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Trial to Make the Case for Widespread Adoption of a Lifesaving LCH Treatment
Key Takeaways
Ashish Kumar, MD, PhD, has shown that MEK inhibitors like trametinib effectively target Langerhans cell histiocytosis (LCH), preventing recurrence and offering a safer treatment alternative to chemotherapy.
A new clinical trial is underway to assess using a novel MEK inhibitor, mirdametinib, for LCH.
CinCSeq and HistioTrakTM are two new molecular tests that enhance the ability to detect genetic alterations and measure treatment success.
Our protocol is as good as or better than chemotherapy, with fewer side effects. Not using these effective, lifesaving drugs to treat children with treatment-resistant, high-risk LCH is almost negligent.
Ashish Kumar, MD, PhD
Ashish Kumar, MD, PhD, hopes a new prospective clinical trial will help more children with Langerhans cell histiocytosis (LCH) get lifesaving drugs.
The director of the Histiocytosis Center at Cincinnati Children’s and his colleagues previously published a retrospective study in the journal Haematologica demonstrating that children suffering from histiocytosis can be treated safely and effectively with oral mitogen-activated protein kinase (MEK) inhibitors, such as trametinib, which target the gene mutations that cause LCH.
Since 2018, Kumar and his team have offered trametinib as a first-line therapy to more than 60 LCH patients, with the vast majority (about 94%) having a complete response and no recurrence.
Trametinib as a first-line therapy has shown a nearly 94% success rate.
Despite that success, physician adoption of the protocol has been slow. The first-line treatment for LCH is, traditionally, chemotherapy. But in 15% to 20% of patients, LCH doesn’t respond. And even when chemotherapy is effective, the one-year relapse rate is as high as 30%.
Kumar believes the new prospective trial—which will assess the safety, efficacy and long-term effects of using a novel MEK inhibitor called mirdametinib for LCH—will prompt more oncologists to consult with him so they can offer trametinib and other MEK inhibitors to their patients.
Kinase Inhibitors as First-Line Therapy
About 10 years ago, Kumar had a patient with LCH whose disease hadn’t responded to multiple courses of chemotherapy. At the time, Kumar had learned about clinical trials that tested the use of dabrafenib in pediatric patients with melanoma and certain brain tumors.
“Like LCH, these diseases are caused by a mutation of the BRAF [V-Raf Murine Sarcoma Viral Oncogene Homolog B] gene,” Kumar says. “The research made me wonder whether dabrafenib could effectively treat LCH. After a great deal of consideration and discussion with the patient’s family, I decided to use it.”
Within four weeks of initiating dabrafenib therapy, tests showed no evidence of disease. A few weeks later, a second patient with chemo-resistant LCH responded to dabrafenib in the same way.
The evidence for this protocol is so strong that encouraging its widespread adoption has become my life’s work.
Ashish Kumar, MD, PhD
“Pediatric oncologists are more comfortable with therapies that have gone through a large, randomized clinical trial, but as with many rare diseases, we don’t have enough patients to do that,” Kumar says. “Based on our evidence, it’s already clear that the treatment with inhibitors works beautifully.”
He adds: “We need to find a way to make these lifesaving treatments accessible to children who need them, no matter where they live.”
New Tests for Measuring Success
Kumar relies on tests like CinCSeq and HistioTrakTM, developed by Cincinnati Children’s Molecular and Genomic Pathology Services (MGPS) Laboratory in the Division of Pathology, to measure the success of his research and treatments.
CinCSeq is a comprehensive next-generation sequencing (NGS) cancer panel for histiocytic and a wide range of pediatric, adolescent and young adult neoplasms. It analyzes blood, tissue, and bone marrow specimens with as little as 300 tumor cells to identify genetic drivers of cancer. In the context of this clinical trial, the CinCSeq test can identify specific rare mutations in the MAP2K1 gene in histiocytosis that confer resistance to treatment with MEK inhibitors. This is an important piece of information for trial eligibility.
“The test covers 531 DNA and 182 RNA cancer-related genes and pinpoints clinically actionable genetic alterations that routine NGS testing methods may miss,” says Somak Roy, MD, director of molecular pathology at Cincinnati Children’s and the developer of the test.
Kumar also uses HistioTrak, a liquid biopsy molecular test, to monitor treatment response in patients with LCH. This test looks for the BRAF V600E mutation, the most common mutation in LCH. HistioTrak is so sensitive that it can detect a single tumor cell in the background of 50,000 normal cells.
Currently, HistioTrak is a qualitative test. The report indicates whether the sample was positive, negative or suspicious for a BRAF V600E mutation. Soon the test will be available as a quantitative test, which will estimate and track the amount of mutated tumor cells in the blood.
Prospective Trial Now Open
Thenew prospective trial is open to patients ages 2 years and older who need treatment for LCH or another histiocytic disorder and have active, measurable disease. It will evaluate mirdametinib’s safety and efficacy as a first-line therapy, or as a second-line therapy for patients whose disease recurs after chemotherapy.
