The researchers tested peripheral blood collected from 150 patients in the TIDEL II protocol for ABCB1 mRNA expression at day 1 and at day 22 of imatinib therapy. Patients in this phase 2 study were assigned to once-daily 600 mg imatinib followed by dose escalation to once-daily 800 mg once daily in suboptimal responders. Those who did not respond to the higher dose could then advance to twice-daily 400 mg nilotinib.
Patients were then classified as either high-fold rise (>2.2) or low-fold rise (<2.2) based on their changes in ABCB1 mRNA expression at day 22.
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High-fold rise in ABCB1 mRNA expression was negatively correlated with imatinib response.
| Outcomes for patients with high-fold rise ABCB1 mRNA expression after 22 days of imatinib therapy versus low-fold rise |
| Outcome | High-fold rise (>2.2) | Low-fold rise (<2.2) | ||||||
| EFS | 70% | 91% | ||||||
| Early molecular response (12 months) | 80% | 91% | ||||||
| Major molecular response (24 months) | 48% | 78% |
BCR-ABL1IS percentage early in therapy is strongly predictive of long-term patient response, but no significant difference in the BCR-ABL1IS percentage at day 1 (P = .120) or day 28 (P = .060) was found.
In a 2014 study, researchers observed no difference in ABCB1 mRNA expression at 12 months in optimal responders, in contrast with those who either failed to respond, responded sub-optimally, or progressed to blast crisis.2 Dr Eadie noted, however, a crucial difference between the 2 studies: “Previous studies looked at only 1 time point, either at diagnosis or after 12 months of therapy, whereas we’ve looked at 2 time points. We found that it wasn’t just the absolute level of ABCB1 mRNA, but the change in a particular patient that was predictive.”
Hetty E. Carraway, MD, MBA, associate professor of oncology at the Cleveland Clinic’s Taussig Cancer Institute in Ohio, told Cancer Therapy Advisor that the ability to test for early indicators of therapy resistance was a “great tool,” but requires further validation.
“There are other reasons patients can have resistance to these agents and, more commonly, the mechanisms of resistance to these agents are through a mutation of the Bcr-Abl kinase domain,” she said. “We’re learning how best to deliver these agents and how to potentially individualize therapy. For the majority of patients who respond well, they’ll do just fine. But novel ways of measuring initial responses to therapy are paramount, so that we can identify patients early who are not going to respond well, and change their therapy early on in treatment.”
According to Dr Carraway, more research needs to be done to determine whether there is value in giving second-generation TKIs to patients who have poor response to the ABCB1 mRNA over-expression.
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“There are different ways to measure mechanisms of resistance, and it is important to figure out why some patients are resistant,” she said. “Though this is a minority population, it’s important to identify those patients and to find therapy appropriate for them.”
References
- Eadie LN, Dang P, Saunders VA. The clinical significance of ABCB1 overexpression in predicting outcome of CML patients undergoing first-line imatinib treatment. Leukemia. 2016 Jul 15. doi: 10.1038/leu.2016.179 [Epub ahead of print]
- Giannoudis A, Davies A, Harris RJ, Lucas CM, Pirmohamed M, Clark RE. The clinical significance of ABCC3 as an imatinib transporter in chronic myeloid leukaemia. Leukemia. 2014;28(6):1360-3. doi: 10.1038/leu.2014.38
