Coordination of care needed to maximize benefit from advances in sickle cell disease

The treatment of sickle cell disease has improved exponentially in the past 2 decades.

Sickle cell disease — an inherited, chronic disorder that impedes the ability of red blood cells to travel throughout the body — leads to intense pain, and increases risk for infection, stroke and pulmonary complications.

Once considered a childhood-only disorder, the life expectancy of a patient with sickle cell disease has increased from 15 years in the 1970s to approximately 50 years today. Some patients with sickle cell disease live into their 60s.

Still, treatment options remain limited.

Although hematopoietic stem cell transplantation (HSCT) is potentially curative, the procedure can cause fatal adverse events. Hydroxyurea is the only other approved therapy for sickle cell disease.

However, as researchers gain a greater understanding of the disorder, potential treatment opportunities are expanding. The ASH Annual Meeting and Exposition in December featured dozens of abstracts on sickle cell disease, suggesting new therapeutic approaches soon might exist.

“There should be a two-pronged approach in looking for potential interventions for sickle cell disease,” Alexis A. Thompson, MD, MPH, hematology section head at Ann and Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics at Northwestern University Feinberg School of Medicine, told HemOnc Today. “When we are looking for a way forward for sickle cell disease, we need to consider rationally designed drugs. And, as we understand more about sickle cell disease, we need to consider the opportunity to take drugs off the shelf that were originally purposed for another indication and ask if those drugs have some efficacy in sickle cell disease.”

Three abstracts presented at ASH highlighted potentially practice-changing approaches for the management of sickle cell disease.

In one study, the use of hydroxyurea in a novel way appeared noninferior to chronic transfusions for preventing stroke in high-risk children with sickle cell anemia. In another, the experimental drug GBT440 reduced the sickling of red blood cells. The third study suggested positive long-term outcomes with HLA-matched sibling HSCT, with many patients experiencing symptom relief for at least 10 years after transplant.

Other research has evaluated the use of gene therapy, as well as pomalidomide (Pomalyst, Celgene) — approved for treatment of multiple myeloma — to try to expand the armamentarium for clinicians who treat sickle cell disease.

However, as improvements continue, the need for additional research into transitional care and management of the condition in adults continues to grow.

HemOnc Today spoke with pediatric and adult sickle cell disease experts about advances in sickle cell disease management, why transitional care should become a research priority, and what recent progress in the field might mean for future treatment of the disorder.

Hydroxyurea for stroke prevention

Stroke is a major complication of sickle cell anemia, a severe and common type of sickle cell disease in which patients have two copies of the hemoglobin S gene. Stroke occurs in approximately 10% of children with sickle cell anemia.

Clinicians screen children for stroke via transcranial Doppler, which identifies those at high risk based on an abnormal elevation of cerebral artery flow velocity.

Lifelong transfusions can prevent stroke in high-risk patients, but these procedures can lead to iron overload or other morbidities.

In the TWiTCH trial, Russell E. Ware, MD, PhD, director of the division of hematology at Cincinnati Children’s Hospital and professor in the department of pediatrics at University of Cincinnati, and colleagues sought to determine if hydroxyurea could serve as an effective alternative to indefinite transfusions for the prevention of primary stroke in this high-risk population.

The analysis included 121 children with sickle cell anemia. Results, presented at ASH, showed hydroxyurea was noninferior to transfusions for maintaining normal transcranial Doppler velocities. At an interim analysis, after which the study closed, transcranial Doppler velocity was 143 cm/sec in the transfusion arm and 138 cm/sec in the hydroxyurea arm.

Further, no child experienced a stroke, and normal transcranial Doppler velocities were maintained in both arms.

“Indefinite transfusions are quite a burden,” Ware told HemOnc Today. “Finding an alternative that is easier to manage and just as effective would be a great achievement — that was the genesis of the TWiTCH study. We concluded that hydroxyurea can serve as a substitute for maintaining the transcranial Doppler velocities and preventing primary stroke.”

