Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

Jonathan W. Friedberg, Jeff Sharman, John Sweetenham, Patrick B. Johnston, Julie M. Vose, Ann LaCasce, Julia Schaefer-Cutillo, Sven De Vos, Rajni Sinha, John P. Leonard, Larry D. Cripe, Stephanie A. Gregory, Michael P. Sterba, Ann M. Lowe, Ronald Levy, Margaret A. Shipp

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559 Scopus citations

Abstract

Certain malignant B cells rely on B-cell receptor (BCR)-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosaassociated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered atwww.clinicaltrials.gov as #NCT00446095.

Original languageEnglish (US)
Pages (from-to)2578-2585
Number of pages8
JournalBlood
Volume115
Issue number13
DOIs
StatePublished - Apr 1 2010

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Friedberg, J. W., Sharman, J., Sweetenham, J., Johnston, P. B., Vose, J. M., LaCasce, A., Schaefer-Cutillo, J., De Vos, S., Sinha, R., Leonard, J. P., Cripe, L. D., Gregory, S. A., Sterba, M. P., Lowe, A. M., Levy, R., & Shipp, M. A. (2010). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 115(13), 2578-2585. https://doi.org/10.1182/blood-2009-08-236471