Bruton tyrosine kinase (BTK) inhibitors are very effective at controlling chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). However, some patients cannot tolerate these drugs or develop mutations that cause resistance to them. Thus, researchers have been investigating other potential targets in the B-cell receptor signaling pathway for developing new therapies. One potential target is spleen tyrosine kinase (SYK), an enzyme upstream of BTK in the B-cell receptor signaling pathway.
At the annual meeting of the American Society of Hematology (ASH) 2021, Steven Bloom, CLL Society’s Chairman of the Board and President, interviewed Dr. Alexey Danilov, Associate Director of the Toni Stephenson Lymphoma Center at City of Hope in Duarte, CA. They discussed the final results of a phase 1/2 clinical trial of entospletinib combined with obinutuzumab in patients with relapsed/refractory CLL. We previously reported on the preliminary results of this trial here.
Takeaways:
- Spleen tyrosine kinase (SYK) is a kinase similar to BTK, but it is upstream of BTK in the B-cell receptor signaling (BCR) pathway, and it is required for activation of BTK.
- Blocking BCR is a potent way to turn off pro-survival signals in CLL / SLL cells and lead to their death. This is why the BTK inhibitors are so effective.
- Entospletinib is an SYK inhibitor that also disrupts B-cell receptor signaling, inhibiting cancer cell growth.
- In this phase 1/2 clinical trial, entospletinib was given in combination with obinutuzumab; a well-established anti-CD20 monoclonal antibody used to treat CLL / SLL.
- 24 patients were enrolled in the study, and efficacy could be evaluated in 21 patients.
- All patients benefited, and most patients responded to treatment (overall response rate of 67%).
- Similar to BTK inhibitors, there were not many complete responses (only 3 out of 21 patients). As expected for most patients, the disease did not wholly disappear, but it was well-controlled.
- Entospletinib seems to have a favorable safety profile without the cardiac side effects that are sometimes seen with ibrutinib.
- The most common adverse event was a low neutrophil count (neutropenia).
- There was only 1 patient out of 21 who discontinued treatment due to an adverse event (liver function test abnormalities that were reversible).
Conclusions:
In an era when targeted agents are increasingly becoming the standard of care for CLL and SLL, therapies with novel targets are welcome additions to the toolkit. These early clinical trial results are favorable for entospletinib, and further clinical trials will be needed to gain FDA approval.
CLL Society is eager to see entospletinib further developed as CLL / SLL patients have limited options when they become refractory or intolerant to a BTKi and venetoclax. We need to do what we can to encourage our friends at the FDA and in industry to work together to safely and quickly bring more drugs such as entospletinib to market for CLL / SLL. Sadly at this time it does not seem that entospletinib is being developed for use CLL / SLL.
Please enjoy this interview with Dr. Danilov from the ASH meeting held in December 2021 in Atlanta, GA, and virtually.
You can read the actual abstract here: Final Results of a Phase 1/2 Study of SYK Inhibitor Entospletinib in Combination with Obinutuzumab in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)
Take care of yourself first.
Ann Liu, PhD
