EUTOS Path to cure Information Case review Case reports

Case 1: Nonadherence

Synopsis

The patient is a 50-year-old woman with de novo CML-CP and a high-risk Sokal score. She is currently receiving Imatinib 400 mg/d. At 3 months, she had not achieved a complete hematologic response (CHR) (Table 1). The lack of a CHR was confirmed at 6 months, and the patient was considered in failure.

Clinical Discussion

The National Comprehensive Cancer Network (NCCN) guidelines and a recent European LeukemiaNet consensus paper cite achievement of a CHR by month 3 of therapy as a minimum initial response and lack of complete hematologic response by month 6 as failure (Table 1).^9,10 Based on these guidelines, this patient was considered a treatment failure. Under the guidelines, “failure” indicates that continuing Glivec/Gleevec therapy at the present dose is no longer appropriate for the individual patient and that an alternative treatment strategy should be considered. In such cases, there are several therapeutic options, including increasing the dose of Imatinib or switching to another tyrosine kinase inhibitor or to combination therapy. Kantarjian and his colleagues, for example, escalated the dose of Imatinib to either 600 mg daily or 400 mg twice a day in 54 patients with CML-CP who showed resistance to, or had relapsed on, Imatinib 400 mg/d.³⁸ Of 20 patients with hematologic resistance or relapse, 13 (65%) achieved a complete (n = 9) or partial (n = 4) hematologic response (HR), and of 34 patients with cytogenetic resistance or relapse, 19 (56%) achieved a complete (n = 6) or partial (n = 7) cytogenetic response (CyR).

Because this patient was treated in an investigational setting, mutation analysis was performed before making any decisions regarding modification of the patient’s Imatinib therapy. However, no mutation in the kinase domain was detected. The trough plasma concentration of Imatinib was then determined and was found to be <0.01 µg/mL at 3, 6, and 9 months despite Imatinib dose escalation to 600 mg/d between 3 and 6 months and to 800 mg/d between 6 and 9 months. This was far below the anticipated trough concentra-tions of ~1.0 µg/mL with Imatinib 400mg/d and 1.4 and 2.9 µg/mL with Imatinib 600 mg/d and 800 mg/d, respectively.

Table 1: Criteria of response to imatinib ⁹

Follow-up

Upon further questioning, the patient acknowledged that she was forcing herself to vomit after taking her prescribed medication. This case of nonadherence illustrates that failure to medicate correctly can result in a low plasma trough concentration and a poor outcome in patients receiving oral targeted agents, including Imatinib, as chronic therapy for cancer. This case also illustrates potentially unexpected behavior in a patient who may be assumed to correctly take her medication, highlighting the need for physicians to thoroughly explore any instances of, and reasons for, patient nonadherence, as well as to reinforce with their patients the importance of following the prescribed medication regimen.

Case 2: Discontinuation of Imatinib Without Recommendation

Synopsis

A second case of nonadherence was that of a 55-year-old man with newly diagnosed CML-CP who had been started on Imatinib 400 mg/d. Over the next 6 months, he achieved a CHR, but by month 9 of therapy, he lost his hematologic response. The patient initially stated he was following his prescribed regimen. However, subsequent testing at that time showed that the patient’s Imatinibplasma concentration was zero. On further questioning, the patient admitted to discontinuing Imatinib therapy without discussing this with his physician.

Clinical Discussion

This case, like the preceding one, illustrates the crucial issue of adherence to chronic oral therapy in patients with malignancies. Chronic administration by the oral route raises a number of concerns not encountered with intermittent parenteral therapy. These concerns include the potential for less than 100% absorption of the administered dose; the fact that the patient may not receive all of the intended dose because he or she does not adhere to the chronic oral ingestion required; and the fact that the drug effect, be it toxic or therapeutic, need not be related to a single administration of the drug. Patients fail to adhere to chronic oral therapy for many reasons, including simply forgetting to take their medication, poor side-effect management, psychological reasons for discontinuing therapy, and the belief that once they have achieved a response and are not experiencing disease symptoms or side effects there is no need to continue therapy. It is important to recognize that disease progression is not necessarily the same as resistance, and that, in some patients, progression or reappearance of disease may reflect patient-initiated discontinuation of therapy rather than disease mutation to a resistant state. These concepts are well recognized in psychiatry, infectious disease, cardiology, hypertension, and other areas of medicine. Recent studies have described patient characteristics associated with decreased adherence; have demonstrated that approximately 30% of patients may discontinue Imatinib for at least 30 days during their first year of therapy; and have calculated the high costs associated with nonadherence to Imatinib therapy.³¹

Follow-up

The importance of continuing Glivec/Gleevec therapy was discussed with the patient, and Imatinib was reinitiated at a dose of 400 mg/d. The patient once again achieved a CHR and went on to achieve a CCyR. Repeat assessment of plasma Imatinib trough concentrations documented them to be consistent and within the range associated with clinical activity.

