Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia.
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), mucosa-associated 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 at www.clinicaltrials.gov as #NCT00446095.
Friedberg
Jonathan W
JW
James P. Wilmot Cancer Center, University of Rochester, NY 14642, USA. jonathan_friedberg@urmc.rochester.edu
Sharman
Jeff
J
Sweetenham
John
J
Johnston
Patrick B
PB
Vose
Julie M
JM
Lacasce
Ann
A
Schaefer-Cutillo
Julia
J
De Vos
Sven
S
Sinha
Rajni
R
Leonard
John P
JP
Cripe
Larry D
LD
Gregory
Stephanie A
SA
Sterba
Michael P
MP
Lowe
Ann M
AM
Levy
Ronald
R
Shipp
Margaret A
MA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000631:Aminopyridines; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines; D016879:Salvage Therapy; D000072377:Syk Kinase; D016896:Treatment Outcome
D000631:Aminopyridines; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib