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 Cripe, Stephanie A. Gregory, Michael P. Sterba, Ann M. Lowe, Ronald Levy, Margaret A. Shipp

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

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B-Cell Chronic Lymphocytic Leukemia
Lymphoid Leukemia
Protein-Tyrosine Kinases
Non-Hodgkin's Lymphoma
B-Cell Lymphoma
B-Lymphocytes
Cells
Mantle-Cell Lymphoma
Lymphoma
Follicular Lymphoma
Lymphoma, Large B-Cell, Diffuse
Diarrhea
Clinical Trials, Phase I
Toxicity
Lymphoid Tissue
Neutropenia
Tumor Cell Line
Thrombocytopenia
Nausea
Disease-Free Survival

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Friedberg, J. W., Sharman, J., Sweetenham, J., Johnston, P. B., Vose, J. M., LaCasce, A., ... 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

Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. / Friedberg, Jonathan W.; Sharman, Jeff; Sweetenham, John; Johnston, Patrick B.; Vose, Julie M.; LaCasce, Ann; Schaefer-Cutillo, Julia; De Vos, Sven; Sinha, Rajni; Leonard, John P.; Cripe, Larry; Gregory, Stephanie A.; Sterba, Michael P.; Lowe, Ann M.; Levy, Ronald; Shipp, Margaret A.

In: Blood, Vol. 115, No. 13, 01.04.2010, p. 2578-2585.

Research output: Contribution to journalArticle

Friedberg, JW, Sharman, J, Sweetenham, J, Johnston, PB, Vose, JM, LaCasce, A, Schaefer-Cutillo, J, De Vos, S, Sinha, R, Leonard, JP, Cripe, L, Gregory, SA, Sterba, MP, Lowe, AM, Levy, R & Shipp, MA 2010, 'Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia', Blood, vol. 115, no. 13, pp. 2578-2585. https://doi.org/10.1182/blood-2009-08-236471
Friedberg, Jonathan W. ; Sharman, Jeff ; Sweetenham, John ; Johnston, Patrick B. ; Vose, Julie M. ; LaCasce, Ann ; Schaefer-Cutillo, Julia ; De Vos, Sven ; Sinha, Rajni ; Leonard, John P. ; Cripe, Larry ; Gregory, Stephanie A. ; Sterba, Michael P. ; Lowe, Ann M. ; Levy, Ronald ; Shipp, Margaret A. / Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. In: Blood. 2010 ; Vol. 115, No. 13. pp. 2578-2585.
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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.",
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