Seeking Clarity In Complexity
In 1832, Thomas Hodgkin published the first classification of a specific blood cancer, starting the field on a long path toward an ever more complicated understanding of the disease. Today, blood cancer encompasses more than 80 unique diseases. The broadest classifications are based on where the cancer starts: lymphomas originate in the lymphatic system, leukemias begin in the blood or bone marrow and myelomas come from plasma cells (a type of immune cell that produces antibodies). From there, the breakdown becomes more complicated and accounts for factors including aggressiveness or persistence of the disease, specific cell type and clinical features.
In recent years, the landscape has become even more complex. Genetic sequencing allows us to further subdivide blood cancers, and also to find common genetic underpinnings between solid tumors like gastrointestinal stromal tumors (GIST) or melanoma. Meanwhile, the number of treatments for blood cancers is also increasing, with new options like targeted therapies or immunotherapies. These medicines may be given on their own or in combination with chemotherapy or other types of medicine.
“The diversity of blood cancers is remarkable, especially when you consider that the goals of treatment can vary for each blood cancer and for each individual person,” says Nancy Valente, M.D., Vice President of Global Product Development for Hematology and Oncology. “An aggressive but potentially curable form of blood cancer like diffuse large B-cell lymphoma is treated differently than a slow-growing, incurable blood cancer like follicular lymphoma.”
The Role of Clinical Trials
Historically, deciding which treatment approach to take was determined by a few factors including, but not limited to, the type of disease, prognosis and available treatment options. Today, doctors face many complex questions about how best to use the bevy of available medicines. The best answers to these questions come from rigorous clinical studies. But with an astronomical number of potential treatment combinations, sequences and comparisons, it isn’t feasible to test every possible regimen for every kind of blood cancer.
Consider the following:
The solution, Valente says, is to take a scientifically driven approach to develop combination therapies and conduct well-designed clinical trials. “We need to be strategic in designing these trials to ensure they can answer the right questions. That’s the only path to determine the relative efficacy and safety of different medicines, or combinations of medicines, in specific patient populations.”
One especially important type of clinical trial is a head-to-head study with a current standard of care. Conducting such trials poses unique challenges – and carries significant risk too. “There’s a high bar to overcome when comparing a new treatment to a strong standard of care therapy,” says Valente. “But the insights gained from such trials are invaluable in helping doctors and patients make the most informed treatment decisions possible.”
Rapid improvements in the treatment landscape pose a challenge to designing head-to-head studies simply because the standard of care may change over the course of the trial, often a period of a few years. One possible solution is to design clinical studies that can yield meaningful results faster. For example, doctors and scientists are interested in evaluating a measure known as minimal residual disease (MRD) status as a potential surrogate endpoint. Emerging research has shown that MRD-negative status, which can be measured at an earlier time in the treatment course, may suggest treatment efficacy before a traditional endpoint like overall survival (OS) can be captured.
Biostatisticians are grappling with these questions as well, and they’re making progress in exploring flexible trials such as adaptive designs. In the future we may see more clinical trials that incorporate multiple arms or treatment stages of various durations, to allow for comparisons of several treatments or sequences within one trial. Even standard assumptions about clinical trial phases are being questioned, and this could have a significant impact on the time – and number of participants – required for clinical development.
Exploring New Horizons
Historically, blood cancer treatment has been very different from treatment of solid tumor cancers. With the advent of cancer immunotherapy, however, this may be changing. “Immunotherapy for blood cancer is an encouraging new area of research,” says Dan Chen, M.D., Ph.D., global head of development for cancer immunotherapies at Genentech. “Clinical trial data for various immunotherapy approaches are increasingly prominent at forums like the American Society of Hematology annual meeting, and we have several ongoing clinical trials evaluating our own immunotherapy pipeline across different blood cancers.”
“This new convergence of immunotherapy and hematology presents a tremendous opportunity for collaboration,” adds Valente. “A multidisciplinary approach is crucial in this new landscape, and our teams are working together across many different areas of expertise to bring fresh perspectives and drive new innovations."
Chen also highlights the importance of personalized medicine in the future of hematology. “We now take a personalized approach from the very start of clinical development, using biomarkers and diagnostics to help us identify the best candidates for clinical trials,” he explains.
And with increased understanding of cancer genetics, there may be more instances in the future where medicines developed for a solid tumor can be used for a blood cancer with the same abnormality. One such study underway sponsored by the National Cancer Institute (NCI) is called NCI-MATCH. This aims to match patients with an advanced solid tumor or lymphoma to an approved or investigational medicine based on the cancer’s genetic profile.
With more knowledge of the biology of blood cancer and potential new treatments, complexity is inevitable. However, it’s possible to use that complexity to our advantage to develop more personalized and tailored options for people upon initial diagnosis, and even in cases of relapse. Though this rapidly shifting landscape has produced gains in certain blood cancers, the hope is that we will see this progress be replicated across all blood cancers. From the complexity, the ultimate goal is to obtain the clarity needed to optimize a unique treatment approach for every individual.
1. National Cancer Institute. SEER Cancer Statistics. https://seer.cancer.gov/csr/1975_2013/browse_csr.php?sectionSEL=19&pageSEL=sect_19_table.26.html [Note: These are not the only types of lymphoma identified by clinicians]