Daratumumab helps to send severe, hard-to-treat GPA into remission

Add-on therapy aids young man failing to respond to standard AAV treatments

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

Share this article:

Share article via email
An illustration of a person's airways.

Daratumumab helped in the remission of severe lung and skin symptoms in a young man with granulomatosis with polyangiitis (GPA), a type of ANCA–associated vasculitis (AAV), scientists in Germany report.

An immunotherapy approved to treat multiple myeloma (sold as Darzalex), daratumumab was added after the patient failed to respond to conventional AAV therapies.

More study is needed to determine daratumumab’s effectiveness in AAV patients whose severe disease does not respond to standard therapies, the scientists noted.

The case study, “Daratumumab for a Patient With Refractory Antineutrophil Cytoplasmatic Antibody-Associated Vasculitis,” was published in the form of a research letter in the journal JAMA Internal Medicine.

Recommended Reading

Gene variant linked to greater relapse risk in PR3-associated AAV

Bleeding into air sacs of lungs put man’s life at risk

AAV is a rare autoimmune disease characterized by inflammation and damage in small blood vessels due to abnormal production of self-reactive antibodies, known as ANCAs. These antibodies bind to and activate immune system cells called neutrophils, which then bind to the cells lining the vessels, causing damage.

GPA is a type of AAV that’s most often associated with ANCAs against proteinase 3 (PR3), a protein found in neutrophils. It is characterized by clumps of immune cells, called granulomas, that form in the vessels, mainly affecting the lungs, kidneys, and upper respiratory tract.

It is generally linked to a lower chance of achieving complete remission and a higher risk of relapses.

The overarching goal of current AAV treatment is to suppress the immune system, preventing the inflammatory attacks that drive the disease. Immunosuppressive treatment to induce remission typically combines glucocorticoids, such as prednisolone, with cyclophosphamide or rituximab.

Rituximab — sold as Rituxan in the U.S., with biosimilars available — promotes the death of B-cells. These immune cells, when activated and then called plasma cells, produce antibodies that include ANCAs.

However, if ANCAs are being “produced by long-lived plasma cells, the immunosuppressive therapies for AAV that are usually administered may be ineffective,” the scientists wrote.

A team at Saarland University Medical Center in Homburg, Germany, described the case of a man with GPA and severe lung and skin involvement, who was successfully treated after daratumumab was added to standard treatments.

Daratumumab, an antibody-based therapy, works by binding to CD38, a protein found at high levels at the surface of long-lived plasma cells, leading to the cells’ death. Used to treat multiple myeloma, a type of blood cancer, the therapy previously was shown to be effective in two people with hard-to-treat systemic lupus erythematosus, another autoimmune disease.

The man, in his late 20s, showed skin ulcers (open sores) on his right foot and severe lung involvement. He was positive for anti-PR3 ANCAs and an examination of tissue from his foot confirmed a GPA diagnosis.

“Kidney involvement was not apparent during the entire course of his disease,” the team wrote.

He received intensive, standard immunosuppressive therapy, including glucocorticoids, rituximab, cyclophosphamide, Tavneos (avacopan) — approved for severe GPA — and plasma exchange, a blood-clearing procedure.

“Clinical disease activity progressed unimpeded” despite these treatments, the scientists wrote.

The man’s lung function gradually worsened over time, and he required increasingly more respiratory support.

After 67 days in the hospital, persistent bleeding into the lungs’ tiny air sacs prompted the use of extracorporeal membrane oxygenation (ECMO), a form life support given to people with life-threatening heart and/or lung problems.

In ECMO, a patient’s blood is pumped to a heart-lung machine that removes carbon dioxide before returning oxygen-rich blood to the person.

Three days later, considering that he continued to be positive for anti-PR3 ANCAs, doctors started treatment with daratumumab “in the light of its effectiveness for patients with systemic lupus erythematosus,” the scientists wrote.

“Daratumumab was administered according to protocols approved for multiple myeloma,” they noted. The man continued to receive oral cyclophosphamide, prednisolone, and Tavneos.

After 11 days on daratumumab, he tested negative for anti-PR3 ANCAs for the first time since his hospital admission. With continued use of daratumumab, cyclophosphamide, and lowering doses of prednisolone, he was successfully removed from ECMO and respiratory support.

The patient was discharged after four months in the hospital, 50 days after starting with daratumumab. The wound on his foot was healing, and he did not require supplemental oxygen. He was maintained on daratumumab and prednisolone therapy, and four months after being discharged he remained in remission.

“A limitation of this case report is that the patient could have improved due to the cumulative intensive immunosuppressive therapy that he received and not specifically because of treatment with daratumumab,” the scientists wrote.

“Nonetheless, the clinical course and apparent response to daratumumab suggest that therapies targeting CD38 should be further studied for patients with severe [treatment-resistant] pulmonary and [skin-affecting] AAV,” they concluded.