title: Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing.
abstract: Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Mrinal M
authors.initials: MM
authors.lastname: Patnaik
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Terra L
authors.initials: TL
authors.lastname: Lasho
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christy M
authors.initials: CM
authors.lastname: Finke
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Hanson
authors.affiliation: Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: King
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Naseema
authors.initials: N
authors.lastname: Gangat
authors.affiliation: Division of Hematology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Ayalew
authors.initials: A
authors.lastname: Tefferi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000754:Anemia, Refractory, with Excess of Blasts / Q000150:complications / Q000235:genetics / Q000401:mortality*; D000756:Anemia, Sideroblastic / Q000150:complications / Q000235:genetics / Q000401:mortality*; D001853:Bone Marrow / Q000737:chemistry / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002869:Chromosome Aberrations; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis / Q000379:methods*; D018450:Disease Progression; D005260:Female; D016368:Frameshift Mutation; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D053208:Kaplan-Meier Estimate; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D000072260:RNA Splicing Factors; D012097:Repressor Proteins / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D013922:Thrombocytosis / Q000209:etiology* / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D002352:Carrier Proteins; D018389:Codon, Nonsense; D006454:Hemoglobins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D012097:Repressor Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; C425066:SETBP1 protein, human; C112491:SF3B1 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2