title: Leukemia-cell proliferation and disease progression in patients with early stage chronic lymphocytic leukemia.
abstract: The clinical course of patients with recently diagnosed early stage chronic lymphocytic leukemia (CLL) is highly variable. We examined the relationship between CLL-cell birth rate and treatment-free survival (TFS) in 97 patients with recently diagnosed, Rai stage 0-II CLL in a blinded, prospective study, using in vivo2H2O labeling. Birth rates ranged from 0.07 to 1.31% new cells per day. With median follow-up of 4.0 years, 33 subjects (34%) required treatment by NCI criteria. High-birth rate was observed in 44% of subjects and was significantly associated with shorter TFS, unmutated IGHV status and expression of ZAP70 and of CD38. In multivariable modeling considering age, gender, Rai stage, expression of ZAP70 or CD38, IGHV mutation status and FISH cytogenetics, only CLL-cell birth rate and IGHV mutation status met criteria for inclusion. Hazard ratios were 3.51 (P=0.002) for high-birth rate and 4.93 (P<0.001) for unmutated IGHV. The association between elevated birth rate and shorter TFS was observed in subjects with either mutated or unmutated IGHVs, and the use of both markers was a better predictor of TFS than either parameter alone. Thus, an increased CLL birth rate in early stage disease is a strong predictor of disease progression and earlier treatment.
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|KineMed Inc., Emeryville, CA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Murphy
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.|CLL Research Consortium, San Diego, CA, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: KineMed Inc., Emeryville, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hayes
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Redd
authors.affiliation: KineMed Inc., Emeryville, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Emson
authors.affiliation: KineMed Inc., Emeryville, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.|CLL Research Consortium, San Diego, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: KineMed Inc., Emeryville, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Turner
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Greaves
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Zent
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: KineMed Inc., Emeryville, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: McConnel
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Barrientos
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: N
authors.initials: N
authors.lastname: Kay
authors.affiliation: KineMed Inc., Emeryville, CA, USA.|Department of Nutritional Science and Toxicology, University of California, Berkeley, CA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Hellerstein
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, NY, USA.|Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Chiorazzi
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Moores Cancer Center, University of California, San Diego, CA, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: CLL Research Consortium, San Diego, CA, USA.|Department of Medicine, Hofstra Northwell School of Medicine, Manhasset, NY, USA.|Feinstein Institute for Medical Research, Manhasset, NY, USA.
authors.forename: K R
authors.initials: KR
authors.lastname: Rai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor