Article

CD49d expression is an independent predictor of overall survival in patients with chronic lymphocytic leukaemia: A prognostic parameter with therapeutic potential

Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
British Journal of Haematology (Impact Factor: 4.71). 03/2008; 140(5):537-46. DOI: 10.1111/j.1365-2141.2007.06965.x
Source: PubMed

ABSTRACT

In vitro studies have demonstrated that surface expression of CD49d on chronic lymphocytic leukaemia (CLL) B cells facilitates leukaemic cell-stromal interactions by binding to fibronectin. This interaction reduces both spontaneous and drug-induced apoptosis. The present study measured CD49d expression by flow cytometry in a cohort of untreated CLL patients previously accrued to a prospective observational study and evaluated the relationship with overall survival (OS). Among the 158 CLL patients tested, the percentage of leukaemic B cells expressing CD49d ranged from 0 to 100%. When all risk factors were treated as continuous variables, CD49d expression showed moderate correlation with expression of ZAP-70 (r = 0.54; P < 0.0001) and CD38 (r = 0.58; P < 0.0001) but not %IGHV mutation. As a continuous variable, CD49d expression strongly correlated with OS (P < 0.0001). Recursive partitioning analysis suggested the 45% threshold of CD49d expression best predicted OS. Multivariate analysis, controlling for disease stage, ZAP-70, IGHV status and fluorescent in situ hybridization defects identified CD49d as an independent predictor of OS and was a better predictor of clinical outcome than ZAP-70, IGHV, or cytogenetics. This observational cohort study suggests that CLL B-cell expression of CD49d is an easily measurable and independent predictor of OS and CD49d expression in CLL. Importantly, anti-CD49d antibodies are already approved for treatment of other human diseases. Clinical testing of anti-CD49d therapy in CLL appears warranted.

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    • "Furthermore, high CD49d expression has been associated with trisomy 12, thus linking a phenotypical marker with a specific cytogenetic CLL subgroup (Zucchetto et al, 2013; Riches et al, 2014). CD49d expression had also been proven to be predictive of overall survival (OS) and treatment-free survival in patients with CLL (Gattei et al, 2008; Rossi et al, 2008; Shanafelt et al, 2008) and was found to be the strongest flow cytometry prognostic marker in a large multicentre study (Bulian et al, 2014). Because of the lack of studies validating this observation and its obvious potential importance in the management of CLL, we evaluated CD49d expression, its clinico-biological correlations, and prognostic significance in a single centre series of 415 patients with CLL. "
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    ABSTRACT: We investigated CD49d (also termed ITGA4) expression and its biological and clinical correlations in 415 patients with chronic lymphocytic leukaemia. CD49d expression was stable over the course of the disease. A high expression of CD49d (>30%) was found in 142/415 (34%) patients and was associated with progressive disease (advanced clinical stage, high serum lactate dehydrogenase or β2 -microglobulin levels; all p < 0·05) and aggressive disease biology (increased ZAP70 or CD38, unmutated IGHV, trisomy 12, mutations of NOTCH1 and SF3B1; all P < 0·05). A higher CD49d expression was also associated with a lower blood lymphocyte count and a higher number of lymphoid areas involved by the disease. Patients with high CD49d expression were treated more frequently (55% vs. 27%; P < 0·001) and earlier (median time to treatment [TTT] 65·4 months vs. not reached; P < 0·001) than those with low CD49d expression. However, no significant differences in response rates were observed. In the subgroup of patients with mutated IGHV, high CD49d expression was predictive of a shorter TTT while other markers, such as ZAP70 and CD38, were not. In conclusion, in this study CD49d expression correlated with high-risk CLL biomarkers and proved to be useful for separating patients with mutated IGHV into two different prognostic groups.
    Full-text · Article · Nov 2015 · British Journal of Haematology
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    • "VLA-4 is variably expressed by CLL patients and predicts disease progression. CLL patients with higher VLA-4 expression are characterized by more rapid disease progression when compared to patients with low expression [23,24]. Moreover, VLA-4 expression increases the ability of CLL cells to access protective niches [25]. "
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    ABSTRACT: CLL cell trafficking between blood and tissue compartments is an integral part of the disease process. Idelalisib, a phosphoinositide 3-kinase delta (PI3Kδ) inhibitor causes rapid lymph node shrinkage, along with an increase in lymphocytosis, prior to inducing objective responses in CLL patients. This characteristic activity presumably is due to CLL cell redistribution from tissues into the blood, but the underlying mechanisms are not fully understood. We therefore analyzed idelalisib effects on CLL cell adhesion to endothelial and bone marrow stromal cells (EC, BMSC). We found that idelalisib inhibited CLL cell adhesion to EC and BMSC under static and shear flow conditions. TNFα-induced VCAM-1 (CD106) expression in supporting layers increased CLL cell adhesion and accentuated the inhibitory effect of idelalisib. Co-culture with EC and BMSC also protected CLL from undergoing apoptosis, and this EC- and BMSC-mediated protection was antagonized by idelalisib. Furthermore, we demonstrate that CLL cell adhesion to EC and VLA-4 (CD49d) resulted in the phosphorylation of Akt, which was sensitive to inhibition by idelalisib. These findings demonstrate that idelalisib interferes with integrin-mediated CLL cell adhesion to EC and BMSC, providing a novel mechanism to explain idelalisib-induced redistribution of CLL cells from tissues into the blood.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "A more recently discovered marker is CD49d, the alpha4 subunit of the VLA-4 integrin (alpha4beta1). High CD49d expression predicts reduced overall survival and time to first treatment in CLL patients [10, 11]. "
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    ABSTRACT: The interactions of chronic lymphocytic leukemia cells with the microenvironment in secondary lymphoid tissues and the bone marrow are known to promote CLL cell survival and proliferation. CD38 and CD49d are both independent prognostic risk parameters in CLL with important roles in shaping these interactions. Both are reported to influence CLL cell trafficking between blood and lymphoid organs as well as their survival and proliferation within the lymphoid organs, thereby impacting the pathophysiology of the disease. The expression of CD38 and CD49d is associated in the majority of cases, and they exist as part of macromolecular complexes. Here, we review the current evidence for the individual and associated contributions of these molecules to CLL pathophysiology.
    Full-text · Article · Nov 2013 · Annals of Hematology
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