High copayment linked to TKI nonadherence, discontinuation in CML

Timothy Graubert, MD

Dusetzina and colleagues address an important challenge in the management of patients with CML. Oral TKIs such as imatinib are highly effective in chronic phase CML; nearly all patients achieve a hematologic response, and the majority have an excellent molecular response. However, it is essential that the malignant clone is exposed to sustained selective pressure.

Not every patient is able to stay on therapy because of intolerance, resistance, noncompliance or other factors. The cost of the drugs to patients is a plausible driver of noncompliance, but the study by Dusetzina and colleagues is the first, to my knowledge, to formally address this point. In a rigorous analysis that controlled for a number of potential confounding variables, the authors convincingly demonstrate a 70% increase (from 10% to 17%) in the frequency of treatment discontinuation in patients with higher vs. lower imatinib copayments.

There are important limitations to this study — some of which were discussed by the authors — that are important to keep in mind. First, this was a retrospective database study, so we cannot directly ascribe a cause-and-effect relationship between higher out-of-pocket costs and lower compliance. Association is not formal proof of causality. Second, the patients in this database were relatively young and had private insurance. Therefore, we cannot directly extrapolate these findings to older patients on Medicare, for example, or patients who are uninsured or who have other forms of insurance. However, the authors speculate (with good reason) that the impact of out-of-pocket expenses might be even more significant in those populations. Finally, the study examines only one drug—imatinib — the first FDA-approved therapy for this disease, and now we have second-generation inhibitors that weren’t evaluated in this study. Again, it is likely that the findings would be even more striking with those therapies because they are more expensive and have higher out-of-pocket costs for patients.

What steps could be taken to address the problem of cost as a barrier to effective treatment for CML? The first would be to reduce the overall cost of these drugs. In fact, as the authors note, the cost of imatinib more than tripled during the study period, and costs for newer generation TKIs are even higher. A distinguished group of CML experts recently argued (Experts in Chronic Myeloid Leukemia. Blood. 2013;121:4439-4442) that there is a moral imperative to reduce the costs of these drugs. Complex market pressures may make this difficult in practice, although the experience with bevacizumab (Avastin, Genentech) suggests that drug manufacturers do have some flexibility to respond to advocacy efforts from patients and physicians. Finally, different reimbursement rates for oral and IV chemotherapy drugs are in conflict with patient preference for oral drugs.

Hopefully, ongoing efforts at the state and federal levels to achieve parity in reimbursement for oral drugs will lead to lower out-of-pocket expenses and higher compliance rates. For highly effective drugs like TKIs for CML, it seems intuitive that lower out-of-pocket expenses could result in lower costs to insurers over the long run, if it means that patients would be less likely to interrupt their therapy, acquire resistance mutations and subsequently require more expensive salvage therapies.

In view of the findings from Dusetzina and colleagues, it will be interesting to see how this dynamic changes once generic imatinib becomes available. If out-of-pocket expenses are lower, compliance rates are predicted to be higher. Of course, cost is not the only factor to weigh in choosing between the available TKIs for CML. There are reasons to potentially prefer some of these other drugs in certain settings, so we’ll have to balance cost, efficacy and side effects of all of these drugs as we manage our patients going forward.