Research News

Above: Left, a normal red blood cell. Right, a red blood cell that has burst, a hallmark of PNH.

Cleveland Clinic researchers have published two of the largest studies to-date on paroxysmal nocturnal hemoglobinuria (PNH). One study, published in Blood, reports hundreds of patients' experiences with new "miracle drugs" called anti-complement inhibitors as they received treatment over many years at Cleveland Clinic's Taussig Cancer Center and other collaborating healthcare facilities.

At the same time, the researchers published promising phase 3 clinical trial results for another new PNH drug called Iptacopan. The results have been published in New England Journal of Medicine and are likely to further improve the standard of care. Together, the two studies arm physicians with evidence to support best practices in treating the rare, potentially fatal blood disease.

Anti-complement inhibitors address the underlying condition that causes PNH, where the immune system attacks and breaks apart red blood cells. While Cleveland Clinic's Carmelo Gurnari, MD, PhD, calls the new treatments "revolutionary," he says that there's still a knowledge gap on how to effectively implement them into patient care. These drugs belong to the most expensive drugs in hematology and oncology and the study outlines their long-term effects and how they change the life of patients.

"Other physicians have called anti-complement inhibitors 'miracle drugs,' but the problem is that physicians don't agree on the best way to transition our patients from their current treatment plans," says Dr. Gurnari, a staff scientist and first author on the study. "Many patients are already taking medication to manage their symptoms – we need to be sure that they receive the maximum benefit when we change our approach and deploy these very expensive agents."

Red blood cells breaking down can cause complications like anemia and thrombosis. Before anti-complement inhibitors were developed, physicians could only prescribe treatment to manage these conditions as they arise. Most individuals living with PNH have been prescribed anti-coagulants to reduce blood clotting associated with thrombosis.

Dr. Gurnari is a staff scientist under the guidance of Jaroslaw Maciejewski, MD, PhD. They both treat patients with PNH and maintain the largest PNH practice in the United States by patient volume. The pair led a comprehensive analysis of how individuals with PNH responded to different combinations of old and new treatments, including anti-coagulants. The multi-site research team included Cleveland Clinic physicians and researchers, including Valeria Visconte, PhD, as well as collaborators from Vanderbilt University, UT Southwestern and Karmanos Cancer Institute.

"There's a misconception that clinical research is done when a drug hits the market," says Dr. Maciejewski, Chair of Translational Hematology and Oncology Research. "Continuous research in a real life setting outside the constraints of a clinical trial is critical to optimize how we use these new drugs so they can actually benefit patients and we – practicing hematologists – can appropriately use them for patient benefit."

Dr. Gurnari's (right) study, now published in Blood, received an award from the American Society of Hematology and the International Paroxysmal Nocturnal Hemoglobinuria Interest Group for its contributions to improving patient treatment and care.

A revolution for PNH

PNH is a rare blood disease where our immune systems attack our red blood cells, causing them to burst inside of our veins. It is named for its most visible symptoms, where the red hemoglobin proteins from the broken blood cells are passed through the urine.

When left untreated, these symptoms can be fatal. Even fifteen years ago the PNH life expectancy ranged from 10-20 years after diagnosis. Anti-complement inhibitors only became available in the last decade, some as recently as 2019. These drugs prevent the inappropriate immune activity against our red blood cells, greatly reducing the occurrence of deadly thrombotic events.

After decades of scientific research to identify and target PNH's root causes, there hasn't been recent progress into researching how individuals respond to different treatments. PNH is so rare that there isn't enough data to develop concrete guidelines for these new anti-complement inhibitors, Dr. Gurnari says. Treatments may depend on an individual physician's choices and practices.

"Some physicians take their patients off all supplemental therapies after prescribing anti-complements, but this can sometimes lead to complications," Dr. Gurnari explains. "Other physicians err on the side of caution and prescribe lifelong anti-thrombosis medication, but this can cause financial strain and require constant monitoring and twice-monthly blood testing."

Finding patterns in patient responses

Drs. Maciejewski and Gurnari established a multi-site collaboration that analyzed individuals receiving PNH treatment over two to 12 years. In the clinic, the team analyzed the patients' overall disease activity and responses to different treatments. In the lab, the team analyzed the patients' blood samples for information about genetic mutations, blood composition and blood clotting characteristics. 

The large-scale study confirmed insights from smaller studies. For example, results indicated that patients with specific characteristics in the PIGA gene had increased likelihood of thrombosis (PNH manifests when an individual develops a mutation in their PIGA gene). These patients will likely need supplemental anti-coagulation therapies, Dr. Gurnari explains.

The results also showed that individuals who responded well to anti-complement therapy could be weaned off additional therapeutics after 3-6 months if the disease remained under control and their red blood cells remained intact.

In addition to studying existing anti-complement therapies and their effects, Drs. Maciejewski and Gurnari are researching other ways to provide patients with the best care possible by developing new medications. Alongside other Cleveland Clinic physicians, Dr. Maciejewski enrolled patients into a phase 3 clinical trial for FDA approval of a new PNH drug. Research is already ongoing to expand on the effect of the new drug and anti-complement inhibitors.

"The knowledge from our research will be a new weapon in the ever-growing armory hematologists have at their disposal to fight PNH," says Dr. Maciejewski.