Leukemic Engraftment In NOD. SCID Mice Is Correlated With Clinical Parameters and Predicts Outcome In Human AML

The NOD. SCID xenotransplantation assay has emerged as a key model system for interrogating the biology of human acute myeloid leukemia (AML). Previous work has established that approximately 50% of AMLs can generate grafts resembling the patient’s leukemia in immunodeficient mice. An understanding of the biologic properties of AML that enable engraftment in xenotransplant assays may aid in the development of prognostic tools and individualized therapy. To investigate these properties in a broad cross-section of human AML, we transplanted bone marrow (BM) or peripheral blood (PB) cells from 307 AML patients intra-femorally into sublethally irradiated NOD. SCID mice pre-treated with an anti-CD122 antibody. Human engraftment in the recipient BM was assessed 8-10 weeks post-transplant via flow cytometry. AML xenografts, defined as a human graft composed of >90% myeloid (CD33+CD19-CD45+) cells, were generated by 134 samples (44%). The remainder (hereafter referred to as non-engrafting samples) generated 3 patterns of non-leukemic engraftment: no human graft, defined as 9 /L in engrafters vs. 67 x10 9 /L in non-engrafters; P=0.01), but there was no correlation with BM blast percentage (mean of 75% vs. 72%; P=0.38). A strong relationship between cytogenetically defined prognostic groups and engraftment ability was observed: AML xenografts were generated by 4/30 samples (13%) with favorable karyotypes, 63/153 (41%) with intermediate karyotypes and 23/43 (53%) with adverse karyotypes (P=0.002). No diagnostic samples harboring PML-RARα translocations were capable of initiating leukemic engraftment ( n =10). Among patients with normal karyotype (NK) AML, the presence of an NPM1 mutation was not related to engraftment ability; however, 17 of 34 diagnostic samples (50%) from FLT3-ITD-positive patients established leukemic xenografts, compared to 11 of 41 (27%) NK FLT3-ITD-negative samples (P=0.04). Of note, AML engraftment ability in NOD. SCID mice was strongly associated with a poor response to standard induction therapy. Complete remission was achieved in only 30 of 59 (51%) patients whose diagnostic samples established AML xenografts, compared to 82 of 103 (80%) non-engrafting samples (P Thus, the NOD. SCID xenotransplant assay identifies a subset of AML patients with aggressive disease that responds poorly to standard induction therapy. Further in depth genomic and transcriptional analysis of our dataset will provide insight into the underlying determinants that link xenograft repopulation characteristics with clinical properties and identify those that could be developed into novel prognostic and predictive signatures. Disclosures: Wang: Trillium Therapeutics/Stem Cell Therapeutics: Research Funding.