Relapsed or Refractory JMML: Study Evaluates Trametinib

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Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive hematologic malignancy affecting young children predominately under the age of 4. The disease is caused by mutations that increase RAS signaling output. While about 50% of patients with JMML are cured after undergoing hematopoietic stem cell transplantation (HSCT), the prognosis is dismal for those children who relapse, with most dying from organ failure due to progressive disease or transformation to acute myeloid leukemia. In the absence of a second stem cell transplant, patients who relapse have a 2-year overall survival of about 10%.

Now, results from a small phase II study evaluating the safety and efficacy of the oral MEK1/2 inhibitor trametinib in patients with advanced JMML may provide another treatment option for patients. The study found that trametinib was effective and safe, with 7 of 10 patients who received the agent alive after a median of 2 years. The study by Stieglitz et al was published in Cancer Discovery.

Study Methodology

The study was conducted by the Children’s Oncology Group under an investigational new drug application for trametinib (IND 3119346) held by the National Cancer Institute. Ten patients with JMML were enrolled in the study from June 2017 to December 2022. The median age of the patients was 23.6 months, and all patients had JMML and harbored mutations in the RAS/MAPK pathway. At study entry, three patients had already experienced disease relapse after receiving a prior HSCT, and seven patients had JMML that was refractory to chemotherapy and had not undergone a stem cell transplant.


The researchers found that 5 of the 10 patients had objective responses to trametinib, with 2 experiencing complete responses and 3 experiencing partial responses. Two additional patients experienced stable disease, and the remaining three patients had progressive disease.

All seven patients who experienced either stable disease or an objective response were alive at a median follow-up of 24 months, and four patients who were previously ineligible for first-line HSCT were able to undergo a transplant after receiving trametinib. None of the patients experienced dose-limiting toxicities or cardiac dysfunction. There was one instance of grade 4 thrombocytopenia, and seven patients reported grade 3 adverse events, including hypertension, neutropenia, anemia, and sepsis.

Molecular analyses of pre- and posttreatment patient samples demonstrated that, in addition to suppressing RAS/MAPK signaling, trametinib also downregulated inflammatory signaling—an unexpected finding that could explain the rapid resolution of many JMML-related symptoms in treated patients, according to first author of the study Elliot Stieglitz, MD, in a statement.

“Although limited by small numbers, our experience indicates that very young children [with JMML] can tolerate and obtain clinical benefit from long-term treatment with a MEK inhibitor,” concluded the study authors.  

Clinical Significance

Based on the findings of this study, the researchers have launched a clinical trial to investigate trametinib plus azacitidine as a first-line treatment for JMML. “Our trial offered an option for parents who did not want to subject their children to a repeat HSCT and, in some cases, helped patients avoid HSCT entirely,” said Dr. Stieglitz, who holds the William Fries II Endowed Professorship in Pediatric Oncology at the Benioff Children’s Hospital at the University of California, San Francisco. “The findings suggest that trametinib may be a less toxic alternative to HSCT for select patients.”

Mignon L. Loh, MD, of the Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, and the Department of Pediatrics, Seattle Children’s Hospital, University of Washington, is the corresponding author of the Cancer Discovery paper.

Disclosure: Funding for this study was provided by the National Cancer Institute, the St. Baldrick’s Foundation, Alex’s Lemonade Stand Foundation Center of Excellence, and the Leukemia & Lymphoma Society. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.