Case 3: CCyR Without MMR

Synopsis

A 51-year-old man was diagnosed in 1998 with Philadelphia chromosome–positive (Ph+) CML-CP (Sokal score, 0.63; Hasford score, 1036). He underwent leukapheresis and was treated with interferon alfa until 2000. Because no CHR was achieved, treatment with Imatinib 400 mg/d was initiated in March 2001. With Imatinib therapy, the patient achieved a major cytogenetic response (MCyR) after 3 months and a CCyR after 6 months. Molecular monitoring with real-time quantitative polymerase chain reaction (RQ-PCR) methodology, performed 6 months after initiation of Imatinib treatment, revealed that, despite having a sustained CCyR, the patient did not achieve an MMR, ie, a ≥3-log reduction in BCR-ABL transcripts compared with baseline value.

In 2005, at which time the patient had been receiving Imatinib for 4 years, his Imatinib trough plasma concentration at steady state was tested on 2 occasions. Levels were 0.61 µg/mL and 0.58 µg/mL, respectively, which is about half the expected concentration. His Imatinib dose was therefore escalated to 600 mg/d. Clinical Discussion Testing for achievement of an MMR is a new approach to monitoring response to Imatinib but is currently not an established criterion of response. However, achievement of an MMR has been associated with a good long-term outcome in CML patients. Follow-up data for the IRIS study have shown that, at 60 months, rates of freedom from progression to AP/BC disease were 100% in patients with newly diagnosed CML and both a CCyR and ≥3-log reduction in BCR-ABL transcripts after 18 months of Glivec/Gleevec therapy, 98% in patients with a CCyR and <3-log reduction in BCR-ABL transcripts, and 87% in patients without CCyR (Figure 4).¹³

Figure 4: Survival without AP/BC by molecular response at 18 months on first-line imatinib

Rate of progression to CML-AP or CML-BC based on molecular response after 18 months of imatinib therapy. At 60 months, 100% of 139 patients with a CCyR and at least a 3-log reduction in levels of BCR-ABL transcripts at 18 months were free from progression to accelerated phase or blast crisis. Corresponding rates for 54 patients with a CCyR and <3-log reduction in transcripts and 88 without a CCyR were 98% and 87%, respectively.
Reprinted with permission from Druker BJ et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.13
Copyright ©2006 Massachusetts Medical Society. All rights reserved.

Therefore, directing therapy to achievement of an MMR in patients being treated for CML appears clinically sound. The European LeukemiaNet ⁹ recommendations suggest that molecular response be checked every 3 months to assess continued reduction of transcripts and to detect signs of loss of response. The NCCN10 guidelines note that molecular monitoring by RQ-PCR analysis of patients who have achieved a CCyR can be extremely useful in determining whether transcript levels are going up or down.¹⁰

The case described here illustrates a situation in which monitoring of Imatinib plasma trough concentrations was useful for the management of CML patients and should be undertaken in cases of treatment failure or suboptimal response. Our group recently demonstrated that the plasma trough concentration of Imatinib is correlated with clinical response.²⁹ In addition, using a receiver operating characteristic (ROC) curve analysis, atrough plasma concentration of 1.002 µg/mL was identified as the efficient plasma threshold for Imatinib levels in vivo (Figure 5). In the study, 26 (76%) of 34 patients with an MMR had Imatinib trough plasma concentrations exceeding the 1.002 µg/mL threshold, whereas 24 (71%) of the 34 patients without an MMR had Imatinib trough plasma levels below this level. These findings suggest that the Imatinib plasma trough concentration should be maintained above 1.0 µg/mL for clinical efficacy for patients with CML-CP to achieve MMR.

Figure 5: Box-plots of imatinib trough plasma levels

The graph shows the dispersion around the median for patients with MMR (n = 34; median = 1.350 μg/mL) and those without (n = 34; median = 0.885 μg/mL). The line across each box is the median, the bottom edge is the first quartile, and the top edge is the third quartile; the error bars represent minimal and maximal values; the orange line shows the 0.4936 μg/mL target concentration required to result in BCR-ABL–positive cell death in vitro; the gray line shows the 1.002 μg/mL efficient plasma threshold for trough imatinib levels in vivo. Of note, 27 patients without an MMR (79%) had imatinib trough plasma levels exceeding the initially described target concentration (0.4936 μg/mL) required to result in BCR-ABL–positive cell death in vitro,²⁹ suggesting that this target is not always sufficient to achieve MMR in vivo.
Reprinted with permission from Picard S et al. Blood. 2007;109:3496-3499. ²⁹

Follow-up

After 3 months on an increased dose of 600 mg, the patient’s Imatinib plasma trough concentration had risen to 1.15 µg/mL, and the patient achieved an MMR that has been sustained for more than 6 months. Although achieving a CCyR remains the accepted marker of successful treatment, the favorable results reported for patients achieving an MMR helped justify our decision to increase the Imatinib dose to a level that resulted in an MMR.

