ZAP-70 Expression Assessed by Immunohistochemistry Correlates with Time to First Treatment in Patients with Chronic Lymphocytic Leukemia

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Blood (ASH Annual Meeting Abstracts) 2009 114: Abstract 4686

ZAP-70 Expression Assessed by Immunohistochemistry Correlates with Time to First

Treatment in Patients with Chronic Lymphocytic Leukemia.

1, Amy Chadburn, MD*,2, Wayne Tam3, Tyrell*,1,

Elstrom, MD1, Jia Ruan, MD, PhD4, Morton *,5, Ely, MD, MPH6,

M. Knowles*,7, P. Leonard5 and R Furman1

1 Weill Cornell Medical College, New York, NY, USA,

2 Pathology, Northwestern University, Chicago, IL, USA,

3 Department of Pathology, Weill Medical College of Cornell University, USA,

4 Medicine and Hematology/Oncology, Weill Cornell Medical College, New York, NY,

USA,

5 Department of Hematology/Oncology, Weill Cornell Medical College, New York,

NY, USA,

6 Weill Cornell/NYPH, New York, NY, USA,

7 Dept of Pathology and Laboratory Medicine, Weill Cornell Medical College, New

York, NY, USA

Abstract 4686

Background: ZAP-70 expression is a prognostic indicator in chronic lymphocytic

leukemia (CLL). Initial studies measured intracellular ZAP-70 expression by flow

cytometry and defined a cut-off of 20% as predictive of time from diagnosis to

initial therapy and overall survival. However, due to technical challenges,

standardization of methods for evaluation of ZAP-70 expression has been

difficult. This has resulted in a limitation of applicability for a potentially

useful clinical test. Immunohistochemistry (IHC) is easy to perform and

interpret, and therefore may be a more reliable and accurate means for assessing

ZAP-70 expression. We investigated the potential prognostic implications of

ZAP-70 expression assessed by IHC.

Methods: We searched our CLL database for all patients seen at Weill Cornell

Medical College between 2007 and 2009 with an identifiable date of diagnosis,

date of first therapy, IgVH mutation status, and ZAP-70 status. All patients

gave informed consent to participate in the research database. Paraffin-embedded

cell blocks were prepared from formalin-fixed peripheral blood mononuclear cells

and evaluated by IHC for PAX5, CD3, and ZAP-70. The entire cell clot was

reviewed. If more than 20% of cells faintly expressed ZAP-70, the ZAP-70 status

was considered to be positive. Patients had IgVH mutations status determined by

a commercial laboratory with <98% sequence homology used as a cut-off. Time from

diagnosis to first treatment (TT) was estimated by the Kaplan-Meier method;

comparisons were performed by log-rank test. Pearson's pairwise correlation

coefficient was used to evaluate the relationship between ZAP-70 and IgVH.

Results: One-hundred thirty-seven patients with date of diagnosis and date of

first treatment were identified in the database. Sixty-six patients have been

treated to date. ZAP-70 status was available for 106 patients, 62 were positive,

44 were negative. In a subset of 20 patients, two blinded pathologists reviewed

IHC and found perfect agreement on ZAP-70 status. IgVH mutation status was

available for 86 patients, 34 were unmutated, and 52 were mutated. Eighty-two

patients had both ZAP-70 status and IgVH mutation status available. There was

good correlation between ZAP-70 and IgVH status (r=0.36, p=0.0008). Seventy-five

percent of those with unmutated IgVH were ZAP-70 positive. Sixty-one percent of

patients with mutated IgVH were ZAP-70 negative. However, only 57% of ZAP-70

positive patients were IgVH unmutated. The predicted median TT was 54 months for

the whole cohort (range 0-376+ months, 95% CI 45-96 months). The median TT was

27 months (range 0-112 months) for ZAP-70-positive patients compared to 96

months (range 0-376+ months) for ZAP-70-negative patients (p=0.002). The median

TT was 32 months (range 0-112 months) for IgVH unmutated patients compared to 88

months (range 0-376+ months) for IgVH mutated patients (p=0.01).

Conclusions: ZAP-70 as measured by IHC was feasible in a large cohort of

patients and ZAP-70 status correlated with time to first treatment. These data

suggest that ZAP-70 assessment by IHC may be a reliable prognostic tool in CLL

and should be evaluated in larger, multicenter clinical studies.

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