Histiocytosis: Still Rare, No Longer Obscure

A dedicated team of experts advances research and care for histiocytosis.

By Maureen Salamon; Photos by Peter Barta and Justin Veneman

For six long months, tiny Jamie Jones lay in a hospital, hooked to a feeding tube. Clinicians puzzled over the mysterious illness that wracked her little body. Her gut could not absorb nutrients, causing severe weight loss. Her liver had grown to fill her belly, which made breathing difficult. Finally, a biopsy revealed that an apparent diaper rash was actually a sign of a rare and dangerous disorder.

Doctors rushed Jamie to St. Jude Children’s Research Hospital. There, she had an incredible turnaround, thanks to her oncologist and the Histiocytosis Treatment Team.

Patrick Campbell, MD, PhD, examines Jamie Jones

Incredible turnaround

Patrick Campbell, MD, PhD, examines Jamie Jones during a recent checkup. “I don’t have the words to explain how it feels to be a parent who watched her child lying there lifeless—and now she’s walking around, smiling and jumping,” says Jamie’s mom. 

The name of Jamie’s diagnosis is a mouthful: Langerhans cell histiocytosis, or LCH. This disease occurs when abnormal immune cells known as histiocytes grow and divide nonstop, often killing healthy cells nearby.

St. Jude is leading international efforts to ensure Jamie and others with histiocytosis benefit from treatment advances.

Now age 4, Jamie continues to receive care at St. Jude, including physical therapy to offset lingering weakness. She loves to sing and dance and play school with her two older sisters.

“I don’t have the words to explain how it feels to be a parent who watched her child lying there lifeless—and now she’s walking around, smiling and jumping,” says Jamie’s mom, Teairra Ramsey. “Just to see her now is a blessing.”

The histiocytosis treatment team sits around a table and discusses treatment plans.

Collaborating for cures

The Histiocytosis Treatment Team includes (from left) oncologist Patrick Campbell, MD, PhD; Melissa Hines, MD, of Critical Care; Kim Nichols, MD, of Cancer Predisposition; and Gabriela Marón, MD, of Infectious Diseases.

A dedicated team of experts

The team that took care of Jamie includes experts in cancer, genetics, critical care, infectious diseases, cancer predisposition and bone marrow transplant.

“I believe the knowledge and expertise of our Histiocytosis Treatment Team rival that of any place in the country or the world,” says Jamie’s oncologist, Patrick Campbell, MD, PhD, St. Jude associate chief medical information officer.

The two main types of histiocytosis are LCH and hemophagocytic lymphohistiocytosis, or HLH. The rarity of these diseases makes them difficult to study and understand.

“All we knew for a long time was that special immune cells called histiocytes were found in the tissue of patients who were sick,” says Melissa Hines, MD, of St. Jude Critical Care. “But what we’ve come to understand is that the way LCH and HLH come about and the illness caused by them are completely different.

“HLH is a defect in the immune system where your body cannot turn off inflammation,” she continues. “Typically, if you get really sick, your body has an automatic stop button to dampen the immune response, but in HLH that emergency stop button doesn’t exist. LCH is quite different. We think LCH is more like cancer than an inflammatory disorder, but it has components of both.”

As many as two dozen children with histiocytic disorders are treated at St. Jude annually. The hospital’s experts also consult on many additional cases.

What are histiocytic disorders?

These conditions affect the immune system. Children with histiocytic disorders have abnormal cells that no longer protect the body against infection. Instead, the cells become overactive, damaging tissues and organs such as the liver, bone marrow, spleen and central nervous system.

Hemophagocytic Lymphohistiocytosis (HLH)

  • In HLH, normal immune cells divide nonstop and release large amounts of certain chemicals into the blood. These chemicals cause the HLH symptoms.
  • About 1 out of every 50,000–100,000 children has HLH.
  • There are 2 major types of HLH:
    • Familial HLH can be passed down through families.
    • Acquired HLH is thought to result from certain infections, cancers and autoimmune disorders.
  • HLH survival rate: about 50%.

Learn more about hemophagic lymphohistiocytosis

Langerhans Cell Histiocytosis (LCH)

  • In LCH, abnormal Langerhans cells, a type of histiocyte, multiply in different tissues. The abnormal cells form tumors and activate other immune cells, causing LCH symptoms.
  • About 2 to 3 out of every 1 million children have LCH.
  • LCH shares similarities to some cancers. LCH often requires treatment with steroids to calm inflammation and chemotherapy to kill amped-up immune cells.
  • Low-risk LCH survival rate: 99%; high-risk: about 80%.

