Session: 618. Acute Myeloid Leukemias: Biomarkers and Molecular Markers in Diagnosis and Prognosis: Poster I
Hematology Disease Topics & Pathways:
AML, Acute Myeloid Malignancies, Research, Translational Research, Genomics, Diseases, Biological Processes, Myeloid Malignancies, Technology and Procedures, Pathogenesis, Molecular testing
Using cytogenetic, FISH and targeted RNA sequencing (RNA-Seq) techniques, we identified 23 adult patients with NUP98 rearrangement MN at our institution since 2016. The cohort included 15 females and 8 males, with ages ranging from 23 to 79 years (median 62 years). There were 11 de novo AML (including 2 myeloid sarcoma, MS), 1 AML progressing from MDS, 2 MDS (one with increased blasts, 8 therapy related t-MN, and 1 uncharacterized MN with refractory T-ALL. Skin and CNS involvement was observed in 1 patient each. All 8 patients with prior hematologic or other malignancies were treated with topo II inhibitors (4/8) and alkylating agents (5/8), and often with radiotherapy (7/8).
Most patients had low hemoglobin and platelets, with white blood cell count ranging from 1.9 to 365.55 K/uL (median 9.3 K/uL). Blast percentages in peripheral blood and bone marrow ranged widely from 0% to 87% (median 20%) and 1% to 93% (median 29%), respectively. Auer rods were observed in 1 case. Blasts consistently express CD13, CD33 and CD117, whereas lack of CD34 was observed in 8 cases (34.8%). Monocytic differentiation was present in 17 patients (73.9%) with CD11b (7/21) and/or CD64 expression (15/21).
Cytogenetic analysis was performed in 21 patients. Of 6 patients with NUP98::NSD1, a normal karyotype was observed in 5 patients, and deletion of 9q as sole abnormality in 1 patient. NGS based genomic copy number alterations were observed in 2 patients including 1 MS. All other patients (except 1 MS) show clonal chromosome abnormalities (CA), and a complex karyotype with ≥3 CA were observed in 6 patients, including 1 with MS and 2 with t-MN. Clonal evolution was observed in 5 patients. FISH analysis using NUP98 break-apart probes was performed in 21 patients and confirmed a split signal pattern in 19 patients, and deletion of the 3’ NUP98 region in 2 patients.
NUP98 translocations and fusions were defined in 19 patients by combining chromosome, FISH and molecular findings, including RNA-Seq confirmation in 16 patients: NUP98::NSD1 (n=6, all with AML), NUP98::DDX10 (n=4, all with t-MN), NUP98::KMT2A (n=2, both with MDS, 1 harboring germline BRCA2 mutations), NUP98::KDM5A (n=2, both with MS), NUP98::HOXD13 (n=1), NUP98::TOP1 (n=1) and NUP98::PRRX2 (n=1, coexisting with ETV6::PDE3A). Two novel NUP98 fusions were detected: NUP98::KAT6B t(10;11) in a t-MDS with history of T-ALL, and NUP98::SATB1 t(3;11) in t-AML with history of breast cancer; both partner genes are implicated in epigenetic regulation. In the remaining 4 patients without defined NUP98 partners,11p15 abnormalities were detected by karyotyping and NUP98 split was confirmed by FISH testing. The presumptive NUP98 partner in 1 patient could be HOXA1 or HOXA9 (7p15). The NUP98 fusions were at exons 9-14 with exon 12 consistently in NUP98::NSD1, exon13 in NUP98::KDM5A, and exon 14 in NUP98::DDX10 and NUP98::TOP1.
NGS testing were performed in 21 patients and pathogenic somatic mutations were detected in 19 patients. The recurrent genetic alterations are NRAS (n=9, 47.3%, including 1 G12, 5 G13, 2 Q61, and 1 A146 codons ), DNMT3A (n=7, 36.8%), FLT3 ITD (n=7, 36.8%), WT1 (n=7, 36.8%), TP53 (n=4, 21%), IDH1/2 (n=3, 15.8%), RUNX1 (n=2, 10.5%), FAT1 (n=2, 10.5%). Other mutations include ASXL1, BCOR, CHEK1, EZH2, KDM6A, GATA2, KMT2D, KRAS, NF1, NPM1, NUP93, SETD2, and STAG2, one each. WT1 mutations are frequent, with 5 cases showing 2 to 5 mutations and 3 of them with bi-allelic WT1 alterations, and in 3 patients WT1 mutations likely acquired during disease progression.
The median follow-up was 13 months. At the last follow-up, 6 patients were alive, while 14 had died (10 died of disease complications), with a median survival of 9 months. Of the 8 cases with blasts <20% at initial presentation, 3 died within 6 months due to causes related or unrelated to the myeloid neoplasm, and 4 progressed to AML despite treatment with a median time to progression of 5.5 months (range: 1 to 27 months).
In summary, adult AML patients with NUP98 fusions are enriched for t-AML/MDS, often have monocytic differentiation, and featured with high prevalence of NRAS, DNMT3A and WT1 mutations, and portend poor outcome.
Disclosures: Berman: Novartis: Honoraria. Stein: Abbvie: Consultancy, Other: consulting fees; Jazz Pharmaceuticals: Consultancy, Other: consulting fees; AstraZeneca: Consultancy, Other: consulting fees; Genentech: Consultancy, Other: consulting fees; Celgene: Consultancy, Other: consulting fees; Astellas Pharmaceuticals: Consultancy, Other: consulting fees; Servier: Consultancy, Other: consulting fees; Gilead: Consultancy, Other: consulting fees; Agios Pharmaceuticals: Consultancy, Other: consulting fees; Daiichi Sankyo, Inc.: Consultancy, Other: consulting fees. Dogan: AstraZeneca: Research Funding.