New targeted therapy, ulixertinib, shows promise for histiocytosis, a rare blood cancer

The first time Joey Carlsen Martinez came to Memorial Sloan Kettering Cancer Center (MSK), he was in terrible shape. He had a rare blood cancer called Erdheim-Chester disease, and his symptoms included crushing fatigue, severe joint pain, and memory loss. He needed a wheelchair to get around.  

Three years later, thanks to an experimental targeted therapy drug treatment for Erdheim-Chester disease that he is receiving at MSK, his life is much improved. 

“Today, I have a mostly normal life,” says Joey, 34, a stay-at-home dad who homeschools his two young daughters. “I still get tired easily, but I go grocery shopping, I cook dinner, and I take care of my family. And because I know how bad things can get, I feel so grateful for everything that I have.” 

Ulixertinib for Erdheim-Chester Disease and Other Forms of Histiocytosis  

Dr. Eli Diamond is an internationally recognized leader in developing new treatments for histiocytosis.

Joey’s extraordinary turnaround is the result of a novel targeted drug called ulixertinib. His doctor, neuro-oncologist and early drug development specialist Eli Diamond, MD, is first author of a paper published October 23, in Cancer Cell that reports outcomes for Joey and four other patients — the first patients to receive ulixertinib for a family of diseases called histiocytosis. Erdheim-Chester disease is a type of histiocytosis. 

The MSK study found four out of five patients with histiocytosis benefited from ulixertinib. Based on that work, ulixertinib is being tested in a bigger phase 2 clinical trial now open at MSK and two other hospitals. 

How MSK Has Led the Development of Histiocytosis Treatments 

Dr. Diamond is an internationally recognized leader in treating histiocytosis and led the development of the only two drugs approved by the U.S. Food and Drug Administration (FDA) for treating histiocytosis — vemurafenib (Zelboraf^®) and cobimetinib (Cotellic^®).  

“The patients in this study were treated on what is called a single-patient investigational new drug (IND) application,” Dr. Diamond explains. “We essentially write an individual clinical trial for each participant. For rare diseases like histiocytosis, this approach is a good way to evaluate potential new treatments on a small number of patients.” 

What Is Histiocytosis and What Symptoms Does It Cause? 

Histiocytosis is a collection of rare diseases diagnosed in only a few hundred people in the United States every year and can affect patients of any age, including children.  

Histiocytosis starts when the body makes too many histiocytes, a type of white blood cell, which can build up and form tumors in any part of the body and cause a broad range of symptoms, including: 

• Bone and joint pain
• General symptoms such as fatigue and malaise 
• Rashes and other skin problems 
• Blurred vision and tumors in or around the eyes and sinuses 
• Problems with the brain including balance issues, memory loss, and hormone imbalances 

Joey experienced all of these symptoms on and off for nearly a decade before he was diagnosed with Erdheim-Chester at age 29.  

Today, Joey is able to live a mostly normal life, thanks to a clinical trial at MSK.

“I finally found out what was wrong with me two months after my wife found out she was pregnant with our first child,” Joey says. “It was a crazy time, especially because nobody had ever heard of this disease.” 

Joey, who lives in Washington state, was fortunate to find a doctor in Seattle who was familiar with treating histiocytosis. He tried three different therapies, and while they helped with some of his symptoms, they caused severe side effects, especially nausea and vomiting. Joey was running out of options. That’s when he heard about Dr. Diamond and decided to make the trip to New York to visit MSK. 

How New Discoveries About the ERK Gene and MEK Protein Led to a New Drug for Histiocytosis 

Laboratory mouse models and other studies have revealed how histiocytosis is driven by mutations in a cell-signaling pathway driven by the protein MEK. The mutations lead to uncontrolled cell growth and, ultimately, cancer. MEK is implicated not only in histiocytosis but several other cancer types, especially melanoma. 

The two previous drugs approved for histiocytosis act on genes within the MEK pathway to block histiocyte growth. The new drug, ulixertinib, also acts on this pathway, but on a different gene, called ERK. 

Research in Dr. Omar Abdel-Wahab’s lab has allowed scientists to better understand histiocytosis and find new ways to stop it.

“MSK has a very active program in histiocytosis, both in the lab and in the clinic,” says MSK physician-scientist Omar Abdel-Wahab, MD, Chair of the Molecular Pharmacology Program in the Sloan Kettering Institute. Dr. Abdel-Wahab is co-senior author of the new paper, along with Benjamin Durham, MD, a former trainee and member of his lab who is now at the Rutgers Cancer Institute. 

 “Drugs that block ERK have been studied for a number of different cancers, but some patients have notable side effects at high doses,” Dr. Diamond explains. “But with histiocytosis, ulixertinib works at very low doses, allowing patients to avoid most of these side effects.” 

Side Effects and Benefits of Ulixertinib for Erdheim-Chester Disease 

For Joey, the only major side effect of ulixertinib has been an acne-like rash. He continues to take the drug daily. Early in his treatment, he had to make frequent trips to MSK, but now Dr. Diamond is able to coordinate with doctors in Seattle so that Joey can have scans and blood tests closer to home. He travels to MSK periodically, and Dr. Diamond partners with his Seattle oncologist to make adjustments to the dosage that Joey is taking, based on his levels of disease and the treatment’s side effects. 

Joey and his wife recently celebrated their sixth wedding anniversary. He is still unable to work full-time but is thankful to be home with his daughters. “I can’t think of another situation in which I’d get to spend so much time with my girls every single day,” he says. “That’s been the biggest blessing out of all of this.”  

Joey has joined support groups for patients with Erdheim-Chester and enjoys helping others with the disease, especially those who are newly diagnosed. “The whole Erdheim-Chester disease community is so amazing,” he says. “I’m so grateful for them, and grateful for Dr. Diamond and the whole team at MSK.” 

MSK’s History of Leadership in Treating Rare Blood Cancers Like Histiocytosis 

MSK’s leadership in developing treatments for histiocytosis is the result of a dedication to fundamental lab research. Fifteen years ago, Dr. Abdel-Wahab developed the first-ever mouse models for studying histiocytosis. These models have allowed researchers to learn much more about the genes and proteins that drive the disease, as well as to test experimental therapies that block them. 

Patient samples sent to MSK by histiocytosis specialists from all over the world also have helped to build a better understanding of these rare diseases. Several of those specialists are co-authors on the Cancer Cell paper. 

“Our work in histiocytosis and the ways this work has ultimately benefited patients all over the world is a great example of the importance of continuing to fund basic and translational lab research,” Dr. Abdel-Wahab says. 

Key Takeaways

• Memorial Sloan Kettering Cancer Center is a leader in lab and clinical research on different forms of histiocytosis, including Erdheim-Chester disease.
• Scientists at MSK, led by physician-scientist Omar Abdel-Wahab, MD, have collected histiocytosis patient samples from all over the world and developed mouse models to study this family of rare blood cancers.
• Based on a single-patient investigational new drug application study from neuro-oncologist and early drug development specialist Eli Diamond, MD, ulixertinib for histiocytosis was found to be beneficial in four out of five people (80%) and is now being studied in a phase 2 clinical trial. 
• Ulixertinib for histiocytosis works by controlling histiocyte cell growth caused by a mutation in the MEK signaling pathway via the ERK gene. 
• Histiocytosis happens when the body makes too many histiocytes, a type of white blood cell, which can build up and form tumors in any part of the body and cause a broad range of symptoms like fatigue, bone pain, trouble with speech and balance, skin rashes, and more. 

Dr. Abdel-Wahab holds the Evnin Family Chair in Molecular Pharmacology.