Mechanisms of Resistance

Despite the impressive results with imatinib, a subset of patients treated with imatinib develops resistance. Failure to achieve a landmark response is considered primary resistance, and this is further subdivided into primary hematologic resistance and primary cytogenetic resistance. Secondary resistance is defined by the achievement and then subsequent loss of a hematologic or cytogenetic response. Hematologic resistance occurs in 2% to 4% of cases, whereas cytogenetic resistance is more common, occurring in 15% to 25% of patients. Mutations in BCR-ABL are rarely responsible for primary resistance. Recent work suggests that primary resistance may be associated with increased transcript levels of the drug metabolism gene prostaglandin–endoperoxide synthase 1/cyclooxgenase 1, and this may serve as a biomarker to distinguish patients with primary resistance to imatinib.

Several mechanisms of resistance to imatinib have been described. These can be classified into two categories: BCR-ABL –dependent and BCR-ABL –independent. The first group includes amplification or overexpression of BCR-ABL or its protein product, and point mutations of the ABL sequence. The second group includes multidrug-resistance expression and overexpression of Src kinases. BCR-ABL –dependent mechanisms are more common, particularly point mutations, which have been identified in approximately 50% of patients who develop clinical resistance to imatinib. More than 90 different mutations have been described and occur in any of the different relevant domains of the kinase, including the ATP-binding domain (also known as P-loop), the catalytic domain, the activation loop, and amino acids that make direct contact with imatinib. The significance of these mutations varies. Although some retain some sensitivity to imatinib at concentrations similar to those of the wild-type sequence others, particularly T315I, are nearly completely insensitive to imatinib. Most of the clinically relevant mutations develop in a few residues in the in the P-loop (G250E, Y253F/H, and E255K/V); the contact site (T315I); and the catalytic domain (M351T and F359V). The P-loop mutations have been suggested to carry an increased risk of rapid blastic transformation and short survival, although the MD Anderson Cancer Center (MDACC) experience does not support this notion. In some patients, more than one mutation may be present at the same time. This phenomenon seems to increase in frequency after treatment with more than one tyrosine kinase mutation. Mutations are quantified by direct sequencing and the sensitivity of such assay varies between 10% and 25%. Other methods, such as denatured high-performance liquid chromatography, increase the sensitivity to 1% to 10%. However, it is unclear at this time if identification of small mutated clones with these highly sensitive methods is clinically relevant.

Other mechanisms of resistance caused by intrinsic factors include BCR-ABL gene amplification, BCR-ABL overexpression, aberrations in other oncogenetic signaling pathways, and the persistence of leukemic stem cells. Extrinsic factors contributing to resistance include those that decrease the blood levels or bioavailability of imatinib, such as patient compliance, drug–drug interactions, drug influx and efflux, and multidrug resistance in sanctuary sites, and microenvironmental factors.

Mutation Screening During Imatinib Therapy

The European LeukemiaNet (ELN) and the National Comprehensive Cancer Network provide guidance for the monitoring of patients with CML. The criteria for defining optimal response, suboptimal response, and failure to respond are outlined in Table 1 . The ELN recommends mutational analysis in instances of suboptimal response or failure to therapy, and always before changing therapy to a second-generation tyrosine kinase inhibitor (TKI). Patients failing TKI therapy should potentially be assessed for compliance to therapy before switch, because it has been shown that patient-reported compliance and actual compliance reported can be discordant, and this may be a reason for treatment failure. The magnitude of increase in BCR-ABL transcript levels that should prompt mutation testing is a topic of debate. Fivefold to 10-fold rises have been proposed as a reasonable trigger for mutation testing. A recent study demonstrated that increases in BCR-ABL mRNA levels of fivefold or more were not sufficiently sensitive in detecting mutations, and that a 2.6-fold increase in BCR-ABL transcripts is a better threshold. In most clinics, however, it may be more reasonable to consider mutation testing when BCR-ABL levels increase at least fivefold, confirmed in an independent test in the same laboratory to confirm that the observed increase is real, and not caused by assay or laboratory variability.

Strategies to Overcome Imatinib Resistance

Multiple strategies to overcome failure to standard dose (400 mg/day) imatinib are under investigation. These include dose escalation of imatinib, switch to a second-generation TKI, other novel TKIs in a clinical trial, non–TKI-based therapy, and allogeneic stem cell transplant in eligible patients.

Imatinib Dose Escalation

Dose escalation can improve the response in a subset of patients with resistance to standard-dose imatinib and was the main option for managing suboptimal responses and treatment failures before the introduction of second-generation TKIs. In a retrospective analysis of patients enrolled in the IRIS trial, Kantarjian and colleagues reported that among 106 patients who required dose escalation because of resistance to standard-dose therapy, freedom-from-progression and OS rates were 89% and 84%, respectively, at 3 years from dose escalation. In another study from MDACC, 84 patients with CML-CP were dose escalated to imatinib, 600 to 800 mg/day, after developing hematologic failure (n = 21) or cytogenetic failure (n = 63) to standard-dose imatinib. Among patients who met the criteria for cytogenetic failure, 75% (47 of 63) responded to imatinib dose escalation. In contrast, in patients where imatinib was dose escalated because of hematologic failure, 48% achieved a complete hematologic response (CHR) and only 14% (3 of 21) achieved a cytogenetic response. Patients more likely to respond to imatinib dose increase are those who have previously achieved a cytogenetic response and then lost it and who have not developed any mutations unresponsive to imatinib. Even in these cases, a switch to a second-generation TKI is preferable unless the patient has no access to these agents.

Several Phase II studies examined the role of a higher dose of imatinib (800 mg) upfront in the treatment of patients with CML. The Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study was a Phase 3 trial comparing the efficacy and safety of high-dose (800 mg/day) with standard-dose imatinib (400 mg/day) in patients with newly diagnosed CML-CP. The primary endpoint of the study was rate of major molecular response (MMR) at 12 months of therapy. A 24-month update on the TOPS data was recently reported. It seems that there was no significant difference between the 800 and 400 mg/day arms for either the CCyR (76% vs 76%, respectively; P = 1.00) or MMR rate (51% vs 54%, respectively; P = .626). Most importantly, thus far at 24 months there were no differences between arms with respect to EFS (95% vs 95%, respectively; P = .71), PFS (98% vs 97%; P = .64), and OS (98% vs 97%, respectively; P = .70), although it is still relatively early. Adverse events tended to be more common among patients in the 800 mg/day arm versus the 400 mg/day arm, as was the rate of discontinuation caused by adverse events (12% vs 5%, respectively). The results from the TOPS study were confirmed in a randomized trial Gruppo Italiano Malattie Ematologiche dell’Adulto 021/ELN assessing the efficacy of imatinib 800 versus 400 mg/day as front-line therapy in high-risk Sokal patients. The primary study endpoint of CCyR at 1 year was not significantly different between patients treated with imatinib 400 (61%) versus 800 mg/day (64%). There was a trend toward higher rates of MMR with 800 compared with 400 mg/day, but the differences were not statistically significant. Adverse events were not significantly different between treatment arms, but compliance was lower in the 800-mg arm (62% received doses >600 mg) compared with the 400-mg arm (87% received doses >350 mg).

Although the aforementioned studies have shown improved CCyR and MMR with a higher dose of imatinib, the follow-up of these studies is short to evaluate for EFS and OS. Hence, at the writing of this article, imatinib at a dose of 400 mg daily is still the preferred regimen of choice in patients newly diagnosed with CML-CP.