Results of the BABY HUG trial — conducted by Thornburg and colleagues and published in Blood — previously demonstrated that hydroxyurea is safe for children as young as 9 months old. The treatment also is affordable, with a monthly supply costing between $20 and $35 at most pharmacies, according to an online search conducted in January.

These data may be practice changing and have a global impact, as the United States accounts for only a small percentage of the global sickle cell disease population.

“It is beneficial for patients across the board,” Elliott Vichinsky, MD, adjunct professor in the department of pediatrics at University of California, San Francisco, director of hematology/oncology at UCSF Benioff Children’s Hospital Oakland, and director of the Northern California Sickle Cell and Thalassemia Centers, told HemOnc Today.

However, hydroxyurea may not prevent the additive consequences of the disease, Vichinsky said.

“The issue around TWiTCH and other trials like it is that the cumulative effects of the disease are extremely morbid. Pediatricians underestimate the growing morbidity because they see the kids at a resilient period and delay new therapies like hydroxyurea or stem cell transplantation,” he said. “By the time they reach the adult programs, they often have irreversible disease problems or vasculopathy.

“I am a strong advocate of early intervention of therapies that change outcomes, and TWiTCH is a groundbreaking trial that offers new options to patients throughout the world,” Vichinsky added. “My concern is for the medical community not to overinterpret the results of a trial with a noninferiority design. This landmark trial needs to be followed by long-term clinical follow-up studies. Transcranial Doppler is used as a surrogate marker for stroke rate — although I believe hydroxyurea will lower the stroke rate, the evidence supporting a proportional lower stroke rate with decreased transcranial Doppler was derived from studies in previously untranfused patients, not this study population.”

The noninferiority design was intentional, because the question being asked was about hydroxyurea being no worse than transfusion, Ware said.

“The study was stopped early after achieving that goal,” Ware said. “That was even more remarkable.”

Thompson agreed, calling the study “practice changing.”

“Given this is a noninferiority trial, this clearly offers a family a choice to continue with transfusions if they so choose,” she said. “But they can be confident that, if they choose to switch to hydroxyurea, their child will not be at an increased risk for a stroke.”

The role of transplant

Patients with sickle cell disease who have a matched-sibling donor and can undergo a transplant may achieve excellent long-term outcomes.

However, only 10% of patients with sickle cell disease have HLA-matched siblings. Further, performing HSCT in a child is risky, as it can result in severe morbidities or death.

Sickle cell disease affects an estimated 20 million to 25 million people worldwide, according to a review published in 2012 in Pediatric Blood & Cancer. However, only 1,200 patients with sickle cell disease have undergone HSCT, according to 2014 data from the Center for International Blood and Marrow Transplant Research.

Barbara Cappelli, MD, research physician at the Centre Scientifique de Monaco and the Eurocord International Registry of Paris, sought to evaluate the outcomes of patients with sickle cell disease who underwent HSCT. They used registry data to address the topic at a large scale, with data from 1,000 matched-sibling transplants conducted in 23 countries from 1986 to 2013.

Results — presented at ASH — showed only 73 patients rejected the transplant, equating to a 93% success rate. The rates of 3-year OS were 99% for patients who received donor cord blood, 94% for those who received donor bone marrow, and 80% for those who received peripheral blood.

“I think most people would opt for this HLA-matched sibling transplant right now, if it were available, because of the high cure rate,” Martin H. Steinberg, MD, professor of medicine at the Center of Excellence in Sickle Cell Disease at Boston Medical Center, and professor of medicine, pediatrics, pathology and laboratory medicine at Boston University School of Medicine, told HemOnc Today. “However, the problem with transplants is complications still occur.”

In the current analysis, 67 patients died, mostly due to graft-versus-host disease or infection.

Because of these risks, the choice between transplant and hydroxyurea may be difficult, Steinberg said.

“Hydroxyurea is a good drug, but it certainly does not cure anybody,” he said. “There are no long-term data right now on hydroxyurea. However, myeloablative transplants wipe out a patient’s bone marrow, so you also worry about myelodysplasia or leukemia down the road.”

Still, clinicians may opt for hydroxyurea over transplant because 5% to 10% of transplants will fail.

