For readers interested in B-Cell Receptor signaling, they might like to read the original fostamatinib study we published in Blood a few years ago.
Hopefully we will get some of the CAL-101 data written up soon.
A lot of this might seem like Greek, but I was asked to write a summary article for "Clinical Oncology News." Here is a link to that article
Here is a small quote:
"The BCR signaling pathway is central to B-cell survival. In laboratory conditions where B-cell signaling could be genetically eliminated, B cells disappeared.1 Pharmacologic intervention in downstream signaling pathway proteins intuitively followed, and inhibition of the proximal signaling enzyme spleen tyrosine kinase (Syk) by fostamatinib was initially proposed in only 2007.2
Since that time, numerous clinical investigations have validated the importance of inhibition of BCR signaling. After Syk activation, BTK propagates the signal leading to downstream activation of phosphoinositide-3 kinase. These latter two proteins are inhibited by ibrutinib and CAL-101 (subsequently GS-1101, now idelalisib), respectively. Following the initial clinical reports of fostamatinib activity,3 the present paper by Advani et al represents the first published report of the clinical activity of ibrutinib.
In CLL, virtually all patients experience a rapid reduction in lymph node size and disease-related cytokines concurrently with a rapid rise in white blood cells (WBCs) as cells redistribute from their protective niches in nodes and marrow into the circulation. Over time, WBCs fall, nodes remain reduced, and improvement in marrow function is common, even in high-risk refractory disease. Different NHLs have been observed to respond as well. Some cases of diffuse large B-cell lymphomas may respond in dramatic fashion, although prospective identification of these patients is an area of intense interest. Patients with mantle cell lymphoma have enjoyed durable disease control with ibrutinib. Follicular lymphoma appears to respond to both ibrutinib and idelalisib, yet the clinical significance in this more indolent population requires further study.
Investigators and patients alike are excited because these oral drugs provide unique activity while being well tolerated in most cases. These drugs will alter the clinical management landscape of patients with B-cell malignancies in the near future and practicing clinicians will need to be aware of this emerging class of therapies.
- Kraus M, Alimzhanov M, Rajewski N, et al. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell. 2004;117:787-800, PMID: 15186779.
- Sharman J, Irish J, Coffee G. Targeting syk kinase for the treatment of b-cell lymphoma. J Clin Oncol. 2007;25(18s):Abstract 3600.
- Friedberg J, Sharman J, Sweetenham J. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578-2585, PMID: 19965662.
I have a bunch of posts I want to write but haven't had time to write them. Hopefully something more soon.