Patients with sickle cell disease (SCD) face chronic and often debilitating complications, but have limited treatment options. Several presentations at this year’s ASH annual meeting focused on promising new treatments for pediatric and adult patients with SCD – including gene therapy and a potentially disease-modifying oral hemoglobin modifier.
ASH Clinical News spoke with Griffin Rodgers, MD, director of the National Institutes of Health’s National Institute of Diabetes and Digestive and Kidney Disease, about the available treatments for patients with SCD and the challenges to improving patients’ experiences. Dr. Rodgers was chair of the session, “Optimizing Therapy in Sickle Cell Disease,” at this year’s annual meeting.
ASH Clinical News: Where are we – patients with sickle cell disease (SCD) and the providers who care for them – now in the management of SCD in the United States?
Griffin Rodgers, MD: We are in a good position. First of all, in contrast to 30 years ago, the average life expectancy for a patient with SCD continues to increase. In large part, this improvement is based upon the results of government-sponsored research in the area of SCD. This research has also added to our understanding of the mechanisms behind this improved longevity; prophylaxis for childhood infectious diseases, for example, accounts for a majority of this improvement in this patient population.
Since life expectancy is improving, clearly clinicians are doing something right. Are there other areas, such as SCD-associated pain, where improvement is still needed?
Previous research has shown that the available therapies can improve the morbidity (including pain and other complications) and overall survival in patients with SCD. But there is always room for improvement, of course. Also, many providers and patients or their family members are either unaware of or have limited access to these therapies.
Hydroxyurea is currently the only drug approved by the U.S. Food and Drug Administration for the treatment of SCD in adults, but it is estimated that only about 30 percent of patients who could benefit from the drug are actually taking it – and that is an optimistic estimate. Getting the word out, to providers and patients and their families, and educating them about hydroxyurea may help increase this percentage.
Why is the percentage of SCD patients receiving hydroxyurea so low?
That is a good question. The American Society of Hematology has taken an aggressive, forward-looking stance to try to educate providers – through regional activities and sessions like the one I chaired at this year’s meeting. And, of course, at the National Institutes of Health, we are continuing to use social media and other outlets to educate the general public.
Hydroxyurea has been around for quite a while, though not in the treatment of SCD; it has been used since the 1950s for the treatment of leukemia and pre-leukemic conditions like polycythemia vera. Because of this initial use, there are still individuals who don’t think of using a form of chemotherapy to treat what is considered a non-malignant disease; however, there are other forms of chemotherapy that are being used to treat a variety of other diseases. Methotrexate, for example, is being used to treat psoriasis. We have to quash the notion that, because a drug was developed for a particular indication, that approved indication is the only use that should be considered.
What topics were addressed in the session on optimizing SCD care?
One of the main topics we addressed in this session was the frequent complications associated with SCD – specifically chronic pain. In this setting, cumulative damage to the central nervous system via this chronic pain can cause neurocognitive impairment. That has implications for patients’ entire lives – for example, education in young pediatric patients and their career choices as they age.
The session also dealt with issues related to clotting and the risk for venous thromboembolism in SCD patients. There are still questions about how to both diagnose and appropriately treat these events.
How does the future of SCD treatment look; are there new therapies on the horizon?
Obviously, we need to increase the use of hydroxyurea, but researchers are looking at other drugs that target some of the downstream complications associated with a vaso-occlusive disease like SCD, rather than drugs that directly treat the underlying hemoglobin disorder and the sickling manifestations.
We know that SCD affects red blood cells and activates the coagulation system and inflammatory pathways because of some of its secondary complications. Targeting some of the coagulation phenomena associated with the disease, as well as the inflammatory component, may be a way to either directly treat patients in acute vaso-occlusive crisis, or to potentially prevent these crises from happening in the first place.
Having been involved with clinical research in SCD, including the research that eventually led to the approval of hydroxyurea, are you optimistic about the future of SCD treatment?
I would characterize the future of SCD therapy by looking at the past. Coined by Linus Pauling in 1949, SCD is the first genetic disease to be understood at the molecular level, giving us an understanding of not only the protein abnormality, but also the genetic underpinnings of the disease. Now, we also have ready access to the stem cells of SCD patients, so treating the upstream complications is an area of active investigation.
At the moment, the most effective way to cure this disease is to perform a bone marrow transplant. Sadly, though, only about 25 percent of patients who could benefit from transplant have identical-matched sibling donors – leaving a vast number of patients still ineligible. There are several approaches to transplantation, and my colleagues at the National Institutes of Health are currently working on developing a less myelosuppressive form of transplantation. We are certainly hoping that approaches and others like it will help make an increasing number of patients eligible for transplantation.
Gene therapy also holds tremendous promise for the future. For SCD patients, gene therapy involves taking a patient’s own bone marrow or stem cells, modifying them in a way that would counteract the effect of the sickle mutation.
Also, in terms of addressing some of the downstream complications of the drugs, finding new therapies that target the coagulation system, the adhesion system, and the inflammatory system are other promising possibilities. New combinations of therapies offered at different times in patients’ disease, as well, may ultimately solve the problem in the vast majority of patients.