Further, because these analyses were drawn from registry data, they may not reflect every transplant experience.

“This was a secondary analysis of a pre-existing dataset that was not designed to ask and answer the question from which the conclusions have been drawn,” Michael R. DeBaun, MD, MPH, director of the Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease and professor of pediatrics and medicine at Vanderbilt University, told HemOnc Today. “It’s hard to determine the value of transplant based on nearly 3 decades of data, during which regimens of transplant and the transplant science have changed dramatically. Not all transplant protocols are created equally.”

Also, the degree of GVHD that patients experienced was not described in the analysis by Cappelli and colleagues.

Overall, HSCT may be the best option for patients with significant morbidity, where the clinical history of the disease will be progressive despite optimal medical therapy, DeBaun said.

Further, despite regular blood transfusion therapy, a subgroup of children with sickle cell anemia with strokes or silent cerebral infarcts will have infarct recurrence, he added.

“We use a model in oncology where we only provide the most aggressive therapy to the patients who declare themselves the sickest,” he said. “Why would I give a transplant with a 5% mortality rate and possibly as high as a 5% severe GVHD rate to a child who is asymptomatic and has a 99% chance to live for the next 15 years while on hydroxyurea?

“Transplant in sickle cell disease is still experimental and should be offered in a clinical trial setting to those with morbidity and at risk for progressive disease,” DeBaun added. “Most adults with sickle cell disease meet the criterion of progressive disease despite optimal medical therapy, but other than children with overt or silent cerebral infarcts, relatively few children meet this criterion.”

Clinician opinions may heavily influence whether patients undergo HSCT.

“If you have an HLA-matched sibling, the data are very well validated that children should have a transplant,” Vichinsky said. “The reason it isn’t used more frequently is unclear to me. I believe physician bias plays a major role in this problem.

“Patients trust doctors, and if doctors even give the impression they are not in favor of it, the families do not want the procedure, no matter what the facts are,” he added. “The pediatric community does not really appreciate the incredible morbidity and deterioration of these patients as they get older.”

‘Blossoming’ of trials

Many other trials are underway to assess novel agents, as well as to evaluate the repurposing of other drugs for sickle cell disease.

For instance, Claire Jane Hemmaway, MD, the lead hematology consultant at Queens Hospital in Essex, United Kingdom, and colleagues presented data at ASH on the experimental drug GBT440 (Global Blood Therapeutics), a novel oral small molecule hemoglobin modifier that works by increasing hemoglobin oxygen affinity.

Data from 30 patients (age range, 18 to 60 years) with the HbSS genotype of sickle cell disease showed those who received GBT440 experienced a greater median change from baseline to day 28 in hemoglobin, erythropoietin levels and reticulocyte count, as well as a reduction in the number of sickle cells, compared with patients who received placebo.

Based in part on these data, the FDA granted GBT440 orphan drug designation.

“At the current time, only hydroxyurea is approved for the treatment of sickle cell disease, and unfortunately, not all patients seem to benefit from this,” Thompson said. “GBT440 had early data that look promising for the management of pain and other sickle cell complications.”

Other innovative approaches also are being studied.

Researchers at Feinstein Institute for Medical Research in New York are repurposing the multiple myeloma drug pomalidomide for sickle cell disease. In a paper published in 2015 in Blood, Delmovits and colleagues showed pomalidomide increased the production of healthy fetal hemoglobin in stem cells derived from healthy volunteers and patients with sickle cell disease. The researchers concluded that pomalidomide may “reprogram” adult progenitor cells toward a manner that resembles fetal production.

Promising preclinical data suggest gene therapy is another area of hope for sickle cell disease.

At ASH, Cavazzana and colleagues presented data on the use of LentiGlobin BB305 (BlueBird Bio), a lentiviral vector that contains an engineered beta^A-T87Q-globin gene, in one patient with severe sickle cell disease and three patients with other hemoglobinopathies.

Nine months after infusion, the patient with sickle cell disease produced about 51.5% antisickling hemoglobin and had not been hospitalized for a sickle cell disease-related event at the time of the presentation.

