Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia

In vivo evidence of immune activation and antitumour response

Asher A. Chanan-Khan, Kasyapa Chitta, Noreen Ersing, Aneel Paulus, Aisha Masood, Taimur Sher, Abhisek Swaika, Paul K. Wallace, Terry L. Mashtare, Greg Wilding, Kelvin Lee, Myron S. Czuczman, Ivan M Borrello, Naveen Bangia

Research output: Contribution to journalArticle

Abstract

Lenalidomide has demonstrated impressive antileukaemic effects in patients with chronic lymphocytic leukaemia (CLL). The mechanism(s) by which it mediates these effects remain unclear. Clinically, CLL patients treated with lenalidomide demonstrate an acute inflammatory reaction, the tumour flare reaction that is suggestive of an immune activation phenomenon. Samples from CLL patients treated with lenalidomide were used to evaluate its effect on the tumour cell and components of its microenvironment (immune cellular and cytokine). Lenalidomide was unable to directly induce apoptosis in CLL cells in vitro, however it modulated costimulatory (CD80, CD83, CD86) surface molecules on CLL cells in vitro and in vivo. Concurrently, we demonstrated that NK cell proliferation was induced by lenalidomide treatment in patients and correlated with clinical response. Cytokine analysis showed increase in levels of TNF-α post-lenalidomide treatment, consistent with acute inflammatory reaction. Furthermore, the basal cytokine profile (high IL-8, MIG, IP-10 and IL-4 levels and low IL-5, MIP1a, MIP1b, IL12/p70) was predictive of clinical response to lenalidomide. Collectively, our correlative studies provide further evidence that the antileukaemic effect of lenalidomide in CLL is mediated not only through modulation of the leukaemic clone but also through elements of the tumour microenvironment.

Original languageEnglish (US)
Pages (from-to)457-467
Number of pages11
JournalBritish Journal of Haematology
Volume155
Issue number4
DOIs
StatePublished - Nov 2011

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B-Cell Chronic Lymphocytic Leukemia
Neoplasms
Cytokines
Cellular Microenvironment
Tumor Microenvironment
lenalidomide
Interleukin-5
Cellular Structures
Interleukin-12
Interleukin-8
Natural Killer Cells
Interleukin-4
Clone Cells
Cell Proliferation
Apoptosis
Therapeutics

Keywords

  • Chronic lymphocytic leukaemia
  • Immune activation
  • Immune cells
  • Lenalidomide
  • Microenvironment

ASJC Scopus subject areas

  • Hematology

Cite this

Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia : In vivo evidence of immune activation and antitumour response. / Chanan-Khan, Asher A.; Chitta, Kasyapa; Ersing, Noreen; Paulus, Aneel; Masood, Aisha; Sher, Taimur; Swaika, Abhisek; Wallace, Paul K.; Mashtare, Terry L.; Wilding, Greg; Lee, Kelvin; Czuczman, Myron S.; Borrello, Ivan M; Bangia, Naveen.

In: British Journal of Haematology, Vol. 155, No. 4, 11.2011, p. 457-467.

Research output: Contribution to journalArticle

Chanan-Khan, AA, Chitta, K, Ersing, N, Paulus, A, Masood, A, Sher, T, Swaika, A, Wallace, PK, Mashtare, TL, Wilding, G, Lee, K, Czuczman, MS, Borrello, IM & Bangia, N 2011, 'Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: In vivo evidence of immune activation and antitumour response', British Journal of Haematology, vol. 155, no. 4, pp. 457-467. https://doi.org/10.1111/j.1365-2141.2011.08882.x
Chanan-Khan, Asher A. ; Chitta, Kasyapa ; Ersing, Noreen ; Paulus, Aneel ; Masood, Aisha ; Sher, Taimur ; Swaika, Abhisek ; Wallace, Paul K. ; Mashtare, Terry L. ; Wilding, Greg ; Lee, Kelvin ; Czuczman, Myron S. ; Borrello, Ivan M ; Bangia, Naveen. / Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia : In vivo evidence of immune activation and antitumour response. In: British Journal of Haematology. 2011 ; Vol. 155, No. 4. pp. 457-467.
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abstract = "Lenalidomide has demonstrated impressive antileukaemic effects in patients with chronic lymphocytic leukaemia (CLL). The mechanism(s) by which it mediates these effects remain unclear. Clinically, CLL patients treated with lenalidomide demonstrate an acute inflammatory reaction, the tumour flare reaction that is suggestive of an immune activation phenomenon. Samples from CLL patients treated with lenalidomide were used to evaluate its effect on the tumour cell and components of its microenvironment (immune cellular and cytokine). Lenalidomide was unable to directly induce apoptosis in CLL cells in vitro, however it modulated costimulatory (CD80, CD83, CD86) surface molecules on CLL cells in vitro and in vivo. Concurrently, we demonstrated that NK cell proliferation was induced by lenalidomide treatment in patients and correlated with clinical response. Cytokine analysis showed increase in levels of TNF-α post-lenalidomide treatment, consistent with acute inflammatory reaction. Furthermore, the basal cytokine profile (high IL-8, MIG, IP-10 and IL-4 levels and low IL-5, MIP1a, MIP1b, IL12/p70) was predictive of clinical response to lenalidomide. Collectively, our correlative studies provide further evidence that the antileukaemic effect of lenalidomide in CLL is mediated not only through modulation of the leukaemic clone but also through elements of the tumour microenvironment.",
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AU - Ersing, Noreen

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AU - Swaika, Abhisek

AU - Wallace, Paul K.

AU - Mashtare, Terry L.

AU - Wilding, Greg

AU - Lee, Kelvin

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