Lymphoma affects an estimated 500,000 people in the United States, with 332,000 of them suffering from non-Hodgkin's lymphoma. Diffuse large B-cell lymphoma is the most common type of NHL and is generally categorized as aggressive, marked by rapidly growing tumors in the lymph nodes, spleen, liver, bone marrow and other organs. A variety of treatment options for NHL exist, including chemotherapy and radiation, but the five-year survival rate for NHL patients is estimated to be around 50%. Even for those who respond to treatment, recurrence of the disease is common.
B cell chronic lymphocytic leukemia (CLL) is the most prevalent B cell malignancy in adults. The disease is characterized by expansion of monoclonal mature B lymphocytes. Despite advances in treatment, the disease remains incurable warranting further efforts to identify novel molecular targets in CLL. B cell receptor (BCR) signaling contributes to apoptosis resistance in CLL limiting the efficacy of therapeutic approaches.
SYK Inhibition
Fostamatinib disodium (FosD), an orally available inhibitor of protein kinase SYK which is currently being developed by Rigel Inc. (1180 Veterans Blvd, South San Francisco, CA 94080) for the treatment of rheumatoid arthritis, has demonstrated significant in vitro activity against B-cell receptor (BCR)-dependent NHLs. FosD disrupts B-cell receptor mediated signaling by inhibiting SYK. Furthermore, FosD blocks IgG receptor (Fc receptor) signaling in macrophages and B-cells, and addresses multiple inflammatory mechanisms including TNF-α, IL-1, and IL-6.
Because SYK is overexpressed in CLL and found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, researchers believe that it plays a role in antigen-independent SYK activation in the pathogenesis of chronic lymphocytic leukaemia, and therefore represents a potential therapeutic target.
In the study by Friedberg et al, FosD, administered as a tablet, produced significant responses in patients who had failed previous treatments for diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma, as well as prolonged stable disease in patients with follicular lymphoma.
Following a phase I dose-limiting study of 13 patients, the regimen of a 200 mg twice-daily dose of FosD was chosen for further evaluation in a phase II study conducted with 68 patients with relapsed or refractory B-cell non-Hodgkin lymphoma. These patients were divided into three groups: those with diffuse large B-cell lymphoma (23 patients), those with follicular lymphoma (21 patients), and those with other B-cell non-Hodgkin lymphomas (24 patients), including chronic lymphocytic leukemia/small lymphocytic lymphoma (11 patients), mantle cell lymphoma (9 patients), MALT lymphoma (3 patients), and lymphoplasmacytic non-Hodgkin lymphoma (1 patient). Patients previously received an average of five therapies, and many had previously received an autologous stem cell transplant or radioimmunotherapy.
The study found that fostamatinib disodium produced complete or partial responses in 21 percent of patients with diffuse large B-cell lymphoma, 54 percent of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, 11 percent of mantle cell lymphoma patients, and 10 percent of those with follicular lymphoma. Stable disease was also seen in an additional 23 patients, including 12 with follicular lymphoma, four with diffuse large B-cell lymphoma, four with mantle cell lymphoma, two with chronic lymphocytic leukemia/small lymphocytic lymphoma, and one with MALT lymphoma. A proportion of these responses was prolonged, with some patients remaining on therapy for more than one year.
Given the refractory nature of these patients’ lymphoma, the toxicity profile was quite favorable. There were four cases of febrile neutropenia with eight patients requiring a dose-modification due to neutropenia, hypertension, liver function test abnormalities, fever, and mucositis.
Based on the results of this study, researchers believe that FosD should be further developed for the treatment of B-cell non-Hodgkin lymphoma (NHL). ‘Despite the fact that the patients enrolled in this trial had advanced disease and had failed treatment with marketed therapies, a significant number of them were particularly responsive to SYK inhibition with FosD,’ Friedberg explained. ‘I am encouraged by this data and look forward to conducting additional trials of FosD, particularly in patients with DLBCL and CLL/SLL types of non-Hodgkin's lymphomas,’ he added.
More research, better results
A growing field of research on the cellular signaling associated with these lymphomas indicates that inhibiting SYK in aberrant cells may control spread of the disease. Two additional research studies on the topic were also being presented at the ASH meeting. They include: Abstract 377, entitled ‘BCR, Signaling Diversity in Human Lymphoma B Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes’ and Abstract 802, entitled ‘BCL-6 Regulates Tonic BCR Signaling in Diffuse Large B-Cell Lymphomas.’ Furthermore, an independent group of European researchers at the University Hospital Freiburg, Freiburg, Germany in collaboration with the Department of Hematology, Pitie-Salpetriere Hospital, Paris, France and the Institute of Cancer, Barts and The London School of Medicine, London, United Kingdom, noted that in contrast to conventional chemotherapy, stimulation with CD40L significantly sensitized CLL cells towards SYK inhibition. In their study, they conclude that SYK inhibition as a rational and promising therapeutic principle in CLL.
For more information, read:
Friedberg JW, Sharman J, Schaefer-Cutillo J, Johnston PB, De Vos S, et al. Fostamatinib Disodium (FosD), An Oral Inhibitor of Syk, Is Well-Tolerated and Has Significant Clinical Activity in Diffuse Large B Cell Lymphoma (DLBCL) and Chronic Lymphocytic Leukemia (SLL/CLL). (Plenary Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #3
Other abstracts:
- Maike Buchner M, Fuchs S, Prinz G, Pfeifer D, et al. Spleen Tyrosine Kinase (SYK) Is Overexpressed and Represents a Potential Therapeutic Target in Chronic Lymphocytic Leukemia (Plenary Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #543
- Irish JM, Houot R, Myklebust JH, Czerwinski DK, et al. Signaling Diversity in Human Lymphoma B Cells and in Tumor Infiltrating T Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes (Oral Session). Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #377
- JuszczynsKi P, Chen L, Polo JM, Ranuncolo SM, et al. BCL6 Regulates Tonic BCR Signaling in Diffuse Large B-Cell Lymphomas by Repressing the SYK Phosphatase, PTPROt.(Oral Session), Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract #802
Also read PubMed abstracts:
- Gobessi S, Laurenti L, Longo PG, Carsetti L, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. Leukemia 2008 Dec 18. [Epub ahead of print]
- Chen L, Monti S, Juszcynski P, Daley J, et al. SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma.Blood 2008 Feb 15;111(4):2230-7. Epub 2007 Nov 15.
- Takano T, Sada K, Yamamura H, et al. Role of protein-tyrosine kinase syk in oxidative stress signaling in B cells. Antioxid Redox Signal 2002 Jun;4(3):533-41
- Weinblatt ME, Kavanaugh A, Bargos-Vargos R, Dikranian AH et al. Treatment of rheumatoid arthritis with syk kinase inhibitor: A twelve-week randomized, placebo-controlled trial. Arthritis Rheumatism. 2008 Nov;58(11):3309-18.
- Irish, J. M., Czerwinski, D. K., Nolan, G. P. & Levy, R. Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood 2006 Nov 1;108(9):3135-42. Epub 2006 Jul 11. PDF Full article
Clinical trials:
- Efficacy and Safety Study of R935788 Tablets to Treat T-Cell Lymphoma (Phase II trial) ClinicalTrials.gov Identifier: NCT00798096, Verified by Rigel Pharmaceuticals, November 2008.
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