Learn more about Langerhans Cell Histiocytosis

 

A spectrum of symptoms

Early recognition and treatment are critical to ensure the best outcomes for LCH and HLH. But identifying and treating these disorders has long been a challenge. Symptoms range from mild, such as a skin rash, to dire, such as multi-organ failure.

Scientists have learned that in some HLH patients, the disorder is caused by inherited changes in certain genes. In other HLH patients, those genes contain no obvious changes; however, the patients may be more apt to develop the disorder after an infection or as a result of a cancer or autoimmune disease.

In LCH, there’s no such risk factor, Campbell explains. While LCH and HLH are quite different, what unites them, he says, is how tough they are to diagnose. The array of symptoms—like Jamie’s—often resembles something else entirely.

The need for research

Five-year survival rates for children with HLH hover at about 50%, reinforcing the need for more research.

Kim Nichols, MD, St. Jude Cancer Predisposition Division director, and her colleagues are working to better understand the cellular processes that cause HLH. In the lab, her team recently discovered a promising new HLH drug. This medication blocks specific signaling pathways to dampen inflammatory responses. The researchers found that the medication significantly lessens disease signs and symptoms. The drug will soon be tested in patients with HLH.

“It’s fantastic to have a Histiocytosis Treatment Team where we can discuss patients and bounce research ideas off each other,” Hines says. “St. Jude can give information back to the scientific communities about what to do with these disorders in the future. The group has allowed us to better solidify research ideas and decide where we’re going to go next as far as testing therapeutics for both LCH and HLH and starting clinical trials.” 

New treatments on the horizon

At St. Jude, histiocytosis treatment is tailored to each patient. Children with mild disease may require only a watch-and-wait approach. Others may become critically ill and need bone marrow transplants to survive. Therapies often include steroids to calm inflammation and chemotherapy to kill amped-up immune cells.

Scientists recently made an important discovery about LCH, the disorder Jamie battled.

Researchers found a mutation in the BRAF gene in LCH tumors. Unlike the gene changes in HLH, the mutations in LCH tumors are not inherited. The BRAF mutation is found in about half of LCH tumors. About 35% of additional LCH tumors have mutations in related genes, Campbell says. The presence of these mutations convinced scientists that LCH is a cancer-like disease.

The altered genes also pointed the way toward using targeted therapy. This treatment attacks overactive immune cells without harming other cells. Oral drugs known as BRAF inhibitors are now being used to treat children with LCH who have failed other treatments and whose disease contains the BRAF mutation. More targeted treatments are on the horizon.

Carlos Rodriguez-Galindo, MD

St. Jude–based NACHO chomps down on research

Carlos Rodriguez-Galindo, MD, has long had a soft spot for so-called orphan diseases. These conditions are so rare that little interest or funding is generated for extensive scientific research. So it seems natural that histiocytosis—a life-threatening group of disorders affecting the immune system—would hit his radar.

Rodriguez-Galindo is executive vice president and chair of Global Pediatric Medicine at St. Jude. He is also a founding member and co-leader of the North American Consortium for Histiocytosis, better known as NACHO.

The consortium consists of nearly three dozen institutions. NACHO’s members work closely to develop new and better treatments for histiocytic disorders and test them in clinical trials.

The clinical trials organized through NACHO are available to children treated at St. Jude, which is the consortium’s center of operations. With so few patients worldwide—perhaps three children in a million—collaborating with others is crucial to finding ways to improve outcomes.

The discovery that Langerhans cell histiocytosis is often driven by a gene mutation implicated in other cancers paved the way for NACHO to sponsor three clinical trials and two basic-science studies.

“Pediatric cancer is already a rare disease, but the rarest of the rare actually may fall through the cracks in terms of benefiting from knowledge, resources and clinical trials,” Rodriguez-Galindo says. “We need to really understand histiocytosis better. We need to find better ways to treat these kids.”

 

That’s progress Jamie and her family appreciate every day.

“She’s had an unbelievably good response,” Campbell says. “Her progress shows the kinds of advances and benefits of these newer therapies.”

Learn more: stjude.org/histiocytosis-treatment

From Promise, Winter 2018

Donate Now Subscribe to Promise

More articles from this issue