Three signs of real progress against sickle cell disease

Reviewed by Alina Shrourou, B.Sc. (Editor)Jun 19 2019

A decade ago, the United Nations declared June 19 to be World Sickle Cell Awareness Day- and for good reason.

This genetic condition warps round red blood cells into crescent-shaped ones that disrupt blood flow, damage organs, and cause frequent bouts of pain. Millions of people worldwide have sickle cell disease (SCD) and hundreds of thousands children and adults die each year from SCD-related infections, strokes, sudden cardiac death, and other complications.

In the U.S., people with sickle cell disease commonly live well into adulthood. Here, survival times have nearly doubled from a median life expectancy of 28 years in 1979 to about 43 years in 2014. Life expectancy continues to improve. However, the disease strikes much harder in limited-resource nations, especially in sub-Saharan Africa, where many children born with sickle cell disease die before their 5th birthday and nearly 90 percent never reach adulthood.

Scientists at Cincinnati Children's have been hunting for years for improved ways to help people with sickle cell disease. Much work remains, but real progress is happening:

Hydroxyurea is safe and effective in Africa

One reason why so many African children die early from sickle cell disease is that few are properly diagnosed early in life, and even fewer have access to disease-modifying therapy. Blood transfusions help manage complications and extend life in developed nations, but are not available or safe in most limited-resource countries.

In recent years, the medication hydroxyurea has emerged in the U.S. and Europe as a far less costly alternative to frequent blood transfusions. However, adopting this newer approach has been uneven in the U.S. and even slower in Africa.

Cincinnati Children's blood disease expert Russell Ware, MD, PhD, is working with partners in four African nations in hopes of speeding things up. In 2015, Ware led a major U.S. clinical trial of hydroxyurea, which ended a year early because the drug was so successful at controlling sickle cell symptoms. Then in December 2018, Ware and colleagues garnered national news attention when their study, published in the prestigious New England Journal of Medicine, demonstrated exciting results among 600 children from the Democratic Republic of Congo, Uganda, Kenya and Angola.

Even in an African setting hydroxyurea is feasible to use, accepted by patients and families, well-tolerated, and safe for children with sickle cell anemia. Almost all of the children had clinical improvements, and the older patients were well enough to attend school."

Co-author Leon Tshilolo, MD, PhD, from the Centre Hospitalier Monkole in the Democratic Republic of the Congo

The study showed that hydroxyurea reduced sickle cell pain by 55%, infections by 38%, malaria by 51%, transfusions by 67%, and death by 70%.

Hydroxyurea is already on the World Health Organization's Essential Medicines list for children, is available in generic form for about 50 cents a pill, and can be stored at room temperature, Ware told the New York Times. For hydroxyurea to become widely available, however, the price needs to be much lower and guidelines for dosing and monitoring need to be established.

Doctors get faster at determining optimal hydroxyurea doses for children with sickle cell disease

A recent clinical trial led by Cincinnati Children's researchers Patrick McGann, MD, MS, and Alexander Vinks, PharmD, PhD, reports success at determining a sickle cell patient's ideal dose of hydroxyurea in a matter of hours instead of the current practice, which often takes six to 12 months.

The process involves rapidly analyzing a few drops of blood at 15 minutes, 60 minutes and 180 minutes after administering an initial dose of the medication. By tracking how fast the drug levels rise and fall over time-;a method called pharmacokinetics-;doctors can set more precise dosing levels from the beginning of treatment. Results from 50 children participating in the clinical trial were published online May 20, 2019, in the American Journal of Hematology.

"This is an exciting study and initiative," McGann says. "Dosing of hydroxyurea varies widely, with some patients requiring nearly double the dose of others. Currently, dosing is done with a "trial and error" approach that takes a long time and many blood draws, which places burdens on families and providers."

The early data indicates that guided dosing isn't just quicker, it's better.

With this personalized dosing method, patients starting with a guided dose achieved higher levels of healthy red blood cells than commonly achieved via standard practice. Also, when the blood testing indicated that higher levels of hydroxyurea were needed, patients tolerated the higher doses without experiencing side effects.

"The dosing model is currently available only through the study, but we are now expanding access through a multi-center clinical trial and then hope to make it widely available," McGann says.

Clinical trial underway for sickle cell gene therapy shows encouraging early results

Even before there was a World Awareness Day, Punam Malik, MD, Director of the Comprehensive Sickle Cell Center at Cincinnati Children's was working on a way to apply emerging genomic technologies toward curing this inherited killer.

The cure isn't here yet, but in December 2018 it took a big step closer. That's when Malik stood before the annual meeting of the American Society of Hematology in San Diego to present data from the first two adult patients to receive a gene therapy she developed here.

"One year after treatment of our first patient, and six months after treatment of our second patient, both have seen a remarkable improvement in the quality of life due to remarkable reduction in disease symptoms. This includes near elimination of chronic pain and sickling events and improved anemia," Malik told the audience. "Although it's still early post-treatment, these preliminary results are quite promising."

Other medical centers also are testing other forms of gene therapy for sickle cell disease. However, the approach Malik proposes involves less intense pre-treatment conditioning, which could make the treatment more practical for hospitals and patients in limited-resource countries.

Cincinnati Children's has partnered with Roivant Sciences to launch a company called Aruvant Sciences to continue developing this potential therapy.