Targeted therapy in juvenile myelomonocytic leukemia: Where are we now?

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive clonal neoplasm of early childhood, classified as an overlap myeloproliferative/myelodysplastic neoplasm by the World Health Organization. In 90% of the patients with JMML, typical initiating mutations in the canonical Ras pathway genes NF1, PTPN11, NRAS, KRAS, and CBL can be identified. Hematopoietic stem cell transplantation (HSCT) currently is the established standard of care in most patients, although long‐term survival is still only 50–60%. Given the limited therapeutic options and the important morbidity and mortality associated with HSCT, new therapeutic approaches are urgently needed. Hyperactivation of the Ras pathway as disease mechanism in JMML lends itself to the use of targeted therapy. Targeted therapy could play an important role in the future treatment of patients with JMML. This review presents a comprehensive overview of targeted therapies already developed and evaluated in vitro and in vivo in patients with JMML.

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

“…With a 5-year EFS of 66% and OS of 74%, our results compare favorably with previous published studies 5,7,8,9,10,26,27,28,29,30 (Supplemental Table 7). The improvement in OS among JMML patients over time has been remarkable, with survival rates increasing from 31% in the 1990s to 72% in the most recent reports.…”

“…Except for a small subset of patients who exhibit spontaneous remissions, the disease usually progresses and leads to death within months of diagnosis. Unlike acute leukemia, intensive chemotherapy is insufficient to eradicate the disease and hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most patients 4,5 . However, the disease's rarity has resulted in only a few large cohorts of HSCT being reported over the last twenty years 6,7,8,9,10 .…”

Neurofibromatosis Symptom-Lacking B-Cell Lineage Acute Lymphoblastic Leukemia with Only an NF1 Gene Pathogenic Variant

“…Blast cells expressed 99.97% CD19 in the immunophenotyping test of this patient, which supports the use of tisagenlecleucel, a chimeric antigen receptor T cell [ 22 ]. Since the Ras pathway is abnormal due to a loss of function of the NF1 gene, farnesyltransferase inhibitor, or MEK pathway (which follows the Ras pathway) inhibitors such as trametinib, selumetinib, or cobimetinib may be considered [ 19 , 23 , 24 , 25 ]. Treatment approaches related to other hematologic neoplasms associated with the Ras pathway should also be considered.…”

“…In juvenile myelomonocytic leukemia, a rare and aggressive type of pediatric leukemia, Ras pathway hyperactivation has been reported with a high frequency of approximately 80–90%, and many studies are being conducted on classification, treatment protocols, and clinical trials. These treatment approaches can be used as a reference when treating B-cell lineage ALL in which the Ras pathway has abnormalities [ 20 , 25 , 26 ]. Since the patient was transferred to another hospital immediately after diagnosis, it was not possible to confirm which treatment protocol was used for this ALL case and whether resistance developed.…”