Art and Science of Never Giving Up

(HealthNewsDigest.com) - In March 2020, at the start of the pandemic, Anya Magnuson's own health was in crisis. The 21-year-old Minnesotan had already endured four brain surgeries, 35 lumbar punctures and about 11 weeks of hospitalization. At various times during the preceding 28 months, she was treated for fungal meningitis, an inflammatory disease known as neurosarcoidosis, and finally a rare blood cancer called Erdheim-Chester disease.

None of the treatments her doctors had prescribed worked; in many cases, they made her condition worse. Her vision was failing. She lost feeling in her feet and could no longer walk. Her headaches were so brutal that after one 13-hour episode of vomiting and writhing in pain, she cried out, "Why can't anyone fix me?"

Ronald Go, M.D., a Mayo Clinic hematologist, and Jithma Abeykoon, M.D., a Mayo Clinic hematology-oncology fellow, two of the large, interdisciplinary team doctors at Mayo Clinic treating Anya, began to question her diagnosis of Erdheim-Chester disease. They wondered whether they should biopsy her spinal cord again. A neurologist consulting on the case thought it would be too risky to perform the procedure in her current state.

While they debated the next steps, the world outside was shutting down. Within Mayo, only surgeries deemed to be "emergency" or "lifesaving" were permitted. Her case was a mystery, and it wasn't clear if a biopsy would provide any answers or just cause more pain.

Anya is exceptional. In high school, she was a National Merit Scholar, editor of her yearbook and an all-conference volleyball player. She became fluent in Spanish while working alongside international students at a Twin Cities amusement park, eventually testing out of four semesters of the subject.

"She was very driven academically but driven to the beat of her own drum," says Colleen.

The headaches began in November 2017 during her second year at Arizona State University in Phoenix. She felt like her head was going to explode. She went to the emergency department, but her symptoms were dismissed as migraines. Her next symptom emerged in early December while she was home for the holidays. She told her mom that her hand was in the wrong place.

The next night Colleen stayed up late, "madly" Googling Anya's symptoms: headaches, blind spots, numbness. It was right after "idiopathic intercranial hypertension" — unexplained high pressure around the brain — came up in her search results that she heard her daughter trip and fall upstairs. She took her to the hospital right away.

Anya spent three weeks in and out of the hospital, making little to no progress. But then she started seeing Johanna Beebe, M.D., a neuro-ophthalmologist who had done her residency at Mayo Clinic.

"We still consider her to be the first person who basically saved Anya's life," says Colleen.

Dr. Beebe spent the Friday afternoon before Christmas writing up Anya's entire medical record and calling her old mentor in the hope of getting Anya admitted to Mayo Clinic.

At Mayo, it was another three weeks of testing to try to figure out what was going on. At that point, the doctors charged with her care still didn't have answers, but they knew they had to do something to relieve the dangerously high pressure on Anya's brain.

In January 2018, they inserted a shunt and performed a craniotomy and brain biopsy, which was inconclusive. With little else to go on, they presumed that she had fungal meningitis and put her on the potent antifungal medication amphotericin.

During the months that followed, Anya endured an infection, emergency surgery, a different shunt, and another brain surgery. Yet she pushed on, traveling to Oklahoma for a photojournalism internship; Phoenix to resume her studies at Arizona State University; and Lima, Peru, for a reporting trip. By the time she returned home from college in May 2019, she had developed another new symptom: numbness in her feet and toes, making it hard to walk. Eoin Flanagan, M.B., B.Ch., a Mayo Clinic neurologist, suspected neurosarcoidosis, an inflammatory disease that affects the nervous system. But positron emission tomography scans revealed strange dark masses along her lower spine.

"It was horrifying," says Colleen. "You do not need to be a doctor to see it and think: Oh my God, that's awful. Whatever that is, it is not good."

The doctors biopsied one of those masses and sent its DNA for sequencing. Though the sequencing wasn't informative, the biopsy itself was. Anya's tumors were chocked full of white blood cells known as histiocytes, a hallmark of Erdheim-Chester disease.

The finding was a surprise. Erdheim-Chester disease typically affects middle-aged men. Even then, it is exceedingly rare. Less than 2,000 cases had ever been reported. Dr. Go said in his 13 years as a community hematologist-oncologist, he had not seen a single case. Until Anya.

The doctors prescribed the off-label use of a targeted drug called cobimetinib, which had been shown to help some patients with Erdheim-Chester disease. However, in Anya's case, it was ineffective and came with debilitating side effects. Next, they tried the immunotherapy drug interferon to stimulate her body to fight the cancer. That backfired, sending her into a downward spiral.

Her headaches became so excruciating she had to leave school. Colleen flew to Arizona to get her, bringing her home in a wheelchair with a gallon-size bag of pain medications in her purse. Back at Mayo, they tried six rounds of the chemotherapy drug methotrexate. The side effects were manageable, but her disease kept progressing.

"Even when things were really bad, every time I drove her down there, I thought: 'She's at Mayo. It's going to be OK because they aren't going to give up.'"

By March 2020, Anya was running out of options. In addition to the tumors in her lower spine, her positron emission tomography scan now showed suspicious activity in her upper spine. Doctors were concerned that she would be paralyzed soon.

They did another biopsy, which Karen Rech, M.D., a Mayo Clinic hematopathologist confirmed was consistent with the diagnosis of Erdheim-Chester disease. In addition, they sent off DNA from her tumor for another round of sequencing. As before, the sequencing failed to turn up any clearly pathogenic mutations. However, the report listed a "variant of unknown significance" — a genetic change whose impact on disease is unclear — in a gene called CSF1R.

Luckily, he was already familiar with CSF1R. The previous day, Dr. Abeykoon had treated one of his patients in the sarcoma clinic with pexidartinib, a CSF1R inhibitor that had been approved for a rare joint tumor known as tenosynovial giant cell tumor. There was a drug that could potentially treat Anya's cancer. But first, the researchers needed to determine whether the CSF1R variant of unknown significance found in her tumor was in fact significant.

CSF1R is part of a family of genes that code for proteins known as colony-stimulating factors, named for their ability to stimulate the growth of entire colonies of cells in laboratory dishes. Mutations that activate genes like CSF1R have been shown to send cells growing out of control, fueling the development of tumors.

Dr. Abeykoon asked Terra Lasho, Ph.D., a Mayo Clinic molecular biologist, to investigate whether Anya's mutation was activating