In this video, Dr. Deborah Stephens, DO, a Chronic Lymphocytic Leukemia (CLL) Specialist, at the University of Utah, Huntsman Cancer Institute in Salt Lake City, UT, is interviewed by CLL Society founder and Chief Medical Officer, Dr. Brian Koffman, MDCM, a retired family physician and a CLL patient. This video was recorded at the 61st Annual Meeting of the American Society of Hematology in 2019, in Orlando, FL.
In the last decade, we have seen tremendous outcomes for CLL patients through the advent of drugs that block the B-Cell Receptor (BCR). In CLL, B-Cell Receptor signaling is responsible for the proliferation of malignant cells. Presently, two pathways within the BCR signaling are targeted by commercial drugs. Ibrutinib (Imbruvica®) and Acalabrutinib (Calquence®) target the Bruton’s Tyrosine Kinase pathway. Idelalisib (Zydelig ®) and duvalisib (Copiktra®) target the phosphatidylinositol 3-kinase (PI3k). Additional agents are under investigation targeting these two pathways, as well as other pathways with no current commercial agents.
Despite the availability of current drugs alone or in combination, some patients do not benefit from current therapy. For example, some patients may develop resistance to the BTK inhibitor agents or are refractory to current targeted therapies.
During ASH 2019, Dr. Stephens’ group presented an abstract entitled: Selinexor Combined with Ibrutinib Demonstrates Tolerability and Efficacy in Advanced B-Cell Malignancies: A Phase I Study.
Selinexor (Xpovio®) recently received approval for treatment in Multiple Myeloma (MM), and Diffuse Large B-Cell Lymphoma (DBCL) patients. Selinexor has two mechanisms of action. First, selinexor is an oral selective inhibitor of nuclear export (SINE) drug. Tumor suppressor proteins (TSPs) suppress the proliferation of malignant cells when they are within the nucleus of the cell. Researchers have determined that in cancerous cells, a “transporter” protein is responsible for shuttling the TSPs out of the nucleus into the cytoplasm where they lose the suppressor capability. Selinexor blocks the transporter XPO1, thereby keeping the TSPs in the nucleus resulting in malignant cell death (apoptosis). Secondly, selinexor down-regulates BTK resulting in a dual blockade of this protein responsible for cancer cell proliferation.
Takeaways:
- Selinexor in this study is dosed at 40mg once weekly. The dose for MM is 80mg on days 1 and 3 of each week. The DBCL dose is 60mg on days 1 and 3 each week.
- Selinexor has a long list of side effects that are dose-dependent and were not as prevalent or severe at the higher doses used ib MM and DBCL.
- Phase I included 33 patients. The breakdown of patients by their condition is: CLL (n=16), Richter’s Transformation (RT) (n=8), DBCL (n=6), and Mantle Cell Lymphoma (MCL) (n=3).
- In total, 81% achieved disease control, with 33% reaching Complete Response (CR) or Partial Response (PR), and 48% achieving stable disease (SD).
- All CLL patients who had not received prior ibrutinib (IB) therapy reached CR or PR, and all those who had taken IB before reached at least SD. Two CLL patients who became resistant to IB due to BTK mutation responded to therapy, and seven previously BTK resistant patients had stable disease.
- One RT patient reached CR, and 5 achieved SD.
Conclusions:
Phase I trials are primarily focused on safety and in determining safe dosing for future phases. This particular trial involved patients who were heavily pre-treated with a median number of prior therapies of four (4).
This trial potentially adds another treatment option for heavily pre-treated patients who currently have poor prognoses.
Because Richter’s Transformation can be aggressive and rapidly progresses, achieving stable disease or CR is promising. Reaching stable disease can buy time for Richter’s patients who need time to find a bone marrow transplant donor and to receive the transplant.
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).
