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Clinical Applications and Utility of a Precision Medicine Approach for Patients With Unexplained Cytopenias



      To demonstrate experience and feasibility of a precision medicine approach for patients with unexplained cytopenias, defined as low blood counts in one or more cell lineages, persistent for 6 months or longer, in the absence of known nutritional, autoimmune, infectious, toxic, and neoplastic (secondary) causes.

      Patients and Methods

      Patients were evaluated in our clinic between November 8, 2016, and January 12, 2018. After a thorough evaluation of known causes, family history, and appropriate clinical assays, genomic evaluation was performed in a stepwise manner, through Sanger, targeted, and/or whole-exome sequencing. Variants were analyzed and discussed in a genomics tumor board attended by clinicians, bioinformaticians, and molecular biologists.


      Sixty-eight patients were evaluated in our clinic. After genomic interrogation, they were classified into inherited bone marrow failure syndromes (IBMFS) (n=24, 35%), cytopenias without a known clinical syndrome which included idiopathic and clonal cytopenias of undetermined significance (CCUS) (n=30, 44%), and patients who did not fit into the above two categories (“others,” n=14, 21%). A significant family history was found in only 17 (25%) patients (9 IBMFS, 2 CCUS, and 6 others), whereas gene variants were found in 43 (63%) patients (34 [79%] pathogenic including 12 IBMFS, 17 CCUS, and 5 others]. Genomic assessment resulted in a change in clinical management in 17 (25%) patients, as evidenced by changes in decisions with regards to therapeutic interventions (n=8, 47%), donor choice (n=6, 35%), and/or choice of conditioning regimen for hematopoietic stem cell transplantation (n=8, 47%).


      We show clinical utility of a real-world algorithmic precision medicine approach for unexplained cytopenias.

      Abbreviations and Acronyms:

      BMFS (bone marrow failure syndromes), CCUS (clonal cytopenia of undetermined significance), CIM (Center for Individualized Medicine), DADA2 (deficiency of adenosine deaminase-2), DBA (Diamond-Blackfan anemia), FA (Fanconi’s anemia), FMPD (familial myeloid predisposition), HSCT (hematopoietic stem cell transplantation), IBMFS (inherited bone marrow failure syndromes), ICUS (idiopathic cytopenias of undetermined significance), IST (immunosuppressive therapy), MDS (myelodysplastic syndromes), NGS (next-generation sequencing), PNH (paroxysmal nocturnal hemoglobinuria), SCN (severe congenital neutropenia), STS (short telomere syndromes), VUS (variant of uncertain significance), WES (whole-exome sequencing)
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