Older age, other disorders at PNH diagnosis linked to poor survival

Mortality significantly increased during first two years after PNH diagnosis

Patricia Inacio PhD avatar

by Patricia Inacio PhD |

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Early mortality in people with paroxysmal nocturnal hemoglobinuria (PNH) is linked to being older and having heart or blood disorders and a history of solid tumors at diagnosis, a Danish study has found.

The leading causes of death among patients were infections and associated blood-related diseases, while the approved therapy Soliris (eculizumab) and the anticoagulant warfarin appear to have protective effects.

The study, “Early Mortality in Paroxysmal Nocturnal Hemoglobinuria,” was published in the journal Cureus.

PNH is characterized by the destruction of red blood cells (hemolysis) due to an attack by a part of the immune system called the complement cascade. This abnormal immune attack causes symptoms that include anemia (low number of red blood cells) and thrombosis, or blood clots forming within blood vessels.

A blood clot-related event, or a thromboembolic event (TE), occurs when a blood clot travels through the bloodstream to another location in the body, where it can block blood flow.

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While TE is a well-established risk factor for worse outcomes in PNH patients, “it is unknown how other cardiovascular risk factors such as diabetes and hypertension [high blood pressure] affect mortality,” the researchers wrote.

To answer this, researchers at Odense University Hospital, in Denmark, analyzed data from 115 PNH patients (median age of 48.2 years at diagnosis, 50.4% women) diagnosed from 1977 to 2016 and who were part of the Danish Hemolysis Cohort.

The cohort combines information from the Danish National Patient Register, the Danish National Prescription Registry, and the Danish Register of Causes of Death. These have information on PNH patients, their hospital-registered simultaneous health conditions (comorbidities), and causes of death.

“For each patient with PNH, we identified up to 50 age- and sex-matched comparators from the general population without PNH,” the researchers wrote. These, totaling 5,723 people, were used as controls.

The proportion of people with cardiovascular risk factors, such as hypertension, diabetes, and obesity, was generally similar between patients and controls.

At study inclusion, 7% of PNH patients and 1.6% of controls were registered with a prior or current thromboembolic event.

A blood disorder called aplastic anemia (AA) and myelodysplastic syndrome (MDS), a rare type of blood cancer, were detected nearly exclusively in the PNH group: AA in 21.7% and MDS in 6.1% vs. fewer than three controls for each condition.

A total of 18 PNH patients (15.7%) died within two years of diagnosis. These patients were more commonly affected by other health conditions at diagnosis compared with the 97 patients who lived longer (83.3% vs. 64.9%).

The increased mortality in older patients could suggest that older patients remain undiagnosed for longer periods and therefore succumb to PNH-related complications shortly after diagnosis and that undertreatment is a potential risk in these high-risk patients.

Risk factors include older age, tumor history, cardiovascular disease

Older age at diagnosis — mean 64.2 vs. 45.3 years — was also associated with early death, along with a previous history of solid tumor and the simultaneous existence of cardiovascular disease.

PNH patients died about 10 years earlier relative to controls (median of 67.3 vs. 77.7 years), and their risk of death was about 10 times higher.

A total of 92.2% PNH patients were alive one year after diagnosis compared with 99.4% of controls. Survival differences increased with time, with 68.4% of PNH patients and 85.8% of controls being alive after 10 years. After 15 years, group differences started to stabilize or to reduce up to 40 years of follow-up, when these showed no major survival differences.

The overall leading causes of death among PNH patients were cardiovascular disease (22.3%) and additional blood disorders (20.7%), but no death was linked to a TE. Simultaneous blood conditions were the cause of death in 3.5% of patients in the first year and in 12.3% after 10 years, while up to 0.2% controls died of such causes during those times.

In PNH patients who died within two years from diagnosis, additional blood conditions (48.4%) and infections (23.6%) were the most common causes of death.

“Among patients and comparators with late mortality, cardiovascular disease was an equally frequently registered cause of death, whereas death from associated [blood] diseases was significantly more frequent among patients [16.5% vs. 1%],” the researchers wrote.

A significantly greater proportion of patients who died earlier were less frequently treated with Soliris and/or warfarin compared with those who lived longer (94.4% vs. 63.9%). Soliris is an approved PNH treatment that blocks complement activation, and warfarin is an anticoagulant marketed as Coumadin, among other brand names.

“The same trend is suggested [when] comparing patients with PNH who received treatment ([Soliris] and/or warfarin) to the patients with PNH who did not receive any such treatment,” the team wrote.

However, only a small proportion of patients were on Soliris alone (5.2%) or in combination with warfarin (4.4%). Therefore, “the very limited number of patients registered with [Soliris] treatment does not allow for conclusions regarding the isolated effect of [Soliris] on survival,” the researchers added.

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A post-hoc analysis, conducted after the data had been collected, showed the survival benefits of treatment were only significant within the first five years following diagnosis.

Overall, these findings highlight early mortality in PNH is associated with older age, cardiovascular conditions, and blood cancers. “In addition, mortality due to [blood-related] disease and infections prevail as frequent causes of death among patients with early mortality,” the researchers wrote.

“The increased mortality in older patients could suggest that older patients remain undiagnosed for longer periods and therefore succumb to PNH-related complications shortly after diagnosis and that undertreatment is a potential risk in these high-risk patients,” the researchers wrote.

“The rarity of the disease calls for international collaboration to investigate rare events and complications associated with PNH, particularly when subgroups such as elderly patients are considered,” they concluded.