However, these data only reflect the experience of one patient.

“Gene therapy is promising, but it is going to be a long haul,” Steinberg said. “Pomalidomide promotes the creation of fetal hemoglobin, but that, too, is still in the very early stages. In the last 5 years or so, there has been a blossoming of new trials. ... There is a lot going on, but we have so few patients in this country that it is hard to recruit to these trials and get results in a reasonable period of time.”

Hurdles remain

Although trial accrual is one barrier to sickle cell disease research, treatment and management issues also remain.

Patients with sickle cell disease who survive to adulthood experience greater complications as they age, including pain-related issues and other morbidities that often are misidentified or untreated. The transitional care of these patients has been identified as a major priority; however, the issue has yet to be addressed adequately.

“We need more providers to manage this care in adult patients,” Ware said. “It is a financial issue. Many of these patients have public insurance that does not reimburse well, and clinicians who do care for adults can only take so many patients. It is the old Medicare–Medicaid problem for any chronic illness: Who is going to take care of the patients?”

Young adults — or those transitioning from pediatric to adult care — appear most vulnerable to sickle cell disease complications. Data from Brosseau and colleagues, published in JAMA, showed patients with sickle cell disease aged 18 to 30 years had more ED visits per year than patients aged 10 to 17 years (1.59 vs. 0.68) or those aged 31 to 45 years (1.59 vs. 1.29).

Further, young adults had more inpatient stays, and they had the highest percentage of frequent acute care visits and return to acute care within 14 days.

Efforts have been made to empower primary care providers to help internists take care of these patients and use hematology specialists sparingly. This might be a productive, if not a permanent, solution, Ware said.

Some clinics transition their patients into adult care by creating a “passport,” or an identification card with a summary of the patient’s health information, which help physicians better identify or understand a patient’s history and condition.

However, greater concerns exist outside of clinics, when patients are seen in community care settings or hospitals.

“There exists a high demand for knowledgeable sickle cell disease health care providers, but a low supply of such providers. Currently, nobody wants to own the problem,” DeBaun said. “It is not part of the [quality indicator] metric for a hospital; thus, it is not a priority for a hospital administrator like a 30-day readmission is, for example.”

Like with care for patients with other chronic diseases, the primary issue is supply and demand, DeBaun said.

“If you look at practices in zip codes that are 99% African American, you will find that many of those primary care providers do not have a single sickle cell patient, despite caring for 5,000 to 10,000 patients in the general population,” DeBaun said. “You ask those doctors, ‘Why aren’t you seeing sickle cell in your neighborhood?’ It’s because they don’t understand the disease.

“There needs to be an effort to educate primary care providers about sickle cell disease, because it is a chronic disease,” he said. “It is the same effort you would need to educate an internist about diabetes or asthma.”

Last April, ASH hosted the ASH Sickle Cell Disease Summit: A Call to Action to identify the highest priority actions needed to improve outcomes for individuals with sickle cell disease in the United States and globally. The summit was a first step to devise a plan with goals for the short term — defined as within 5 years — and long term, defined as 5 to 10 years.

More than 60 stakeholders attended the summit, including clinicians and researchers; federal agency partners; and representatives from the sickle cell disease community, industry and foundations.

“The summit set the stage for developing a collaborative and forward-looking initiative,” ASH said in a statement provided to HemOnc Today. “The discussions identified key partners and yielded ideas that addressed issues which included reimbursement concerns, models of multidisciplinary quality-focused care, existing gaps in research, as well as the education and training of care providers.”

Based on these conversations and feedback received, ASH plans to release a whitepaper titled “Call to Action on Sickle Cell Disease” later this year.

Efforts like this and others should help to coordinate care, experts said.

“Ultimately, what patients need is access to care and someone who is caring about them,” Vichinsky said. “If you are a good doctor in the community and you are interested in the patient and you can recognize what you don’t know, you can find help.

