William J. Cardarelli, PharmD, is an experienced pharmacy administrator for more than 20 years, with a large breadth of experience in cost containment and resource allocation in the managed care arena. He has held progressive management responsibilities at Harvard Community Health Plan, Harvard Pilgrim Health Care, and Harvard Vanguard Medical Associates. In addition, he continues his academic responsibilities as the principal manager of an ASHP-certified residency program in managed care in collaboration with the Massachusetts College of Pharmacy.
In an interview, Dr Cardarelli shared his thoughts on considerations for the treatment of older adults with acute myeloid leukemia (AML), addressing financial issues, the prospect of standardized care for this disease, and priorities for the development of novel therapies.
What are some of the factors that contribute to increased cost and subsequent economic burden for patients with AML?
AML is associated with very high morbidity rates that begins with a very high hospitalization cost. Patients are diagnosed and more often than not undergo consolidation therapy, which requires hospitalized for about 3 weeks. Approximately 80% of patients do very well; that is, they are hospitalized, go into remission, stay in remission, and they come out of the hospital and are labeled a “treatment success.”
For those patients who do not successfully complete treatment, one of two things occur. They either have such an adverse reaction to the therapy that it is impossible for them continue, which ultimately requires additional treatment in the hospital. The other occurrence is they may have such horrific side effects that they become incapable of completing the therapy, and they relapse almost immediately. For those patients, considerable costs are incurred, and post-treatment morbidity and mortality are highly likely.
As AML treatment continues to evolve, which factors are the most important for the development of novel therapies?
As of right now, manufacturers seem to prioritize getting through that initial consolidation treatment and providing patients with a decent quality of life. The good news is we are beginning to transition towards lines of therapy that identify specific translocations of genes. Genetic abnormalities are identified, and patients are directed to newer treatments that are better targeted towards the specific genetic malformations that they have. With this approach, patients have a better outcome as well as a better quality of life.
How does the standard of care differ for older patients with AML?
There is a tremendous need to minimize the infections, anemia, and hemorrhages that patients incur as a part of treatment. It really depends upon the classification of the drug itself; what mutations one encounters through the diagnostic pathway, as well as the age and performance status of the patient. The molecular abnormalities help to better determine the patient’s risk group. Therefore, at least indirectly, we can determine what the predictable outcome is for these patients.
There are a couple of staging systems available today. There is the World Health Organization (WHO) classification system, which has been out there for many years, as well as the French American British classification system. The WHO classification system is based upon the presence or absence of certain genetic makeups. The system looks specifically at approximately six balance translocations. It is much more specific in terms of which eight categories have malformations and, in part, what those malformations will ultimately entail. It is a better predictive model in terms of understanding the ultimate outcome for patients.
There are also charts available that help predict what the ultimate expectation around survival will be, as well as what the proper therapeutic remnants are and what supportive care might be needed. All of them help the physician to better guess as to what the ultimate projection will be for the outcome of a particular patient. Remember, this is predictive modeling—an inexact science at best.
What are some of the barriers to optimal AML treatment?
The largest barrier to AML treatment right now is undoubtedly expenses. However, all of the barriers are somewhat interrelated to one another; the barriers that are put in place by insurance companies lead to higher out-of-pocket expenses for patients. Insurance companies decide to not prefer a specific drug for a particular patient. That raises the copay for that drug, or perhaps does not cover the product at all. There is some science behind what products are actually defined as covered and which products are not. I do not want to imply that the decision is totally random because it is not. The coverage status is based upon the cytogenics of the disease, the cost of the drugs, and the molecular abnormalities identified, so it is not a black and white cause and effect system. There is an interplay between all of these different factors.
Due to the heterogeneous makeup of AML across all patients, are clinical pathways truly suitable in this disease setting?
I am a believer in clinical pathways based upon peer review of individual medications. When I hear the word “pathway,” I think of pathway companies that design treatments based upon scientific review of the agents. Some of them do it with the sole reasoning of restricting care based upon cost. Others do it with allowing treatment by the agents that have demonstrated the best outcomes based upon peer-reviewed journal article. Still some of them do it based upon the utility cost of the medication. Under the Affordable Care Act, technically it is not legal to restrict care based upon a cost utility analysis; yet, there are certainly some organizations that would prefer to do it that way.
Among the P&T committees that I have served on over the years, the best ones are the ones that blend all of these practices. Clearly, you have a fiduciary responsibility to the organization for which you work to provide them with the lowest cost, highest quality care. At the same time, you need to be able to supply the patients who try all of those initial products with some options if they have failed on those. What is really important to consider when you begin the second, third, or fourth line of treatment is what do you do with certain mutations. The scientific industry has responded by developing products that deal with specific mutations (eg, NPMI mutations). How well or how poorly considerations of these mutations have been indoctrinated into everyday care is open to debate.
Is there a balance that can be struck in AML between personalized care with standardized care?
There certainly needs to be a space for balance. If you can take a patient, or a cohort of patients of which 80% will respond to the “gold standard,” then that therapy that should be tried first. However, as I stated before, for those patients who do not respond, due perhaps to a specific mutation, there needs to be a mechanism for accessing other medications with the opportunity to get successfully treated and go into remission. In other words, you really need access to both standardized and personalized care. The question in my mind is: How do you jointly express them?
I should note that there is a difference in the way that we approach treatment here in the US compared with Europe. In the latter, it tends to be more of a cut and dry scientific approach, with an emphasis on a cost-utility approach. The National Institute of Clinical Excellence very clearly defines whether you will be allowed drug XYZ or drug ABC because it reaches a certain cost utility milepost with regard to return on investment. That approach does not play very well in the US market. We tend to want access to all of the different drugs and allow our physicians the autonomy to make treatment decisions after consulting with their patients. AML is one of the more expensive diseases because it has one of the higher incidence rates of all blood malignancies. The high incidence of AML is accompanied by one of the most expensive treatment courses of any blood malignancy. Hospitalizations contribute to these high costs as well.
When you look at any hematological cancer, there will always be remission, followed by relapse, remission, relapse, and so forth and so on. Mutations allow for a rather effective way of becoming resistant to these treatments very, very quickly. How we respond to the signaling process that builds remission is certainly a challenge. We have a disease state with about 20,000 to 25,0000 diagnoses annually, primarily in adults, with an even split between male and female individuals. It is also considered a disease of older men – over the age of 45 with a median onset of about 65 years. This naturally leads us into the Medicare population, where out-of-pocket expense becomes a concern. CMS becomes a major player as patients age into the Medicare benefit. We need to do the best that we can in terms of providing these patients with ample opportunity to receive optimal treatment, and therein lies the challenge because these treatments are not inexpensive.
