Last year, the Food and Drug Administration (FDA) approved a total of 46 drugs, tying a record set for approvals in 2015. Cancer medications accounted for the majority of these approvals, with 16 oncology and 11 hematology drugs approved, marking a year of rapid innovations in treatment. Remarkably, 4 of these treatments were indicated for acute myeloid leukemia (AML), a disease that had not seen any new treatment options in several decades.Prior to these new drug approvals, the standard of care for AML was relatively straightforward. Patients are stratified into different risk groups based on genetic markers and other patient factors, to predict prognosis and likelihood of responding to chemotherapy. Beyond that, because there were few options for treatment, the usefulness of a clinical pathway approach to this disease was minimal compared with some other disease states with more complex treatment algorithms.
In response to the new approvals (Box 1), the National Comprehensive Cancer Network (NCCN) updated its clinical practice guidelines for the treatment of AML in February 2018.1 Updates include recommendations for molecular testing of an expanded range of gene mutations in all patients, and additional recommended regimens for induction, consolidation, and relapsed disease treatment for different subsets of patients. The increased complexity of these treatment strategies, and the potential costs associated with them, add a new dimension to the design of clinical pathways for AML.
To gain perspective on where clinical pathways for AML are expected to go from here, Journal of Clinical Pathways spoke with Chadi Nabhan, MD, MBA, FACP, vice president and chief medical officer at Cardinal Health Specialty Solutions.
Dr Nabhan has more than 17 years of clinical practice experience and is board certified in internal medicine, medical oncology, and hematology. Most recently, Dr Nabhan served as the associate professor of medicine at the University of Chicago Medicine and held administrative roles as medical director, outpatient clinical cancer center and clinics and medical director, international programs-cancer. In these roles, he directed complex clinical operations and spearheaded efforts to redesign clinical operations to improve patients’ flow, access, throughput, and satisfaction.
Dr Nabhan shared his insights about the anticipated clinical and economic impact of newly available treatments for AML and discusses how payers and clinical pathways developers are likely to respond to the changing landscape for this disease.
JCP: After decades without any new treatment options for AML, 4 new drugs for AML were approved last year. What do each of these new drugs bring to the table in terms of improving outcomes for patients?
Dr Nabhan: This is correct. Four new drugs have been approved for patients with AML, and each one brings unique characteristics that demonstrate advances in understanding the pathobiology and the challenges that AML patients suffer from.
Mylotarg (gemtuzumab ozogamicin) is an anti-CD33 monoclonal antibody that was approved by the FDA again after being pulled off the market several years ago. As CD33 is expressed on myeloblasts, targeting this protein seemed logical. This antibody is approved for relapsed and/or refractory AML patients.
Another drug that is approved for relapsed and/or refractory AML is Idhifa (enasidenib). This drug targets the IDH2 mutation that is present in a subset of patients (8%-10%). IDH2 mutations inhibit the normal maturation of myeloid cells; accordingly, this new therapy targets the essence of how AML develops and evolves.
The third drug is Rydapt (midostaurin) which was approved for newly diagnosed AML patients who carry the FLT3 mutation as detected by an FDA-approved test. This drug would be combined with the traditional cytotoxic chemotherapy that is normally delivered to AML patients, commonly referred to as 7+3 regimen (cytarabine and daunorubicin). FLT3 mutation is present in a subset of AML patients and porteinds poor prognosis. Having a therapeutic option for these patients is essential and shows the ability to design therapeutics even for difficult to treat patient populations.
Lastly, Vyxeos (daunorubicin and cytarabine) was also approved for newly diagnosed therapy-related AML or AML patients with myelodysplastic changes. This agent is essentially a fixed-combination of the usual chemotherapy drugs used in AML (cytarabine and daunorubicin). It is a unique liposomal formulation that delivers a fixed ratio of these 2 agents.
Are these new drugs having an impact, or expected to have an impact, on standard of care for patients with AML?
As these 4 drugs have all been approved in 2017, it might be too soon to quantify the actual impact that they have had on AML patients, but it is certainly hoped that they would. AML has always been a difficult disease to treat with few therapeutic options. These options are more commonly offered to younger patients who have few comorbidities if any. The above choices allow patients who previously would not have received any therapy to potentially receive treatment that might be beneficial.
What is the anticipated economic impact of new and upcoming treatments for AML?
As a disease, AML carries significant economic burden on patients, families, and the health care system. AML patients are often hospitalized, require emergency room visits, blood product transfusions, and other medical procedures. In addition, therapeutic options for AML patients are likely going to be pricey. Balancing these incremental costs against the value derived from these therapies is not an easy task and often is challenging.
Given the lack of any new therapeutic choices for this disease in many decades, any new choices are always welcome. Looking at the economics will need to be individualized at first and looked at on a patient-by-patient basis. There might be a role for using the NCCN Evidence Blocks and the American Society of Clinical Oncology (ASCO) Value Framework to improve a shared decision-making process to decide when these agents should be used and to ensure that patients who are most likely to benefit are receiving these treatments.
In summary, it might be too soon to assess the overall economic impact, but if I am to guess, I believe that these agents are likely to improve quality of life, outcomes, and reduce disease burden—translating in totality into good economic value to all stakeholders involved and, most importantly, to patients.
Traditionally there have not been clinical pathways in place for AML, correct? Is the introduction of these new treatments and others on the horizon likely to change that?
In the past, clinical pathways were not commonly used for most cancers, but that has changed. Cancers that are more commonly diagnosed were the first to adopt clinical pathways. This was the case mainly because there were studies that were done at larger scales for common diseases, where evidence-based data allowed for the development pathways that most physicians agreed on. That did not apply to rare and less common diseases that were approached on a consensus basis.
There are clear guidelines developed by the NCCN member institutions on how best to approach newly diagnosed and relapsed/refractory AML patients. There are also ASCO and American Society of Hematology statements on testing and treating this disease developed by thought leaders in the field.
Given these newer therapies, and the fact that some are developed for specific subsets of AML that need to be tested for a particular mutation (IDH2 or FLT3) or the presence of an antigen (CD33), developing pathways for AML continues to evolve. Most vendors now do offer AML pathways in discussions with each institution or health care entity that is adopting these pathways.
How are drugs that only affect a portion of patients with AML—for example, younger patients or patients with a particular gene mutation—typically addressed by payers? Are they being excluded in favor of standard therapies, or are they allowed as long as they are being used appropriately?
From a payer perspective, having the right patient receive the right therapy at the right time is a welcome progress in treating this disease where, historically, many were being treated but only the minority responded. Payers will likely demand that genomic/mutational tests [to identify patients who are candidates for targeted therapies] be performed in a highly qualified facility using technology that is approved by the FDA before allowing a targeted drug to be dispensed. I am not aware that payers have denied these treatments as long as prescribed on label.
Would the approach to developing a clinical pathway for AML be likely to be the same as or different from current payer management approaches?
I suspect that the general principle in developing pathways for AML will be the same as other diseases: differentiating AML into various subsets based on the presence of genetic mutations, and then selecting the most effective therapy if available and based on evidence. If two options exist, then choosing the one with lesser toxicity seems reasonable. If both efficacy and toxicity are comparable between two treatments, the one with more economic value is likely to be chosen and advocated by payers.
I believe that providers need guidance into how some of these genetic tests are performed as well as education into how they are interpreted. These companion diagnostics are to be integrated into the clinical pathways moving forward.
Reference
1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2018. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed April 25, 2018.
