An Australian study of newly diagnosed CML patients concentrated on OCT-1 activity as a predictor of molecular response and progression-free survival (PFS) treated with imatinib. The study, entitled, “Chronic phase chronic myeloid leukemia patients with low OCT -1 activity randomized to high dose imatinib achieve better responses, and lower failure rates, than those randomized to standard dose”, is slated to be published in Haematologica in an upcoming issue, and was made available ahead of print as an early release paper (doi: 10.3324/ haematol.2011. 056457). The study looked at patients who were taking either 400 mg or 800 mg of imatinib daily and attempted to see if levels of OCT-1 activity had any predictive value. For a highly detailed discussion of the relationship between OCT-1 levels and imatinib uptake for CML patients, please see the article “Suboptimal response in CML linked to Gleevec uptake into leukemia cells” written by LRG Science Director, Jerry Call from the February 2008 edition of the LRG newsletter.
OCT-1 (Organic Cation Transporter 1) is a protein that is responsible for transporting imatinib into the target BCRABL positive cells (tumor cells). BCRABL is the oncogene that causes CML, and mutations in BCR-ABL are the primary means by which a CML patient becomes resistant to imatinib.
The findings of the study were of some interest for CML patients, but also should serve as a prompt for discussion and perhaps a call for further research for GIST. A relationship between imatinib dosage and OCT-1 activity was found for some patients but not for others, as Table 1 shows. (Also see accompanying Figure 1 (page 10) for information about response over time.) Thus, for patients on low dose (400 mg) imatinib, the rate of Major Metabolic Response (MMR) differed significantly among patients with low and high OCT-1 activity levels, with high OCT-1 level patients seeing markedly better results. The significance of this difference did not extend to patients with varying OCT-1 levels that were on a high dose (800 mg) of imatinib. In addition, the researchers looked at trough plasma levels and their relationship to rate of MMR, and found that those patients who had both low trough imatinib levels (defined as <1200 ng/ml) and low levels of OCT-1 activity achieved the lowest rates of MMR (47%) when compared to the other patients in the study, and this difference was statistically significant (p=0.009). In addition, this group also had the highest rate of imatinib failure, a finding that was also statistically significant (p<0.001).
White and colleagues have provided a much better picture of which CML patients might benefit from a higher dose of Gleevec. Using a combination of OCT-1 activity, imatinib plasma levels and imatinib dose, they were able demonstrate that those with low OCT-1 activity (2/3 of patients), adjusting dose for patients with low plasma levels could significantly improve results.
The findings of this study are important for CML patients, but also raise a few questions for the GIST community to consider as well. While OCT-1 activity levels were not correlated with MMR for all CML patients, they were a good predictor of outcomes for one particular subset of patients: those on a low dose of imatinib that had high levels of OCT-1 activity fared much better than those on the same dose with low levels of activity. For these patients, knowing the levels of OCT-1 activity is an important factor that, in the words of the researchers, “provides a valuable prognostic tool to determine the up-front dose of imatinib in newly diagnosed chronic phase chronic myeloid leukemia patients.” In summary, for CML patients, this test may become extremely important in the future.
The question then, is what about GIST patients? Would testing for OCT-1 activity levels be just as beneficial? Is there a similar relationship between these levels, imatinib dose, and progression-free survival? What about the role of plasma levels for imatinib and OCT-1 activity? At this point, there are no definitive answers to these questions. While CML and GIST do have their similarities, there are of course differences as well, and it is possible that OCT-1 plays a different role in each disease.
One fundamental difference has to do with drugs available beyond the first line of treatment. CML patients that don’t respond well to imatinib have second and third line drugs that are very effective for most patients. While GIST patients do have treatment options beyond imatinib, and they are effective for some patients, they are not as effective for as broad a group as with CML. Because of this, resistance is a bigger issue for GIST patients, who do not have as many broadly effective drugs beyond the first-line to fall back on, and for most patients, is extremely hard to overcome once it has developed. Thus, the best approach may be to try to prevent resistance before it happens, as opposed to trying to reverse it when it occurs. Further research into which patients need a higher dose (or plasma level) of imatinib is one of the most promising ways to prevent resistance, and this study may help provide some clues to help drive that research.
The only way to determine the role of OCT-1 is to conduct further research, both on GIST tumors, to get a general understanding of what role OCT -1 may play, and through clinical trials, to see if there is any correlation between these levels, plasma levels of imatinib, and increased survival among GIST patients. A collaborative effort may be the best approach, with GIST researchers working with their CML counterparts to augment existing research and help determine if additional research can be conducted that would directly benefit GIST patients.