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 Bruce 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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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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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

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 Bruce; Vose, Julie M.; LaCasce, Ann; Schaefer-Cutillo, Julia; De Vos, Sven; Sinha, Rajni; Leonard, John P.; Cripe, Larry D.; 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, LD, 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 Bruce ; Vose, Julie M. ; LaCasce, Ann ; Schaefer-Cutillo, Julia ; De Vos, Sven ; Sinha, Rajni ; Leonard, John P. ; Cripe, Larry D. ; 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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