do not respond very well or lose their response fairly rapidly. There are a number of indirect methods of assessing adherence, but microelectronic monitoring systems are considered to be the “gold standard.”

Marin and colleagues at Hammersmith Hospital used microelectronic monitoring systems to determine whether variability in adherence could account for the variability in level of molecular responses achieved with imatinib.8 In patients who achieved complete cytogenetic response, achievement of a major molecular response was strongly associated with adherence. The 6-year probability of achieving a major molecular response was significantly higher in patients having an adherence rate of higher than 90% compared to those with rates of 90% or lower (94.5% vs 28.4%, P < .001). ■

References

1. Hochhaus A, Druker BJ, Larson RA, et al: IRIS 6-year follow-up: Sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood 110(suppl 11):Abstract 25, 2007.

2. Sokol, JE, Cox EB, Baccarani M, et al: Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 63:789-799, 1984.

3. Hasford J, Pfirrmann M, Hehlmann R, et al: A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90:850-858, 1998.

4. Hasford J, Baccarani M, Hoffmann V, et al: Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: The EUTOS score. Blood 118:686-692, 2011.

5. Marin D, Ibrahim AM, Lucas C, et al: Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J Clin Oncol 20:232-238, 2012.

6. Hanfstein B, Muller MC, Hehlmann R, et al: Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia 26:22096-22102, 2012.

7. Marin D, Kaeda J, Szydlo R, et al: Monitoring patients in complete cytogenetic remission after treatment of CML in chronic phase with imatinib: Patterns of residual leukaemia and prognostic factors for cytogenetic relapse. Leukemia 19:507-512, 2005.

8. Marin D, Bazeos A, Mahon F-X, et al: Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol 28:2381-2388, 2010.



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