Risk Stratified Treatment for Patients with Newly Diagnosed Juvenile Myelomonocytic Leukemia: A Phase 1/2 Non-Randomized Study of Trametinib and Azacitidine with or without Chemotherapy

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2023-11, Vol.142 (Supplement 1), p.3210-3210
Main Authors: Stieglitz, Elliot, Chi, Yueh-Yun, Chang, Bill H., Tasian, Sarah K., Yohe, Marielle, Dvorak, Christopher C, Southworth, Erica, Long-Boyle, Janel R., Van Ziffle, Jessica, Abdullaev, Zied, Leong, Roy, Wayne, Alan S., Bhojwani, Deepa, Loh, Mignon L.
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of childhood. The biochemical hallmark of JMML is aberrant signaling through the Ras pathway caused by initiating mutations in NF1, NRAS, KRAS, RRAS, RRAS2, SH2B3, PTPN11,or CBL. While hematopoietic stem cell transplantation (HSCT) can be curative, 5-year event-free survival of children with JMML after HSCT is only ~50%. Recently, several studies have identified mutational burden and DNA methylation as predictive of clinical outcomes in patients with JMML. In the T2020-004 phase 1/2 clinical trial, we will define lower-risk patients as those with one somatic alteration and low DNA methylation and high-risk patients as those with more than one somatic alteration or intermediate/high DNA methylation. Trametinib is an orally bioavailable, reversible, highly selective allosteric inhibitor of MEK1/2 in the Ras/MAPK signaling pathway. Trametinib is FDA-approved for the treatment of adults with advanced melanoma with BRAF V600E or V600K mutations and in children with Ras-mutant solid tumors in combination with dabrafenib. Clinical investigation of trametinib monotherapy via the Children's Oncology Group ADVL1521 phase 2 trial (NCT03190915) showed efficacy in children with relapsed/refractory JMML. Phase 2 clinical trial evaluation of azacitidine in children with newly-diagnosed JMML was also efficacious and led to its FDA approval. In this trial, trametinib will be tested in combination with azacitidine in lower-risk patients and in combination with azacitidine and chemotherapy for high-risk patients. Study Design and Methods: This is a non-randomized, risk stratified, Phase 1/2 study for patients with newly-diagnosed JMML (NCT05849662) conducted via the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium with safety and efficacy phases for both lower-risk and high-risk cohorts. Lower-risk patients will receive trametinib once-daily for 28 days in combination with azacitidine administered daily for five days per cycle. Lower-risk patients can receive up to 12 cycles and will proceed to HSCT only if they experience progressive disease or relapse. High-risk patients will receive trametinib administered once-daily for 28 days in combination with azacitidine, fludarabine, and cytarabine (aza/FLA) administered daily for five days per cycle. High-risk patients will receive up to two cycles of therapy before proceeding to HSCT off protocol. Key Eligibil
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2023-177838