“There needs to be a graduated network that includes primary care; a local or regional program that can do transfusions, transcranial Doppler, etc; and a tertiary program that does transplants and new-phase therapy,” he added. “It needs to be integrated in a spoke-and-wheel way to all work together.” – by Anthony SanFilippo

References:

Aygun B and Odame I. Pediatr Blood Cancer. 2012;doi:10.1002/pbc.24175.

Brosseau DC, et al. JAMA. 2010;doi:10.1001/jama.2010.378.

Dulmovits BM, et al. Blood. 2015;doi:10.1182/blood-2015-09-667923.

Thornburg CD, et al. Blood. 2012;doi:10.1182/blood-2012-03-419879.

The following were presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

Cappelli B, et al. Abstract 541.

Cavazzana M, et al. Abstract 202.

Lehrer-Graiwer J, et al. Abstract 542.

Ware RE, et al. Abstract 3.

For more information:

Michael R. DeBaun, MD, MPH, can be reached at m.debaun@vanderbilt.edu.

Martin H. Steinberg, MD, can be reached at mhsteinb@bu.edu.

Alexis A. Thompson, MD, MPH, can be reached at a-thompson@northwestern.edu.

Elliott Vichinsky, MD, can be reached at evichinsky@mail.cho.org.

Russell E. Ware, MD, PhD, can be reached at russell.ware@cchmc.org.

Disclosure: Thompson reports a consultant/advisory role with ApoPharma Inc. Vichinsky reports research funding from and consultant/advisory roles with Bayer and Novartis. DeBaun, Steinberg and Ware report no relevant financial disclosures.

 

 

Should hydroxyurea be offered to all children with sickle cell anemia before the onset of symptoms?

All children with sickle cell disease and sickle beta thalassemia should receive hydroxyurea starting at 9 months of age.

I started offering hydroxyurea to children and counseled their families about the benefits of this medication in the late 1990s; but, many were skeptical and others took it only irregularly. There was some negative material regarding the potential carcinogenicity of hydroxyurea, which prevented many families from accepting hydroxyurea or continuing to give it to their children.

Our center participated and enrolled a large number of patients in BABY HUG, a randomized study in which children aged 9 to 18 months received hydroxyurea or placebo for 2 years.

It took more than a decade for study results to become available. Although the study did not demonstrate efficacy in decreasing organ damage, there were tremendous benefits in decreasing clinical events. The participants had normal growth, and there was a strong suggestion of improvement in cognitive function and transcranial Doppler (TCD) velocities compared with placebo. Most importantly, hydroxyurea has been safe, with minimal side effects in clinical trials and practice so far.

Cumulative experience with hydroxyurea shows no evidence of carcinogenicity. Questions about safety of hydroxyurea for spermatogenesis, fertility and growing fetus remain, but so far there is no proof that hydroxyurea is harmful in these situations.

The results of the SWiTCH study show noninferiority of switching to hydroxyurea in patients who received transfusions for at least 3 years for a history of stroke or abnormal TCD. Other studies have shown benefits of hydroxyurea on TCD velocities. Because central nervous system disease affects almost half of children with sickle cell disease, a strong case can be made to use it for primary prophylaxis.

There are no biomarkers that can reliably predict complications or severity of disease. Substantial morbidity and complications can develop early in life.

Also, there is early evidence that significant cognitive loss can occur during the first few years of life. The brain growth is rapid during infancy and toddler years, and poor perfusion and hypoxia can leave damage that may not be realized until much later.

Hydroxyurea decreases adhesion of cells to endothelium and improves blood flow. These benefits are realized in the form of improved TCD velocity and improved transcranial oxygen saturation for brain tissue.

Although no studies have been conducted to demonstrate its efficacy in primary prevention of CNS disease, there are enough data to justify further studies.

The only side effects that have been encountered are mild to moderate transient neutropenia and, rarely, hyperpigmentation of skin and nails.

Hydroxyurea is relatively inexpensive, tasteless and easy to administer. Many pharmacies can prepare liquid preparations on request with flavoring. Frequent clinic visits are helpful to parents to answer questions and for adherence counseling.

Although no panacea, hydroxyurea is the only medication that can decrease morbidity, complications and improve survival. It should be started as early as possible to prevent complications.

