Four causative genes are certified in this packet: ARHGAP26 (chromosome 5), CBL (chromosome 11), NF1 (chromosome 17), and PTPN11 (chromosome 12). No ClinGen clinical validity classifications are provided for individual gene-disease associations in this packet. The certified inheritance patterns include multifactorial and autosomal dominant inheritance. This combination reflects the established understanding that JMML arises primarily through somatic molecular alterations in myeloid progenitor cells (accounting for the multifactorial pattern), while a subset of cases occurs in the context of germline predisposition associated with one of the certified genes, which follows an autosomal dominant inheritance pattern.

No certified diagnostic method list is present in this packet. JMML is defined as a myelodysplastic and myeloproliferative neoplasm of childhood, and evaluation encompasses assessment of bone marrow and peripheral blood findings reflecting granulocytic and monocytic lineage proliferation consistent with the disease definition. The condition is listed under OMIM entry 607785.

Azacitidine is certified as an FDA-approved therapy with active market status, available in three certified records: VIDAZA (approved May 2004), an azacitidine formulation (approved April 2016), and ONUREG (approved September 2020). The orphan drug record for Vidaza also carries orphan approval status with a specific indication of treatment of juvenile myelomonocytic leukemia.

Additional orphan-designation records are present for dasatinib (designated for chronic myeloid leukemia) and one further investigational compound (designated for a related myeloid malignancy indication). These designation records do not establish FDA approval, current availability, or confirmed efficacy for JMML.

Certified active trial records include Phase 1 and Phase 2 investigations: a study of tagraxofusp in combination with decitabine in myelomonocytic/myeloproliferative neoplasms (NCT05038592); a study of oral LY3410738 for hematologic malignancies with IDH1 or IDH2 mutations (NCT04603001); a Phase 2 allogeneic hematopoietic stem cell transplant study in hematologic disorders (NCT03314974); a Phase 1 CD4-directed CAR-T cell therapy study for chronic myelomonocytic leukemia (NCT06071624); and a Phase 1 study of alpha-emitter-labeled antibody followed by donor stem cell transplant for high-risk acute leukemia and myelodysplastic syndrome (NCT03670966). These trials represent investigational approaches and do not establish standard-of-care status.

No certified natural history or prognosis data is present in this packet.

Numerous active trial records are certified for JMML and related myeloid malignancies, with 111 active records documented. The certified trial portfolio spans cytotoxic combination regimens, targeted molecular agents, cellular immunotherapies (including CAR-T and NK cell approaches), allogeneic hematopoietic stem cell transplant protocols, and pediatric leukemia screening platforms. The Pediatric Acute Leukemia (PedAL) Screening Trial (NCT04726241), a Leukemia and Lymphoma Society and Children's Oncology Group initiative, is included among certified records. The research landscape digest documents 251 total classified publications, with basic science and preclinical investigation as the dominant research type, 51 reviews, and 48 case reports. Biomarker and gene therapy research activity is also represented in the landscape.