Clinical Relevant Alterations Identified By Comprehensive Genomic Profiling Can Potentially Improve Therapeutic Option and Change Prognosis in Hematologic Malignancies
Authors: He Jie , Patel Minal , Phillip Irene , Bailey Mark , Berman Ellin , Park Jae H. , Shukla Neerav N , Chung Stephen S. , Castro-Malaspina Hugo , Douer Dan , Nahas Michelle , Otto Geoff , Vergilio Jo-Anne , Mughal Tariq I , Ross Jeff , Stephens Phil , Tallman Martin S. , Miller Vincent A. , van den Brink Marcel , Lipson Doron , Levine Ross L. 
Published: October 2019

Abstract
Background:
Hybrid capture based comprehensive genomic profiling (CGP) in a spectrum of human leukemias has led to a deepened understanding of biological mechanism of leukemogenesis and improved risk stratification and has provided additional options for targeted therapy beyond standard chemotherapy or transplantation. However, most adults with leukemia still relapse after initial therapy, and incorporating comprehensive genomic profiling results into clinical practice still requires clear guidelines and evidence on how this compares with the conventional diagnosis approach. Here we analyzed a consecutive series of 116 acute leukemia patients profiled by FoundationOne Heme to learn how the results compared with current standard of care diagnosis and how any additional insights into the genomic alterations may lead to a changed or improved diagnosis, therapy and prognosis.
Methods:
A total of 116 consecutive newly diagnosed or relapse/refractory leukemia patients from Memorial Sloan Kettering Cancer Center were profiled by FoundationOne Heme. DNA and RNA integrated next-generation sequencing was performed in a CLIA-certified, CAP-accredited, NYS-approved laboratory for comprehensive genomic profiling. All captured libraries were sequenced to high depth averaging 569X for DNA (405 genes) and >3M unique pairs for RNA (265 genes). Somatic variants identified included short variants, copy number amplification and loss and rearrangements. Ninety-nine patients had Karyotyping and/or FISH performed at the same time to allow comparing results between platforms.
Results:
The age of this clinical sample cohort range from 19 to 85, with median age of 54. The diagnosis included AML (49), ALL (29), LGL (12), CML (7), MDS (4), and 16 other subtypes. CGP was performed at the time of diagnosis (47 patients, 41%), relapsed/refractory (58 patients, 50%), stable disease (7 patients, 6%) and complete remission (3 patients, 3%). CGP successfully reported 308 alterations in 103 patients with an average of 3.0 alterations per patient, including 158 base substitutions, 75 indels, 21 copy number amplification or loss, and 54 rearrangements.
High concordance of known translocations, including BCR-ABL1, RUNX1T1-RUNX1, PML-RARA, MLLT10-MICALM, MLL-rearrangement, ETV-6 rearrangement and EVI1 rearrangement, were observed between FoundationOne Heme and Karyotpye/FISH in 76 out of 78 cases (97%). In addition to genomic abnormalities identified by Karyotype/FISH, CGP identified additional clinically relevant alterations in 61 cases (59%). These alterations included genes associated with new targeted therapies, such as FLT3, IDH1/2, KRAS/NRAS/BRAF and KIT and known/novel prognostic biomarkers, including TP53, NF1, CDKN2A/B, and RB1 (Figure 1). Novel fusions involved in NUP98, ABL1, PDGFRB, JAK2 were found in 12 patients, and 4 known/novel Ph-like ALL signature fusions were identified which can inform the use of clinically available targeted therapies for these patients with high-risk ALL.
Conclusion:
CGP has high concordance with standard of care testing (Karyotyping/FISH) with respect to the detection of known translocations/fusion genes. More importantly, CGP allowed for the identification of additional clinically relevant genomic alterations in a substantial fraction of leukemia patients seen in routine clinical care. These data demonstrate CGP can inform novel therapeutic interventions, improve accuracy of clinical diagnosis, and provide added value to improve prognosis prediction in adult leukemia.
Figure 1 Figure 1.

Disclosures
He: Foundation Medicine, Inc: Employment, Equity Ownership. Bailey:Foundation Medicine, Inc: Employment, Equity Ownership. Park:Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Douer:Shire: Consultancy, Speakers Bureau; Pfizer: Consultancy; Jazz Pharmaceuticals: Honoraria; Gilled Sciences, Inc: Consultancy; Spectrum: Consultancy. Nahas:Foundation medicine: Employment. Otto:Foundation Medicine, Inc: Employment. Vergilio:Foundation Medicine: Employment. Mughal:Foundation Medicine: Employment, Equity Ownership. Ross:Foundation Medicine, Inc: Employment. Stephens:Foundation Medicine, Inc: Employment, Equity Ownership. Miller:Foundation Medicine: Employment, Equity Ownership. Lipson:Foundation Medicine, Inc: Employment.