Autologous Stem Cell Transplantation Versus Bortezomib-Melphalan-Prednisone for Newly Diagnosed Multiple Myeloma: Second Interim Analysis of the Phase 3 EMN02/HO95 Study

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to GM-CSF. Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, IL-3, and SCF in a NOD/SCID-IL2Rγ null background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34 + cells (n=8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n=10 additional patients) resulted in robust engraftment of CMML in BM (25-96% human chimerism), spleen (9-85%), liver (34-97%), and lung (11-83%) of recipients (n=82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34 + cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34 + cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n=4 patients, n=12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically-accurate preclinical models of these disorders.