Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia.
Leukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70-negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease, including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70-positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years.
Rassenti
Laura Z
LZ
The Chronic Lymphocytic Leukemia Research Consortium, La Jolla, CA, USA.
Jain
Sonia
S
Keating
Michael J
MJ
Wierda
William G
WG
Grever
Michael R
MR
Byrd
John C
JC
Kay
Neil E
NE
Brown
Jennifer R
JR
Gribben
John G
JG
Neuberg
Donna S
DS
He
Feng
F
Greaves
Andrew W
AW
Rai
Kanti R
KR
Kipps
Thomas J
TJ
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012307:Risk Factors; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D051746:ZAP-70 Protein-Tyrosine Kinase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1