Therapy Shows Promise for Rare Leukemia in Children

Kinase inhibitor trametinib may spare patients from intensive treatments, such as stem cell transplant, for An aggressive form of blood cancer in Small Children.

Researchers say they have found a new way to treat a very rare and aggressive blood cancer that primarily strikes babies and toddlers, a therapy that may spare them from more grueling treatments, according to clinical trial results published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR).

The disease, called juvenile myelomonocytic leukemia (JMML), is often treated with hematopoietic stem cell transplant (HSCT), with or without prior chemotherapy. 

Relapse often occurs after the stem cell transplant, and 90 percent of patients who relapse will die within two years if they don’t receive a second transplant, according to Mignon Loh, MD, senior author of the study report. Dr. Loh is director of the Ben Towne Center for Childhood Cancer Research and the head of pediatric hematology, oncology, bone marrow transplant, and cellular therapy at Seattle Children’s Hospital. 

“We’re subjecting these very young children to HSCT, which is one of the most intensive cancer treatments we have available,” said Elliot Stieglitz, MD, the study’s first author who holds the William Fries II Endowed Professorship in Pediatric Oncology at the Benioff Children’s Hospital at the University of California San Francisco (UCSF).

“If that treatment doesn’t work, the only option is to try again with the exact same therapy,” he added. “Unfortunately, only 30% of patients have a long-term response to a second transplant.” 

Previous research indicated that the growth of JMML cells might be inhibited by a kinase inhibitor called trametinib (Mekinist). It works by blocking the action of a mutated protein, MEK, that signals cancer cells to multiply, through the RAS/MAPK cellular pathway.  

Prior studies, led by co-author Kevin Shannon, MD, the Roma and Marvin Auerback distinguished professor in pediatric molecular oncology at UCSF, demonstrated that MEK inhibitors, including trametinib, showed antitumor activity in JMML mouse models.

Dr. Loh, Dr. Stieglitz, and colleagues conducted a phase II clinical trial through the Children’s Oncology Group consortium to evaluate the safety and efficacy of trametinib in 10 pediatric patients with JMML. The median age of enrolled patients was just under two years, and all of them had JMML that harbored mutations in the RAS/MAPK pathway. When they entered the study, three of the young patients had already experienced relapse of their disease after receiving stem cell transplants, and seven patients had JMML that resisted chemotherapy and had not received transplants.

Five of 10 patients had objective responses to trametinib, with two complete responses and three 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 this treatment after receiving trametinib. 

None of the patients experienced dose-limiting toxicities or cardiac dysfunction. There was one instance of grade 4 thrombocytopenia and seven grade 3 adverse events, including hypertension, neutropenia, anemia, and sepsis.

“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. “The findings suggest that trametinib may be a less toxic alternative to HSCT for select patients.” 

Dr. Loh added, “We may not eliminate HSCT for all patients, but this study shows that there is much more hope for JMML patients and their families than we previously thought. This is a really important message for families of young children with this disease.”