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References:

Ware RE, et al. Blood. 2012;doi:10.1182/blood-2011-11-392340.

Wang WC, et al. Lancet. 2011;doi:10.1016/S0140-6736(11)60355-3.

Sohail Rana, MD, is director of community outreach and education at the Center for Sickle Cell Disease, as well as director of pediatric hematology/HIV services and professor of pediatrics and child health at Howard University. He can be reached at srana@howard.edu. Disclosure: Rana reports no relevant financial disclosures.

Hydroxyurea may not be worth the potential benefit in children with no or few sickle cell complications.

How should we approach treatment with hydroxyurea in young children with sickle cell anemia? The NHLBI Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014 includes many recommendations for the treatment of children and adults with sickle cell anemia, including two that directly address this question.

The first — “educate all patients with sickle cell anemia and their family members about hydroxyurea therapy” — was a consensus based on the expertise of the panel, and it has been widely accepted by pediatric hematologists.

The second — originally proposed to say, “In infants and children with sickle cell anemia, treat with hydroxyurea regardless of clinical severity to reduce sickle cell disease-related complications” — was revised after extensive public comments to say, “In infants 9 months of age and older ... offer treatment with hydroxyurea regardless of clinical severity.” This was a strong recommendation for children aged 9 to 42 months and a moderate recommendation for those aged older than 42 months.

Why did this recommendation lead to such controversy? It was predominantly based on the secondary outcomes from the BABY HUG study, a rigorous randomized controlled trial to evaluate the effect of hydroxyurea vs. placebo to preserve splenic and renal function.

The study included 193 children aged 9 to 18 months with sickle cell anemia without selection for clinical severity who were randomly assigned to hydroxyurea 20 mg/kg per day (n = 96) or placebo (n = 97) for 2 years. The study did not demonstrate a difference in the primary endpoints.

Hydroxyurea had few significant adverse effects in this age group, with only mild to moderate neutropenia occurring more frequently in the hydroxyurea arm than in the placebo group (107 events vs. 34 events) and no increase in serious infections.

Children randomly assigned to hydroxyurea had fewer hospitalizations and episodes of pain, dactylitis and acute chest syndrome. However, the majority (58%) of children on placebo had few of these events — 23% had none, 15% had one event, and 20% had two or three events over 2 years of follow-up.

Other studies — including several cohort studies in adults and two cohorts of children conducted in Brazil and Belgium have shown a survival benefit for hydroxyurea, but have limited hydroxyurea use to those with more severe disease.

The burdens of hydroxyurea treatment — which include more frequent follow-up visits, laboratory testing and an additional daily medication that can be difficult to obtain as a solution — need to be balanced against the potential benefit for an individual patient, and the values and preferences of the patient and their parents.

 

References:

Evidence-Based Management of Sickle Cell Disease: Expert Panel Report 2014. National Heart, Lung, and Blood Institute. Available at: www.nhlbi.nih.gov/health-pro/guidelines/sickle-cell-disease-guidelines. Accessed Feb. 1, 2016.

Le PQ, et al. Pediatr Blood Cancer. 2015;doi:10.1002/pbc.25608.

Lobo CL, et al. Br J Haematol. 2013;161:852-60.

Smith-Whitley K. Blood. 2014;doi:10.1182/blood-2014-07-577619.

Steinberg MH, et al. JAMA. 2003;289:1645-51.

Thornburg CD, et al. Blood. 2012;doi:10.1182/blood-2012-03-419879.

Voskaridou E, et al. Blood. 2010;doi:10.1182/blood-2009-05-221333.

Wang WC, et al. Lancet. 2011;doi:10.1016/S0140-6736(11)60355-3.

John J. Strouse, MD, PhD, is assistant professor of hematology in the division of pediatric hematology at Johns Hopkins University Children’s Center. He can be reached at jj@jhmi.edu. Disclosure: Strouse reports that he is an investigator on a NIH-supported study of hydroxyurea for the primary prevention of brain injury in young children with sickle cell anemia.