Molecular Features in the Diagnosis of Myeloid Neoplasms in Down Syndrome Patients Less Than Four Years of Age: Experience from a Single Institution

Abstract Introduction: Patients with Down syndrome (DS) have an increased risk of hematological disorders, including transient abnormal myelopoiesis (TAM), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Twenty percent of patients with TAM subsequently develop myeloid neoplasm in the first 4 years of life. MDS represents a clonal aberration thought to be a pre-leukemic condition characterized clinically by cytopenias and erythroid, myeloid and/or megakaryocytic dysplasia in the bone marrow with or without increase in blasts and harbors a concordant, clone-specific mutation of GATA1. WHO 2016 classification of hematopoietic neoplasms does not distinguish between MDS and AML, as their overall prognosis appears to be similar. However, due to the rarity of this disorder, limited clinical and laboratory data is available, contributing to difficulties in establishing the diagnosis. Here we describe our center's recent experience with the diagnosis and molecular findings of myeloid neoplasm associated with Down syndrome (MN-DS). Design/Method: Retrospective review of the patient's electronic medical record and review of the literature was conducted. Routine karyotype, fluorescent in-situ hybridization (FISH) and next generation sequencing (NGS) studies were reviewed where available. Results: Six patients with DS diagnosed with AML or MDS were identified over a 3-year period. Mean age of the cohort was 18.5 (range 12-24) months with a slight female predominance. Three patients had a history of TAM, all of which resolved without intervention. Three patients had asymptomatic thrombocytopenia after birth without blasts or GATA1 mutation confirmation. One of the three patients with a history of TAM presented with overt AML, while in the others diagnosis was challenging. By WHO 2008 classification of myeloid neoplasms, four patients had refractory anemia with excess blasts, one had refractory cytopenia with multilineage dysplasia, and one had AML. For two patients, in whom myeloid directed next generation sequencing was obtained, mutations were found in GATA1, EZH2, and NRAS. One of the patients in our series presented with AML with gain of MECOM, RPN1 loss and D5S23 deletion by FISH and succumbed to relapsed disease. All patients were treated per Children's Oncology Group AAML1531 arm A protocol that included 3 induction cycles and 2 intensification cycles, except for a single patient that received one cycle per AAML0431 and completed therapy per AAML1531 arm B high risk due to persistent disease following initial induction cycle. Two patients are currently receiving treatment, three have no evidence of disease recurrence on follow up ranging from 2 to 18 months, and one of the patients has died due to relapsed/refractory disease. Conclusions: We present six cases of MN-DS in patients less than four years of age. Our cohort is representative of the diversity encountered in this rare disease including patients with 1) isolated cytopenia in the absence of overt morphological findings, 2) myelodysplasia, and 3) AML. In our patient with overt AML there were karyotypic features such as gain of MECOM, which with specific translocation partners has previously been described to portend a poor prognosis. This and other cytogenetic features perhaps warrant further investigation given our patient's refractory disease. In the patient with refractory cytopenia without blasts, there was a subpopulation of cells identified by NGS panel showing mutations in GATA1, EZH2, and NRAS that led to a diagnosis of MDS/MN-DS. Four of the patients had aberrant myeloid populations and dysplasia fitting diagnostic criteria for MDS. Establishing the clonal nature of the disease either by karyotype/FISH or NGS may help with the identification, treatment and prognostication of this unique patient population, and may aid in the diagnosis of MN-DS, which may be challenging in patients with DS once they have recovered from TAM. Disclosures No relevant conflicts of interest to declare.