Should a new (and cheap) test for chronic lymphocytic leukemia be a component of prior-authorization protocols?
Thomas Morrow, MD
Technology, the focus of this column, has virtually exploded in the past several years. Most managed care decision-makers have focused on the cost of the new therapeutic regimes, with particular interest in the latest budget busters, namely the biologic drugs. Seldom do managed care fiscal agents see a new technology that offers the opportunity to reduce the cost of the biologic medications.
FC minimal disease testing offers just that opportunity.
Chronic lymphocytic leukemia (CLL) is the second most common type of leukemia in the United States with about 10,000 cases diagnosed each year. It is very uncommon under age 45, with about 95 percent of all new cases diagnosed in patients over age 50. This type of leukemia is different from the other types of leukemia in that radiation and benzene exposure are not known risk factors.
If one word could be used to describe this disease, the word would be "gradual." Early signs and symptoms are few and well-being is preserved until much later in the disease progression. Gradually, the patient develops constitutional symptoms of fatigue, weight loss, shortness of breath, and more frequent infections. Often the diagnosis is made after a routine physical exam reveals an enlarged lymph node or elevated lymphocyte count on blood screens. Diagnosis is confirmed with a bone marrow biopsy. There are three different types of CLL: T-cell, B-cell, or NK-cell (natural killer).
This indolent disease was considered incurable two decades ago. Therapy has evolved from administering alkylating agents such as chlorambucil to the purine analog fludarabine and more recently to monoclonal antibodies — alemtuzumab (Campath) and rituximab (Rituxan). This progression has offered significant improvements in clinical response, but has also created a conundrum — clinical response does not correlate with long-term survival, in contrast to other leukemias.
In analyzing the correlation between clinical response and long-term survival, researchers have focused on the National Cancer Institute 1996 criteria of clinical response. Other tests are available to detect the actual DNA of leukemic cells using polymerase chain reaction, so named because it uses an enzyme to replicate DNA to obtain sufficient quantities to analyze. In recent studies, prolonged progression-free survival is improved if the polymerase chain reaction is negative, meaning that there is not enough of the abnormal DNA in the sample to analyze.
Minimal residual disease
Even when the polymerase chain reaction is negative, there are probably a number of malignant cells still alive that are undetectable, and sometimes referred to as minimal residual disease (MDR). These residual cells then repopulate, resulting in a relapse. If these few cells are eradicated, we may have a longer disease-free survival — or dare we say a cure? But, the problem is detecting these isolated, rare cells.
Technology has again come to our aid in the form of a new test. Scientists have developed a new method to detect these small amounts of cancer cells in patients with B-cell chronic lymphocytic leukemia (B-CLL). This test utilizes a four-color flow cytometry (FC) technology that can detect even a single B-CLL cell in 10,000 white blood cells.
FC refers to a process whereby cells suspended in a flowing saline stream move past a stationary set of detectors. These detectors can simultaneously measure several cellular parameters on a cell-by-cell basis. This contrasts with spectrophotometry, where measurements are done on the entire bulk of the sample, and light microscopy, a time-consuming and expensive procedure that requires years of specialized training.
The cell sample is exposed to specialized antibodies that are conjugated with fluorochromes called fluorescent probes. There are extensive libraries of antibody-fluorochrome probes to detect a variety of different cell types. Once exposed to these antibodies, all cells with the specific receptor for one of the probes will fluoresce under a special laser. All of this is tracked by a computer.
The data are reviewed by a specially-trained technologist who, in a labor-intensive phase, groups similar cells together in a process termed gating and sends the results to the pathologist. The pathologist can then analyze the various cell groups and estimate the number of specific types of cells, both normal and abnormal. FC can be used to diagnose a disease as well as to follow post-therapy response.
Six different markers
FC allows correlation of up to six different markers on a single cell and is much faster than immunohistochemistry (IHC), which can only analyze one marker per slide. In addition, FC can be used on peripheral blood, bone marrow aspirate, and cerebrospinal fluid — samples that are not able to be analyzed by IHC. Overall, FC is less expensive and much faster (one to two lab hours) to process than IHC, although the interpretation by a skilled technician remains.
The one disadvantage of FC is that the architecture of a sample is lost as the cells are analyzed in a suspension, making this method less desirable than tumor sections or slides in solid tumors where the architecture of the tumor is important in staging.
Because this new technology detects very low levels of B-cell leukemic cells, it will enable clinicians to cease therapy with a level of clinical certainty unheard of in the recent past, thus potentially preventing unnecessary courses of expensive therapy. Common current therapy includes Campath, costing about $64,000 for a three month course, and Rituxan and Fludara, costing about $20,000 for a six-month course. When FC is used to detect MRD, patients avoid the painful, invasive bone marrow biopsy. This FC-MRD test retails for about $1,500.
How should managed care respond to this new test? First, decision makers need to make sure they follow developments in the field of testing. As previous columns have indicated, genetic testing is expanding at a considerable rate. Technology such as FC testing is also likely to become a major focus of attention as vast libraries of the fluorescent probes are developed to detect numerous different cancers.
FC will become a normal part of clinical practice rapidly. How will it be covered? Should FC become a requested component of the prior authorization protocols for various expensive drug regimes? Does your organization have the technical expertise to develop combined testing/therapeutic prior authorization processes? Should these requests be processed by the pharmacy department or medical department? Technology has opened new frontiers in therapy management, but also has required our decision-makers to be more highly educated.
Thomas Morrow, MD, is president of the National Association of Managed Care Physicians and vice president and medical director of Matria Health Care. He has 20 years of managed care experience at the payer or health plan level.
Dr. Morrow discloses that he has received honoraria or other financial benefit during the last three years from the following commercial companies: Amgen, Amylin Pharmaceuticals, AstraZeneca, Biogen Idec, Centocor, Galderma, Genentech, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Novo Nordisk, Pfizer, Procter & Gamble, Q-Med, Sanofi-Aventis, Teva Pharmaceuticals Industries, UCB, and Wyeth.