Haematologica, Vol 94, Issue 9, 1266-1273 doi:10.3324/haematol.2009.005835
Copyright © 2009 by Ferrata Storti Foundation

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Chronic Lymphocytic Leukemia

Lenalidomide-induced upregulation of CD80 on tumor cells correlates with T-cell activation, the rapid onset of a cytokine release syndrome and leukemic cell clearance in chronic lymphocytic leukemia

Georg Aue¹, Ndegwa Njuguna¹, Xin Tian², Susan Soto¹, Thomas Hughes³, Berengere Vire¹, Keyvan Keyvanfar¹, Federica Gibellini¹, Janet Valdez¹, Carol Boss¹, Leigh Samsel⁴, J. Philip McCoy, Jr⁴, Wyndham H. Wilson⁵, Stefania Pittaluga⁶, Adrian Wiestner¹

¹ Hematology Branch, NHLBI
² Office of Biostatistics Research, NHLBI
³ Department of Pharmacy, Clinical Center
⁴ Flow Cytometry Core Facility, NHLBI
⁵ Metabolism Branch, CCR, NCI
⁶ Laboratory of Pathology, NCI, of the National Institutes of Health, Bethesda, MD, USA

Correspondence: Adrian Wiestner MD, PhD, Hematology Branch, NHLBI, NIH Bld 10, CRC 3-5140 10, Center Drive 20892-1202 Bethesda, MD, USA. Email:wiestnera{at}mail.nih.gov

Background: In chronic lymphocytic leukemia lenalidomide causes striking immune activation, possibly leading to clearance of tumor cells. We conducted this study to investigate the mechanism of action of lenalidomide and the basis for its unique toxicities in chronic lymphocytic leukemia.

Design and Methods: Patients with relapsed chronic lymphocytic leukemia were treated with lenalidomide 20 mg (n=10) or 10 mg (n=8) daily for 3 weeks on a 6-week cycle. Correlative studies assessed expression of co-stimulatory molecules on tumor cells, T-cell activation, cytokine levels, and changes in lymphocyte subsets.

Results: Lenalidomide upregulated the co-stimulatory molecule CD80 on chronic lymphocytic leukemia and mantle cell lymphoma cells but not on normal peripheral blood B cells in vitro. T-cell activation was apparent in chronic lymphocytic leukemia, weak in mantle cell lymphoma, but absent in normal peripheral blood mononuclear cells and correlated with the upregulation of CD80 on B cells. Strong CD80 upregulation and T-cell activation predicted more severe side effects, manifesting in 83% of patients as a cytokine release syndrome within 8–72 h after the first dose of lenalidomide. Serum levels of various cytokines, including tumor necrosis factor-, increased during treatment. CD80 upregulation on tumor cells correlated with rapid clearance of leukemic cells from the peripheral blood. In contrast, neither the severity of the cytokine release syndrome nor the degree of T-cell activation in vitro correlated with clinical response.

Conclusions: Upregulation of CD80 on tumor cells and T-cell activation correlate with unique toxicities of lenalidomide in chronic lymphocytic leukemia. However, T-cell activation appears to be dispensable for the drug’s anti-tumor effects. This provides a rationale for combinations of lenalidomide with fludarabine or alemtuzumab.

Key words: chronic lymphocytic leukemia, lenalidomide, tumor flare, CD80, cytokine release syndrome.

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