Doubling Time of Soluble CD23 Is an Additional Prognostic Factor in ZAP 70 Positive CLL Patients.
Authors: Meuleman Nathalie , Lagneaux Laurence , Bennani Jalil , Delforge Alain , Bron Dominique 
Published: April 2020

Abstract
Background: Chronic lymphocytic leukemia (CLL) is a disease with unpredictable natural history in stage A patients (pts). Recently, It has been demonstrated that ZAP-70 and IgVH mutational status are powerful biological prognostic factors and we previously reported that the doubling time of soluble CD23 (sCD23DT) is a prognostic factor for progression of disease in untreated stage A CLL. Therefore we prospectively evaluated ZAP-70 protein expression and IgVH mutational status in untreated stage A B-CLL pts and correlated these markers with sCD23DT.
Methods: sCD23 level was evaluated by commercially available enzyme-linked immunosorbent assay (ELISA). ZAP-70 expression is determined in leukemic cells by flow cytometry, and positive expression was defined as &gt;20% positive cells. When tests became available, ZAP-70 gene expression and IgVH mutational status were also evaluated in all pts included in the sCD23 study.
Results: 47 pts with untreated stage A B-CLL are evaluable for the sCD23DT. ZAP-70 and mutational status were evaluated in 34pts. Median age was 62 (42–82) years. The median follow-up was 58 (16–129) months. The sCD23DT was clearly associated with progression to upper stages requiring a treatment: median time to progression was 25 Mos in pts with sCD23 DT inferior to one year comparing to 141 months in pts with sCD23 DT superior to one year (p&lt;0.0001). Time to progression in the group of pts with positive ZAP-70 expression was 19.1 mos comparing to 86.1 mos in ZAP-70 negative group (p=0.0001) Time to progression to treatment for pts with unmutated IgVH was 15,9 mos and 86,1 mos for pts with mutated status (p&lt;0.001). In the group of pts with ZAP-70 positive expression 6pts (67%) needed a treatment. Among ZAP-70+ and sCD23DT&lt; 1 year pts, 100% (6/6) required a treatment. For pts with positive ZAP-70 and a sCD23DT superior to one year, 100% (3/3) of pts do not need a treatment (p=0.0188). In the group of good prognosis pts with negative ZAP-70, 24% (6/25) of the pts required a treatment, median time to progression for these pts was 66,6 mos. in the ZAP-70 negative pts population, 3/25 (12%) have a sCD23DT&lt;1 year and 2 of these pts required a treatment for disease progression. Among the pts with indolent progression, negative ZAP-70 and who do not need a treatment, 96 % of the pts have a sCD23DT superior to one year. In the group of pts with unmutated status (n=8), 88% of the pts needed a treatment and all the pts had a sCD23DT inferior to one year, the only pts who did not required a treatment had a sCD23DT superior to one year. Among patients with mutated IgVH 73% did not require a treatment and 95% of those pts had a sCD23DT superior to one year. Among the mutated pts who progressed to treatment 42% had a sCD23DT inferior to one year, the 58% of treated pts with sCD23DT superior to one year and unmutated status had a median time to progression of 68 mos. In conclusion, CLL patients can be divided into different risk categories according to sCD23 serial determinations. sCD23DT is an additional important prognostic marker for disease progression even in ZAP-70 positive patients.