Trametinib Demonstrates Potential as a First-Line Treatment for Pediatric Patients with JMML


Trametinib may become an alternative treatment to hematopoietic stem cell transplantation in patients with relapsed or refractory juvenile myelomonocytic leukemia (JMML).

Trametinib (Mekinist; Novartis) has the potential to change the treatment landscape for pediatric patients with relapsed or refractory (R/R) juvenile myelomonocytic leukemia (JMML) based on promising results from a phase 2 clinical trial (NCT03190915).Published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR), the results show that trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth, resulting in the initiation of a clinical trial to evaluate trametinib as a first-line treatment for pediatric patients.

pediatric cancer jmml

The findings and further investigations hold great promise for the future of treatment for pediatric patients with JMML. Image Credit: © wolfhound911 -

JMML is a very rare, aggressive form of childhood leukemia caused by an overproduction of monocytes and immature white blood cells called blasts. Combined, the accumulation of white blood cells overcrowds healthy red blood cells and platelets in the bone marrow, leading to symptoms such as anemia, frequent infections, fevers, fatigue, and prolonged bleeding from minor cuts. The current standard-of-care treatment for pediatric patients with JMML is hematopoietic stem cell transplant (HSCT), with or without prior chemotherapy. Unfortunately, post-transplant relapse is common; without a second transplant, 90% of patients die within 2 years, and only 30% of patients have long-term responses to a second HSCT treatment.1,2

However, researchers recently identified that the growth of JMML cells is reliant on the RAS/MAPK cellular signaling pathway, leading them to hypothesize that inhibiting MEK, a protein within the pathway, may be a more effective alternative compared with HSCT.1

“JMML is a disease characterized by increased numbers of monocytes. We observed a marked contraction in the number and percentage of monocytes (and macrophages) and a resultant decrease in inflammatory signaling after exposure to trametinib. While it is not yet known if trametinib was preferentially targeting monocytes in JMML because they are mutated, we suspect based on ongoing work in other diseases that MEK inhibition targets monocytes and macrophages regardless of their mutational status,” Elliot Stieglitz, MD, holder of the William Fries II Endowed Professorship in Pediatric Oncology at the Benioff Children’s Hospital at the University of California San Francisco (UCSF), said in an interview with the Pharmacy Times. “We hypothesize that the decrease in inflammatory signaling from monocytes/macrophages (which also happen to drive oncogenic signaling in JMML) lead to the rapid resolution of symptoms amongst responders.”

Based on these findings, the study authors conducted a phase 2 clinical trial to evaluate the safety and efficacy of trametinib. The study involved 10 pediatric patients with JMML and mutations in the RAS/MAPK pathway, with a median age of 23.6 months. Of the patients, 3 relapsed after prior HSCT and 7 were refractory to chemotherapy and had not undergone HSCT.1,3

After trametinib treatment, 7 out of the 10 patients had either objective response to treatment or experienced stable disease, with 2 complete responses and 3 partial responses. All were alive at a median follow-up of 24 months, and 4 of the patients previously ineligible for first-line HSCT were able to receive the treatment following trametinib. The remaining 3 patients did not respond well to treatment and had progressive disease.1,3

The study authors observed no dose-limiting or cardiac dysfunction amongst the patients, although there was 1 instance of grade 4 thrombocytopenia and 7 grade 3 adverse events, including hypertension, neutropenia, anemia, and sepsis.1,3

A key finding of the study demonstrated the ability for trametinib to suppress RAS/MAPK signaling, as well as downregulate inflammatory signaling, which was an unexpected discovery.1

“This study reinforces that monocytes are the predominant driver of JMML but also raises interesting questions about B cells that need to be addressed in future experiments. Of note, we observed a surprisingly high number and percentage of B cells in patients when they presented with relapsed or refractory disease that resolved after exposure to trametinib,” said Stieglitz.

The significance of the phase 2 clinical trial results warrants further investigation of trametinib use in pediatric patients with JMML and RAS/MAPK pathway mutations. In an upcoming clinical trial (NCT05849662), Stieglitz and his associates will explore use of trametinib in combination with azacitidine (Vidaza; Bristol-Myers Squibb Company).4,5

“We hypothesize that for certain patients (likely those with a single RAS pathway mutation) that trametinib may be sufficient to control but not eliminate the disease. We are going to prospectively test this in an upcoming trial (NCT05849662) where patients with 1 mutation (and low DNA methylation) will be treated with trametinib and azacitidine. These patients will only proceed to stem cell transplantation in the event of progressive disease. We are therefore testing whether JMML can be treated as a chronic disease analogous to CML for certain patients,” shared Stieglitz.

The findings and further investigations hold great promise for the future of treatment for pediatric patients with JMML, potentially offering alternatives treatment options for parents who want to avoid repeat HSCT, indicating trametinib is a less invasive alternative for select patients.1

“We have entered a new era of targeted therapies for the treatment of RAS-driven malignancies,” stated Stieglitz. “We hope this study demonstrates that JMML is a unique leukemia that is exclusively initiated by mutations in the RAS pathway and that future clinical trials with direct inhibitors of RAS should be tested in this disease.”


  1. Trametinib Shows Promise for Children with Relapsed or Refractory JMML. Association of Cancer Research. June 11, 2024. Accessed June 14, 2024.
  2. Juvenile myelomonocytic leukemia. St. Jude’s Children’s Hospital. Accessed June 14, 2024.
  3. Stieglitz E, Lee A, Angus S. Efficacy of the allosteric MEK inhibitor trametinib in relapsed and refractory juvenile myelomonocytic leukemia: a report from the children’s oncology group. Cancer Discov. June 11, 2024. Accessed June 14, 2024. DOI: 10.1158/2159-8290.CD-23-1376
  4. Trametinib in treating patients with relapsed or refractory juvenile myelomonocytic leukemia. Identifier: NCT03190915. Stieglitz E. National Cancer Institute, Children’s Oncology Group. November 8, 2023. Accessed June 14, 2024.
  5. A phase I/II study of Ttametinib and azacitidine for patients with newly diagnosed juvenile myelomonocytic leukemia. Identifier: NCT05849662. Therapeutic Advances In Childhood Leukemia Consortium. May 20, 2024. Accessed June 14, 2024.

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