A CML Patient With Elevated BCR-ABL at 3 Months: To Switch or Not to Switch?

Elias Jabbour, MD

Associate Professor
Department of Leukemia
The University of Texas MD Anderson Cancer Center
Houston, Texas


Elias Jabbour, MD, has disclosed that he has received consulting fees from Ariad, Bristol-Myers Squibb, Pfizer, and Teva and funds for research support from Amgen, Ariad, and Pfizer.


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Released: April 27, 2015

A CML Patient With Elevated BCR-ABL at 3 Months: To Switch or Not to Switch?

Case
The patient is a 58-year-old male diagnosed with chronic myeloid leukemia (CML). He has a low SOKAL score, and no comorbidities except for type 2 diabetes. He was started on imatinib 400 mg/day, achieved a complete hematologic response within a week, and was followed regularly. At his 3-month follow-up, we tested for BCR-ABL and karyotype. His BCR-ABL/ABL ratio was found to be 18% on the International Scale, and his karyotype was found to have 9 metaphases out of 20 positive for the Philadelphia chromosome.

Treatment
The big question is: How do we treat this patient at this stage? Based on NCCN recommendations, this patient clearly did not meet the 3-month milestone of less than 10% BCR-ABL. In addition, a paper by Marin and colleagues highlights the importance of treating patients with CML to a BCR-ABL level of less than 10% at 3 months. In that study, patients with CML who achieved a BCR-ABL level of less than 10% at 3 months had a significantly higher survival rate at 8 years than patients with a BCR-ABL level greater than 10% (93% vs 57%, respectively; P < .001). My colleagues and others have highlighted the importance of early response, but there are several reports highlighting that the BCR-ABL level at 6 months matters more. European LeukemiaNet recommendations, for example, suggest assessing at 6 months as well as at 3 months. So this patient can still achieve the milestones at 6 months. We still have to determine, however, why he is not improving.

Adherence
First of all, it is crucial to consider whether the patient is taking his medication. Another paper by Marin and colleagues showed that patients with CML who had 90% or greater adherence to imatinib treatment had a significantly greater probability of achieving a major molecular response or complete molecular response than those with worse adherence. Missing as few as 3 doses in a month may affect treatment. Adherence is a major issue, and patients, intentionally or not, may stop taking their medication. For example, the patient may have stopped taking his medication because he experienced adverse events.

Let’s say this patient is not taking his medication. Therefore, his elevated BCR-ABL level may mean he is not getting the adequate dose of imatinib. Switching him to another tyrosine kinase inhibitor (TKI) at 3 months may not accomplish anything if he remains nonadherent to that therapy as prescribed. At this stage, assess the treatment. Discuss with the patient if he is taking his medication, and if not, what are the reasons? Address the root causes of his nonadherence, and emphasize the importance of taking his therapy.

Switching
If it is still unclear whether he has been adherent, take the elevated BCR-ABL level as a warning sign, and reassess at 6 months. If his BCR-ABL level is less than 10% at 6 months, maintain the imatinib. If it’s still greater than 10%, it is time to switch therapy to a second-generation or third-generation TKI, based on comorbidities and mutation analysis. Options include dasatinib or bosutinib, or if the T315I mutation is present, ponatinib. We wouldn’t favor nilotinib in this case because of the patient’s preexisting diabetes.

For this patient, we continued monitoring his BCR-ABL level, and at 6 months it was at 19%. At that time, we switched him to another TKI based on mutations analysis and comorbidities. No specific mutation was identified and the patient was started on dasatinib 100 mg/day.

This case highlights the importance of close monitoring not only of BCR-ABL levels in patients with CML but also determining patient adherence as well.

Your Thoughts?
How do you determine when to switch therapy in your practice? Let us know with your comments below and in the poll question on this page. Please also be sure to check out our decision support tool, “Chronic Myeloid Leukemia: Expert Guidance on Monitoring Response to First-line Tyrosine Kinase Inhibitor Therapy,” enter your patient’s duration and response to first-line TKI therapy, and then find out how 5 CML experts would handle the case.

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