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ASH 2019: Dr. Alexey Danilov and Dr. John Pagel discuss New Drug Targeting SYK Pathway Provides Hope When Used in Combination with Obinutuzumab

This content was current as of the date it was released. In science and medicine, information is constantly changing and may become out-of-date as new data emerge.

In this video, Dr. Alexey Danilov, MD, PhD, the Associate Director of the Toni Stevenson Lymphoma Center at City of Hope Comprehensive Cancer Center, in Duarte, CA is  interviewed by Dr. John Pagel, MD, PhD, the Chief of Hematology at Swedish Cancer Center, in Seattle, WA. This video was recorded at the 61st Annual Meeting of the American Society of Hematology, in 2019, in Orlando, Florida. Both Drs. Pagel and Danilov serve on the CLL Society Medical Advisory Board and Dr. Pagel is a member of the Board of Directors.

Dr. Danilov discusses the abstract he presented at ASH 2019, entitled: SYK Inhibitor Entospletinib in Combination with Obinutuzumab Demonstrates Efficacy in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL). This study is a Phase I/II clinical trial intended to assess the safety and tolerability of this drug combination and to identify the optimal dose for Phase II expansion, in which more than the original 35 patients will be enrolled.

The B-cell Receptor (BCR) signaling kinases plays an important role as targets in the management of chronic lymphocytic leukemia (CLL), in patients today. The best known signaling kinase for many patients is the Bruton’s Tyrosine Kinase (BTK), which is the target for drugs such as ibrutinib and acalabrutinib. Spleen Tyrosine Kinase (SYK) occurs upstream (or before) BTK in the overall B-cell Receptor signaling pathway. Entospletinib has been found to inhibit SYK, which results in overcoming the antiapoptotic (anti-death) effects of SYK, which in turn leads to proliferation of CLL cells. Obinituzumab is a CD20 monoclonal antibody recommended for use in combination with other drugs, such as acalabrutinib or venetoclax as first line therapy according to the preferred regimens in the NCCN Guidelines (12/2019). Obinituzumab may be used as monotherapy in relapsed/refractory CLL patients without 17p deletion or TP53 Mutation.

Takeaways:

  • This trial enrolled approximately 35 patients; however, only 20 patients are included at the point this data was reported. Of that number, approximately half were considered to have high-risk factors, such as complex karyotype (3 or more gross abnormalities in chromosomes), deletion 17p, TP53 mutation or notch mutations.
  • The toxicity profile was good with only one of the original 20 discontinuing the trial for adverse outcomes over the first eighteen months of the trial.
  • Every patient benefitted by lymph node size reduction and using strict clinical trial criteria. There was an overall response rate of 83% with 65% attaining a partial response (PR) and 17% attaining a complete response. Of the three (3) patients who reached CR, two had undetectable Minimal Residual Disease (uMRD) in the Bone Marrow.
  • Entospletinib is an orally administered pill that is taken twice a day and the obinituzumab is an intravenous infusion given during the first six months according to the standard dosing schedule.

Conclusions:

As with other advances in CLL treatment, the growing number of targeted agents allows more options for physicians and patients to receive individualized care.

When asked where this combination therapy might be used in the future if the clinical trials prove successful, Dr. Danilov suggested the following:

  • The combination appears to have potential as a new treatment option with very high tolerability and efficacy rates.
  • May be good for patients who either cannot tolerate a BTKi, due to adverse reactions, or whose disease progresses on a BTKi.
  • May be good for patients who relapse on venetoclax.

For more information about this clinical trial, which is not currently recruiting but likely will in the future go to https://clinicaltrials.gov/ct2/show/NCT03010358.

To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials.

Thanks for reading this summary and viewing this interview:

Stay strong, we are all in this together!

Thomas. E. Henry III, MBA, RPh, CPh


Thomas Henry is a Registered Pharmacist and CLL Patient. He is President and Senior Consultant for Burlington Consulting Associates, a company that provides consulting services to health systems nationwide. Tom is a CLL Society Medical Advisory Board member and strives to educate other CLL patients through his blog https//www.cllpharmacist.com. He has a forty-two-year career in pharmacy and has served as Chief Pharmacy Officer at two Top-15 Comprehensive Cancer Centers, Moffitt (Tampa, FL) and Roswell Park (Buffalo, NY).