Case 4: Drug-Drug Interaction

Synopsis

A 64-year-old man presented with CML-CP and a history of seizure disorder. The patient’s only medication at presentation was phenytoin 300 mg/d. The patient was started on Imatinib 400 mg/d and tolerated therapy well; however, he failed to achieve an HR. His Imatinib trough plasma concentration was found to be much lower than the concentrations found inother CML patients taking Imatinib 400 mg/d. The patient stated that he was adherent to his daily Imatinib therapy. A drug-drug interaction between Imatinib and phenytoin was therefore suspected. A similar low trough plasma concentration was obtained 1 week after the first trough plasma level was determined.

Clinical Discussion

The patient’s failure to achieve a response to Imatinib appropriately raised suspicion of inadequate Imatinib concentrations produced by his 400-mg/d dose. This hypothesis was confirmed by assessment of Imatinib trough plasma concentrations. Low plasma concentrations of Imatinib can result from a variety of causes, including nonadherence and high Imatinib clearance. The fact that the repeat Imatinib value was similar to the initial low value confirmed the drug level test and argued for a phenytoin-induced increase in Imatinib clearance as the cause for the low, and probably subtherapeutic, Imatinib concentrations in this patient. Phenytoin, a known inducer of the major Imatinib-metabolizing enzyme CYP3A4, has been documented as increasing Glivec/Gleevec clearance approximately 4-fold.⁴¹ Given the apparent involvement of phenytoin in the patient’s failure to respond to Imatinib, change of the antiseizure medication to a nonenzyme-inducing antiseizure medication was indicated. An alternative strategy, if the patient’s seizures were not well-controlled with a nonenzyme-inducing antiseizure medication, would have been to continue his phenytoin, increase the Imatinib dose, and monitor the Imatinib trough plasma concentration to see if it increased to a therapeutic range.

Follow-up

The patient’s antiseizure medication was changed from phenytoin to valproic acid without adverse neurologic consequences. The patient rapidly achieved a CHR, and thereafter, a sustained CCyR and complete molecular response (CMR). One month after the change in antiseizure medication, the patient’s Glivec/Gleevec trough plasma level was in the range observed in other CML patients taking Glivec/Gleevec 400 mg/d. These responses following the change in antiseizure medication confirmed our suspicion of a drug-drug interaction as causing increased Glivec/Gleevec clearance and low Glivec/Gleevec levels. It should be remembered that drug-drug interactions can occur with over-the-counter and herbal medications that patients may neglect or be unwilling to divulge to physicians taking a history. An example of such an interaction is that of Glivec/Gleevec with St. John’s wort: St. John’s wort–associated induction of Glivec/Gleevec clearance results in subtherapeutic Glivec/Gleevec concentrations.^42,43

Case 5: Low Imatinib Clearance

Case Synopsis

A 45-year-old woman with newly diagnosed CML-CP was started on Imatinib 300 mg twice a day. On this regimen, she developed grade 3/4 musculoskeletal pain, as well as bone marrow hypoplasia associated with transfusion-dependentanemia. Administering erythropoietin and reducing the Imatinib dose to 200 mg twice a day failed to reverse the anemia. The patient’s Imatinib trough plasma concentration was 3.1 µg/mL, which was much higher than expected with a 400-mg/d dose. The patient achieved a CMR but remained transfusion dependent. Repeat testing revealed Imatinib trough plasma concentrations above 3.0 µg/mL.

Clinical Discussion

This patient had lower Imatinib clearance than most patients and therefore maintained higher-than-expected Imatinib trough plasma concentrations while on standard doses of therapy. Although the patient achieved a response with standard-dose therapy, she experienced unacceptable toxicity. Documentation of the higher trough plasma concentrations led physicians to explore whether decreasing the patient’s dose of Imatinib would allow maintenance of therapeutic levels of drug while producing concentrations lower than those responsible for the hematologic toxicity she was experiencing.

Follow-up

The patient’s Glivec/Gleevec dosage was reduced to 300 mg/d, after which she became transfusion independent. Over the next 12 months, repeat testing revealed Glivec/Gleevec trough plasma concentrations of approximately 2.0 µg/mL, and the patient went on to achieve a CMR. Thus, the strategy of close plasma concentration monitoring and dose reduction (although to a level below that currently recommended) resulted in clinical benefits for the patient.

CONCLUSION

Although Imatinib is highly effective in treating patients with CML, inadequate drug exposure due to pharmacokinetic factors or patient nonadherence to therapy may compromise clinical outcomes. Testing of Imatinib trough plasma levels may provide a simple and rapid means for determining whether target levels of Imatinib are being achieved and for alerting physicians to institute appropriate corrective measures when inadequate levels are detected, eg, in cases of nonadherence, drug-drug interactions, and patient pharmacokinetic variability. Moreover, given the relative ease and rapidity of Imatinib trough plasma level testing, it is conceivable that such testing should be performed prior to mutational analysis in patients displaying suboptimal responses. Results from plasma drug level testing may aid in distinguishing nonadherence or the presence of drug disposition-altering pharmacokinetic factors from a lack ofresponsiveness to Imatinib.

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Created by: Hellenbrecht , generated 2008/01/08 , last changed: 2008/07/24