title: Cytogenetic and molecular predictors of response in patients with myeloid malignancies without del[5q] treated with lenalidomide.
abstract: BACKGROUND
  While lenalidomide (LEN) shows high efficacy in myelodysplastic syndromes (MDS) with del[5q], responses can be also seen in patients presenting without del[5q]. We hypothesized that improved detection of chromosomal abnormalities with new karyotyping tools may better predict response to LEN.
  
  
  METHODS
  We have studied clinical, molecular and cytogenetic features of 42 patients with MDS, myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes and secondary acute myeloid leukemia (sAML) without del[5q] by metaphase cytogenetics (MC) who underwent therapy with LEN.
  
  
  RESULTS
  Fluorescence in situ hybridization (FISH) or single nucleotide polymorphism array (SNP-A)-based karyotyping marginally increased the diagnostic yield over MC, detecting 2/42 (4.8%) additional cases with del[5q], one of whom were responded to LEN. Responses were more often observed in patients with a normal karyotype by MC (60% vs abnormal MC; 17%, p = .08) and those with gain of chromosome 8 material by either of all 3 karyotyping methods (83% vs all other chromosomal abnormalities; 44% p = .11). However, 5 out of those 6 patients received combined LEN/AZA therapy and it may also suggest those with gain of chromosome 8 material respond well to AZA. The addition of FISH or SNP-A did not improve the predictive value of normal cytogenetics by MC. Mutational analysis of TET2, UTX, CBL, EZH2, ASXL1, TP53, RAS, IDH1/2, and DNMT-3A was performed on 21 of 41 patients, and revealed 13 mutations in 11 patients, but did not show any molecular markers of responsiveness to LEN.
  
  
  CONCLUSIONS
  Normal karyotype and gain of chromosome 8 material was predictive of response to LEN in non-del[5q] patients with myeloid malignancies.
authors.affiliation: Department of Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Anna
authors.initials: A
authors.lastname: Jankowska
authors.forename: Andres
authors.initials: A
authors.lastname: Jerez
authors.forename: Hadrian
authors.initials: H
authors.lastname: Szpurka
authors.forename: Christine L
authors.initials: CL
authors.lastname: O'Keefe
authors.forename: Kathryn
authors.initials: K
authors.lastname: Guinta
authors.forename: Manuel
authors.initials: M
authors.lastname: Afable
authors.forename: Ramon
authors.initials: R
authors.lastname: Tiu
authors.forename: Kathy L
authors.initials: KL
authors.lastname: McGraw
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciejewski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D000077269:Lenalidomide; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C000717967:DNMT3A protein, human; D013792:Thalidomide; D000090205:DNA Methyltransferase 3A; D000077269:Lenalidomide