De Novo Myelodysplastic Syndromes in Patients 20-50 Years Old Characterized By Frequent Mutations in TP53 and Transcription-Related Genes
Authors: Epstein-Peterson Zachary D. , Spitzer Barbara , McCarter Joseph , McGovern Erin , Levine Ross L. , Tallman Martin S. 
Published: November 2019

Introduction: Myelodysplastic syndromes (MDS) comprise a spectrum of clonal bone marrow failure syndromes and are principally seen in older adults, with a median age at diagnosis of greater than 65 years and increasing incidence with advancing age. Significant advances have been made in elucidating the molecular pathogenesis of these conditions, especially in defining recurrent genetic mutations in MDS. However, as most patients with MDS are over 60 years old, much of these data concerning mutational patterns and disease biology come from this same population. Additionally, children with MDS are known to have different clinical presentations and cytogenetic profiles from those seen in older adults. Little has been published on the clinical and molecular features of younger adult patients with MDS, and whether these patients demonstrate unique disease biology features has not been elucidated.
Methods: We identified all patients evaluated for MDS (including chronic myelomonocytic leukemia) at our institution aged 20-50 at diagnosis since 1980, excluding patients who had received prior cytotoxic chemotherapy, those with a known or suspected underlying bone marrow failure syndrome, or occupational exposure to benzene. Patient, disease, and treatment information was extracted for analysis. We designated cytogenetic risk profiles according to the Revised International Prognostic Scoring System for MDS (IPSS-R, Greenberg PL, et al. Blood 120.12 (2012): 2454-2465) and calculated MDACC (Kantarjian H, et al. Cancer 113.6 (2008): 1351-1361) and IPSS-R prognostic risk scores at diagnosis in patients with available information. Patients were characterized molecularly where either clinical sequencing had been performed, or archival DNA was available for analysis. Sequencing was performed through Foundation Medicine (N = 1), Genoptix (N = 1) or an in-house proprietary assay/archival DNA analysis (N = 35 total patients; multiple assays, evaluating 30-400 genes implicated in myeloid neoplasia). Mutations at high VAF and not characteristic of myeloid diseases were excluded as possible germline variants. For 15 patients, archival samples were analyzed using a similar platform to the clinical in-house assays of 476 genes.
Results: Seventy one patients were included in our cohort; Table 1 displays full patient characteristics. The median age at diagnosis of MDS was 41 years (range 21-50, SD = 8.1). The most common MDS subtypes were excess blasts 2 (EB2) and multilineage dysplasia (MLD) (each 30% of cases). Most patients underwent allogeneic transplantation (53 patients, 79%). Five-year overall survival (OS) was 52.7% (95% CI 41.4-65.6). The median overall survival was 6.1 years and median follow-up for survivors was 6.7 years. Fifteen patients experienced progression to acute myeloid leukemia (AML) and 10 relapsed with AML after upfront transplant for MDS.
By cytogenetics alone, MDACC, and IPSS-R, there was a near-equal distribution among prognostic risk groups for >intermediate- compared to <=intermediate-risk. The most common cytogenetic abnormalities were deletion 5q in 13 patients, trisomy 8 in 11 patients, and monosomy 7 in 7 patients. Forty one total patients had sequencing data available: 4 patients with limited targeted genetic testing alone and 37 with sequencing panels. Table 2 and Figures 1-3 display sequencing results. Four patients (Table 2) underwent focused sequencing rather than a full panel. Upfront sequencing data was available in 21 patients (within 6 months of diagnosis, without treatment), and 5 patients had progressed to AML at the time of sequencing. TP53 mutations were most common (9 mutations in 8 patients), followed by ASXL1 and SF3B1 (5 patients each). Six patients had no mutations present.
Conclusions:
Our preliminary data demonstrate that in patients with de novo MDS diagnosed at age 20-50, there are similar patterns of specific cytogenetic changes and prognostic risk categories compared to older adult patients. Molecular alterations broadly appear similar as well, both in the categories of genes mutated and in specific genes involved. When compared qualitatively to large adult datasets (Haferlach T, et al. Leukemia 28.2 (2014): 241), there is a trend towards more mutations in genes involved in transcription. Further studies are warranted to validate these results and further delineate pathobiologic and clinical differences between these two patient populations.

Disclosures
Levine: Celgene: Consultancy, Research Funding; Lilly: Honoraria; Amgen: Honoraria; Gilead: Consultancy; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Prelude Therapeutics: Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees. Tallman:Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Biosight: Research Funding; UpToDate: Patents & Royalties; Biosight: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Biosight: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.