Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi‐institutional study

Abstract

Background Monocyte-derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell-cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte-derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. Methods We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Results Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk-stratification of CLL patients for TTT. Conclusions Elevated AMC at diagnosis is associated with inferior CLL patient outcomes and accelerated disease progression. Monocyte-derived cells in the CLL microenvironment promote CLL cell survival and proliferation. Together, these findings suggest that monocytes and monocyte-derived cells are rational therapeutic targets in CLL.

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

“…We showed [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and inflammation [12]. Key role of monocytes in CLL is also supported by observations in animal model of CLL, where depletion of monocytes and macrophages resulted in a control of CLL development and reparation of immune dysfunction in vivo [35].…”

“…Because our multivariate analysis revealed a significant relationship between the activation of immune cells and disease course, we explored their prognostic value. We showed [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and inflammation [12].…”

Colony-Stimulating Factor-1 Receptor Is Required for Nurse-like Cell Survival in Chronic Lymphocytic Leukemia

“…Furthermore, many of the factors previously implicated in supporting the growth and survival of CLL cells, including stromal cell-derived factor-1 (SDF-1) and B-lymphocyte stimulator (BLyS)/B-cell activating factor (BAFF), are produced by monocytes and their progeny, including LAM (7). Collectively, these findings may explain the clinical observation that CLL patients presenting with a monocytosis in peripheral blood experience more rapid disease progression (8, 9). Consistent with this notion, a population of monocyte-derived cells, or nurse-like cells (NLC), can be generated in bulk PBMC, or in cocultures of malignant B cells with either autologous or allogeneic monocytes (10–12).…”

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukemia using patient similarity networks

“…In particular, a high percentage of intermediate monocytes (> 5.4%) was prognostic for progressive disease and these patients have 2.5-fold higher likelihood of event than those with low percentage of intermediate monocytes, irrespective of the treatment. The importance of monocytes for the prognosis of CLL patients has been demonstrated in recent studies showing association of monocyte counts, particularly of circulating classical monocytes, with time to the rst therapy, aggressiveness and disease outcome [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and in ammation [12].…”

“…The importance of monocytes for the prognosis of CLL patients has been demonstrated in recent studies showing association of monocyte counts, particularly of circulating classical monocytes, with time to the rst therapy, aggressiveness and disease outcome [33,34]. Regarding monocytes and monocyte-derived cells in CLL, there is already evidence that they promote CLL cell survival and proliferation [34], and have deregulated genes involved in phagocytosis and in ammation [12]. Key role of monocytes in CLL is also supported by observations in animal model of CLL, where depletion of monocytes and macrophages resulted in a control of CLL development and reparation of immune dysfunction in vivo [35].…”