Abstract High throughput genomic studies have identified novel recurrent somatic alterations with prognostic or therapeutic relevance in hematological malignancies. By contrast, few studies have investigated the impact on pathologic assessment, and clinicopathologic diagnosis. We therefore assessed the impact of a CLIA-certified CAP-accredited comprehensive clinical grade next-generation sequencing-based assay, FoundationOne Heme (FOH), on hematopathologic assessment of patients at our institution. The FOH assay targets 405 cancer-related genes and 31 frequently rearranged genes by DNA-capture and sequencing, and 265 frequently-rearranged genes by RNA-capture and sequencing. We prospectively tested 92 cases as part of routine clinical practice, including malignant lymphoid neoplasms (n=51) and suspected myeloid malignancies (n=41). (Table 1) The samples submitted included 30 blood, 38 bone marrow and 24 FFPE specimens. We were able to obtain genomic profiling data in90 of the 92 submitted cases (98%) including all FFPE specimens. A total of 282 genomic abnormalities (range 0-11, average 3.2 abnormalities/case) including substitutions, insertions/deletions and gene fusions were detected. There was excellent concordance between conventional cytogenetic or molecular genetic assays and FOH assay. Only 10 cases lacked any genomic abnormality. Six of these were morphologically normal bone marrows submitted to rule out myeloid neoplasia. Of the 4 remaining cases without recurrent somatic alterations, 2 cases were derived from myeloma patients where the sample analyzed had less than 20% plasma cells and 2 cases were from patients with myelodysplasia with likely low tumor content. In 84 cases with a diagnosis of hematologic malignancy, we identified genomic abnormalities with diagnostic relevance in 42 cases (50%). Most importantly, in 12 cases (14% of cohort), the presence of specific genomic alterations led to a change or refinement of the diagnosis. (Table 2) This included two cases in which a diagnosis of T-LGL was confirmed based on the presence of STAT3 mutations, three cases of lymphoma/myeloma in which a specific diagnosis was reached based on identification of pathogenic fusions/rearrangements, and 4 cases of MPN/MDS which could be confirmed based on the presence of known MPN/MDS disease alleles. In addition, we identified genomic alterations with prognostic relevance in 54 cases (64%), and with potential therapeutic impact in 64 cases (76%). Our data demonstrate that the FOH assay can be performed with a very high success rate (98%) in a routine clinical setting and that comprehensive genomic profiling can substantively impact pathologic assessment and diagnosis of a wide spectrum of hematologic malignancies. Genomic testing provided critical diagnostic information in half of the cases, in some instances refining or changing the conventional pathological diagnosis. These findings suggest that comprehensive targeted genomic testing has an important role to play not only in identifying prognostic and therapeutic targets but also in hematopathology diagnosis, and should be considered as a first line testing platform in hematologic malignancies. Table 1:Clinical characteristicsTotal number of casesN=92 Median age58 (18-82) SexMale58 (63%)Female34 (37%) Myeloid neoplasms33 (36%)AML14MDS11MPN6CMML1CML1 Lymphoid neoplasms51 (55%)DLBCL17B-ALL6TLPD6MCL5Myeloma5CLL3MZL3FL3BCL-NOS2CHL1 Normal marrow6 (7%) Sample failed2 (2%) Genomic abnormalities in hematologic malignancies80/84 (93%)Diagnostic42/84 (50%)Prognostic54/84 (64%)Potential therapeutic64/84 (76%) Table 2: Genomic changes which led to improved diagnosis and classification of the hematologic malignancy Case Diagnosis/Problem Genomic alteration Final/refined diagnosis 1 Neutropenia, T-LGL? STAT3 (N647I) T-LGL 2 Neutropenia, T-LGL? STAT3 (D661Y) T-LGL 3 T-LPD? JAK3 (M511I) T-PLL 4 T-LPD? TET2 (Q1523*), TP53 (R175G) PTCL, NOS 5 Transformed FL CIITA-DSCAML1 (Fusion) PMBL 6 CHL vs ALCL IGH-BCL2 (Rearrang.) DLBCL 7 BCL-NOS IGL-MYC (Rearrang.) BCL between DLBCL/BL 8 Myeloma IGH-MAF8 (Rearrang.) High risk myeloma 9 MDS? STK11 (F354L) RUNX1-MECOM (Fusion) MDS 10 MDS? MLL (ITD) MDS 11 MDS? KDM6A MDS 12 MPN MPL (R514_W515>KK) ET Disclosures Moskowitz: Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Research Funding; Merck: Research Funding. Horwitz:Research: Celgene, Millennium, Infinity, Kiowa-Kirin, Seattle Genetics, Spectrum•Consulting: Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Millennium, seattle genetics: Consultancy, Honoraria, Research Funding. Stein:Janssen Pharmaceuticals: Consultancy. He:Foundation Medicine: Employment. Stephens:Foundation Medicine, Inc. : Employment, Equity Ownership. Miller:Foundation Medicine: Employment. Younes:Novartis: Research Funding; J & J: Research Funding; Curis: Research Funding; Bayer; Bristol Meyer Squibb; Celgene; Incyte; Janssen R & D; Sanofi; Seattle Genetics; Takeda Millenium: Honoraria. Dogan:Foundation Medicine: Consultancy.