Targeted Therapies in CLL – Kinase Inhibitors

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Targeted Therapies in CLL – Kinase Inhibitors

November 19, 2015

If CLL is likened to an engine whose accelerator is stuck and the brakes have failed, kinase inhibitors are one solution towards disengaging that stuck accelerator and Dr. Choi’s lecture described how BCL2 inhibitors restore the brakes.

At the April 2015 CLL Patient Education and Empowerment meeting held in conjunction with the CLL Research Consortium meeting at UCSD in San Diego, Dr. Jeffrey Jones from the Division of Hematology at The Ohio State University gave a very dynamic lecture about the use of kinase inhibitors in the treatment of CLL.

The B cell receptor leads to a whole cascade of signals and two of the more clinically relevant ones include P13K, which is the target of idelalisib and BTK which is the target of ibrutinib. These kinases inhibitors work similar in the way of a lock and key where the kinase inhibitor is the key and the protein kinase is the lock.

Dr. Jones reviews the data that led to the approval of idelalisib and ibrutinib, as well as the adverse events associated with each product. He also discussed the theories about progression of the disease and why drugs stop working. He also shared some insight into how decisions are made about whether to treat with ibrutinib or idelalisib, and how treatment success is dependent on the patient’s ability to comply or tolerate therapy.

Ibrutinib	Idelalisib
Appears better tolerated long term Concerns for patients receiving blood thinners or with abnormal heart rhythms Responses may last longer Interactions with other medications are important	Significant side effects (especially inflammation of the lung and gut and abnormal liver tests are more common) Stopping for side effects/toxicity appears to be more common during idelalisib therapy

Because of the success of ibrutinib and idelalisib, there are a number of second generation kinase inhibitors that are being studied.

Target	Study Drug	Details
P13Kᵧ	Duvalisib (IPI-145)	Potential to work after BTK relapse Phase 3 studies underway
	TGR-1202	Structurally different from others which may limit immune side effects (vs idelalisib)
	ACP-319	Structure, activity similar to idelalisib
BTK	ACP-196	More potent and specific than ibrutinib Blocks BTK in same way as ibrutinib Phase 3 studies starting
BTK	ONO-4059	Reversible inhibitor Blocks BTK in a different way than ibrutinib
SYK	Entospletinib (GS9973)	Active as a single agent SYK is early in the signaling pathway so potentially useful when idelalisib or ibrutinib stop working

Dr. Jones also described a number of clinical trials that are ongoing for treatment-naïve patients with CLL, specifically ECOG 912 comparing FCR to Rituximab/ibrutinib in patients under 70 and Alliance a041202 for patients aged 65 or over comparing Bendamustine/rituximab to Ibrutinib/rituximab to Ibrutinib. He also described an early intervention trial CLL12, being run by the German CLL Study Group. There are expectations for a similar trial to be opened in the US.

Finally, in a forward looking statement, Dr. Jones listed some next steps in the study of kinase inhibitors, such as its role in frontline therapy, the management of genetic high-risk disease, and for which patients would discontinuation of ibrutinib be considered safe.

Enjoy Dr. Jones’s lecture from the Patient Education and Empowerment Meeting