CD69 is independently prognostic in chronic lymphocytic leukemia: a comprehensive clinical and biological profiling study

Abstract

BackgroundCD69 is expressed in several hemopoietic cells and is an early activation marker in chronic lymphocytic leukemia. Chronic lymphocytic leukemia is a clinically heterogeneous disease which needs novel prognostic parameters which can be easily and efficiently managed. Design and MethodsWe investigated CD69 by flow cytometry in a series of 417 patients affected by chronic lymphocytic leukemia and compared this to other biological and clinical prognosticators. ResultsCD69 was associated with Rai stages (P=0.00002), b2-microglobulin (P=0.0005) and soluble CD23 (P<0.0001). CD69 and ZAP-70 (P=0.018) or CD38 (P=0.00015) or immunoglobulin variable heavy chain gene mutations (P=0.0005) were also significantly correlated. Clinically, CD69 positive chronic lymphocytic leukemias received chemotherapy more frequently (74%; P<0.0001), and presented a shorter duration of response after fludarabine plus rituximab (P=0.010) as well as shorter progression free survival and overall survival (P<0.0001). CD69 demonstrated true additive prognostic properties, since the CD69 + plus ZAP-70 + or CD38 + or immunoglobulin variable heavy chain gene unmutated patients had the worst progression free survival and overall survival (P<0.0001). Interestingly, low CD69 expression was necessary to correctly prognosticate the longer progression free survival of patients with a low tumor burden of b2-microglobulin (P=0.002), of soluble CD23 (P=0.020), or of Rai stages 0-I (P=0.005). CD69 was confirmed to be an independent prognostic factor in multivariate analysis of progression free survival (P=0.017) and overall survival (P=0.039). ConclusionsOur data indicate that CD69 is significantly correlated with poor clinical and biological prognostic factors and is confirmed to be an independent disease prognosticator. This supports its introduction in a routine laboratory assessment and, possibly, in a prognostic scoring system for chronic lymphocytic leukemia, after an adequate standardization process.

T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers

“…45 Moreover CLL patients had significantly higher numbers of proliferating CD4 + and CD8 + T cells, which was more evident at disease progression.…”

B-cell prolymphocytic leukemia: a specific subgroup of mantle cell lymphoma

“…CD29 and CD49d together form the VLA-4 protein; CD49d is known to empower CLL cells to migrate into lymphoid tissue. 36,37 CD69, an early activation marker in CLL correlating with a poor prognosis, 38 was heterogeneously expressed in MCL and B-PLL. Altogether, the genes found to be differentially expressed among CLL, MCL, and B-PLL are in line with data reported for CLL and MCL in literature and thereby confirm the suitability of our approach.…”

Clinical significance of LAIR1 (CD305) as assessed by flow cytometry in a prospective series of patients with chronic lymphocytic leukemia

“…Differently from others, this unsupervised procedure did not consider any clinical parameter to set the cut-off, obviating selection bias. 8,9,12 Interestingly, LAIR1 expression was related to the occurrence of autoimmune phenomena. Both a direct antiglobulin test and autoimmune hemolytic anemia were more frequently observed in LAIR1 -patients, with a quite high percentage of LAIR1 -patients having autoimmune hemolytic anemia (7.2%) at presentation with CLL.…”

“…In line with our findings, Del Poeta et al recently reported a reduced prognostic power of CD49d when all significant prognostic factors for CLL were included in the multivariate analysis. 12 The cut-off for positivity of LAIR1 was set at 30%. This choice of cut-off was made considering the distribution of frequencies of positive cells in our cohort of patients, as previously done by Damle et al for CD38 4 (Online Supplementary Methods and Figure 1).…”

“…1,6,7 Recently, CD49d and other markers, such as CD25, CD26 and CD69, have been advocated as being predictive and reliable in identifying patients with peculiar molecular characteristics of disease and different prognoses. [8][9][10][11][12] Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), also known as CD305, is a transmembrane glycoprotein that acts as an inhibitory receptor and is expressed by most immune cells. The known LAIR1 ligands are extracellular matrix collagen and C1q, the first component of the complement.…”