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Phase 1b trial of atacicept, a recombinant protein binding BLyS and APRIL, in patients with chronic lymphocytic leukemia

Leukemia volume 26, pages 841–844 (2012)Cite this article

Chronic lymphocytic leukemia (CLL) is a common form of leukemia in the Western world, with an incidence rate of 5/100 000, and predominantly occurs in older people, with a median age at diagnosis of 70 years. This group of patients often does not qualify for intense combination chemotherapy, thereby stressing the need for alternative treatment options. CLL is mostly characterized by accumulation of malignant B-cells resistant to apoptosis. Two members of the tumor necrosis factor superfamily, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), are involved in constitutively active survival-signaling pathways such as NFκB activation, and protect CLL cells from spontaneous apoptosis.1 BLyS and APRIL interact with the tumor necrosis factor receptor TACI (transmembrane activator and CAML-interactor) and with BCMA (B-cell maturation antigen). In addition, BLyS specifically binds to the BAFF-Receptor (BAFF-R). Whereas normal B-lymphocytes express little to no BLyS or APRIL, these proteins are highly expressed in CLL cells, and CLL patients with a low percentage of leukemic cells expressing BLyS or APRIL have a significant longer overall survival than patients with BlyS- or APRIL-positive leukemic cells.2 The blood level of soluble APRIL is elevated in patients with CLL and correlates with disease stage.3 Moreover, elevated serum BLyS levels are found in patients with familial CLL, and correlate with a single-nucleotide polymorphism (SNP) in the BLyS promoter region.4

Importantly, an allelic variation in the TNFRSF13B gene encoding for the TACI protein is associated with CLL susceptibility, suggesting a potential role for TACI in disease development.5 These genetic associations and the fact that BLyS and APRIL support in vitro CLL cell survival provide a strong rationale for targeting these proteins.

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Acknowledgements

This trial was funded by Merck Serono SA. We thank Benoit Destenaves for genomic analysis; Giacomo Mordenti for the statistical analysis; Ralf Baumann, a medical writer and Merck Serono SA employee, for preparing the study report; and Ekaterine Asatiani and Stacey R Dillon for detailed review of the manuscript.

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Authors and Affiliations

  1. Department I of Internal Medicine, Center for Integrated Oncology, University of Cologne, Cologne, Germany

    D M Kofler, B B Gawlik, T Elter, C-M Wendtner & M Hallek

  2. Cluster of Excellence for Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany

    D M Kofler, C-M Wendtner & M Hallek

  3. Clinical Development Unit for Small Molecules in Onco-Hematology, Merck Serono SA, Geneva, Switzerland

    A Gianella-Borradori

  4. Department I of Internal Medicine, Klinikum Schwabing, Munich, Germany

    C-M Wendtner

Authors
  1. D M Kofler
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  2. B B Gawlik
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  3. T Elter
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  4. A Gianella-Borradori
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  6. M Hallek
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Corresponding author

Correspondence to D M Kofler.

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Competing interests

At the time the study was conducted, AGB was an employee of Merck Serono SA. The other authors declare no conflict of interest.

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Author contributions

DMK, AGB, CMW and MH designed the research protocol; DMK, BBG, TE, CMW and MH were involved in treating patients and collecting data; DMK, CMW and MH wrote the paper, with contributions from the other authors. All authors approved the final version of the paper.

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Kofler, D., Gawlik, B., Elter, T. et al. Phase 1b trial of atacicept, a recombinant protein binding BLyS and APRIL, in patients with chronic lymphocytic leukemia. Leukemia 26, 841–844 (2012). https://doi.org/10.1038/leu.2011.286

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