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

Abstract

Objective: 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.

Results: 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%).

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

Figure 1:

Figure 1A shows diagnostic algorithm followed by our clinic. Figure 1B shows the variant decision tree adopted by our team. Nutritional causes include deficiencies of iron, B12, copper, folate and pyridoxine. A wide array of drugs, toxins, infections and inflammatory etiology is considered at the discretion of the referring hematologist. Consumptive etiology includes splenomegaly and various causes of intravascular and extravascular hemolysis. Abbreviations: MDS = myelodysplastic syndromes; PNH = paroxysmal nocturnal hemoglobinuria; STS = short telomere syndrome; CIM = center for individualized medicine; SDS = Shwachman-Diamond syndrome; DBA = Diamond-Blackfan anemia, GATA2 = GATA-binding factor 2; FMPD = familial myeloid predisposition syndromes; FA = Fanconi anemia; FLOW-FISH = flow cytometry-fluorescent in-situ hybridization; NGS = next generation sequencing; WES = whole exome sequencing; CCUS = clonal cytopenia of undetermined significance; ICUS = idiopathic cytopenia of undetermined significance; ACMG = American College of Medical Genetics and Genomics; VUS = variant of uncertain significance; HGMD = Human Gene Mutation Database; COSMIC = Catalogue of Somatic Mutations in Cancer; SIFT = Sorting Intolerant From Tolerant; M-CAP = Mendelian Clinically Applicable Pathogenicity score; P²T = Protein Panoramic Annotation Tool; PCAN = Phenotype Consensus Analysis; RNAseq = RNA sequencing; PCR = polymerase chain reaction; CLIA = Clinical Laboratory Improvement Amendments.

Figure 1:

Figure 1A shows diagnostic algorithm followed by our clinic. Figure 1B shows the variant decision tree adopted by our team. Nutritional causes include deficiencies of iron, B12, copper, folate and pyridoxine. A wide array of drugs, toxins, infections and inflammatory etiology is considered at the discretion of the referring hematologist. Consumptive etiology includes splenomegaly and various causes of intravascular and extravascular hemolysis. Abbreviations: MDS = myelodysplastic syndromes; PNH = paroxysmal nocturnal hemoglobinuria; STS = short telomere syndrome; CIM = center for individualized medicine; SDS = Shwachman-Diamond syndrome; DBA = Diamond-Blackfan anemia, GATA2 = GATA-binding factor 2; FMPD = familial myeloid predisposition syndromes; FA = Fanconi anemia; FLOW-FISH = flow cytometry-fluorescent in-situ hybridization; NGS = next generation sequencing; WES = whole exome sequencing; CCUS = clonal cytopenia of undetermined significance; ICUS = idiopathic cytopenia of undetermined significance; ACMG = American College of Medical Genetics and Genomics; VUS = variant of uncertain significance; HGMD = Human Gene Mutation Database; COSMIC = Catalogue of Somatic Mutations in Cancer; SIFT = Sorting Intolerant From Tolerant; M-CAP = Mendelian Clinically Applicable Pathogenicity score; P²T = Protein Panoramic Annotation Tool; PCAN = Phenotype Consensus Analysis; RNAseq = RNA sequencing; PCR = polymerase chain reaction; CLIA = Clinical Laboratory Improvement Amendments.

Figure 2:

Figure representing a visual description of the different diagnoses included in our cohort of patients with unexplained cytopenias. We divided the patients into three primary categories; IBMFS (n=24, 35%), cytopenias without a known clinical syndrome (n=30, 44%) and other patients which did not fit either of the two categories (n=14, 21%). Abbreviations: IBMFS = inherited bone marrow failure syndromes; STS = short telomere syndromes; DBA = Diamond-Blackfan anemia; DADA2 = deficiency of adenosine deaminase-2; SCN = severe congenital neutropenia; FA: Fanconi’s anemia; ICUS = idiopathic cytopenias of undetermined significance; CCUS = clonal cytopenias of undetermined significance; FMPD = familial myeloid predisposition; BMFS = bone marrow failure syndromes.