ASH 2020: Dr. Meghan Thompson – Can APR-246 Restore the Wild-Type Function of the P53 Gene in Chronic Lymphocytic Leukemia (CLL)

In this video, Dr. Meghan C Thompson, MD, a second-year fellow in the CLL Program at Memorial Sloan Kettering Comprehensive Cancer Center, in New York City, is interviewed by CLL Society founder and Chief Medical Officer Dr. Brian Koffman  MD, a retired family physician and a CLL patient. This video was recorded at the 62nd Annual Meeting of the American Society of Hematology in December 2020 in a virtual format

There have been many advances in Chronic Lymphocytic Leukemia (CLL) treatment over the past decade. We know that an unmet need is treating patients who do not respond well to chemoimmunotherapy (CIT) or targeted therapies. Two frequently used targeted therapies are ibrutinib (Imbruvica®) and venetoclax (Venclexta®).

Patients who suffer from disruption of the “wild-type” or normal function of the TP53 gene are among the group with poorer prognoses and outcomes. The TP53 gene is responsible for many processes within our cells, but one of the most critical functions it performs is regulating apoptosis (programmed cell death). When this gene is absent or non-functioning, cells do not die when they should, a  problem in many cancers including CLL.

Disruption of TP53 gene function occurs in two ways in CLL:

1. The short “p” arm of the seventeenth chromosome is missing or deleted [deletion (17p]. Because the p arm of the 17^th chromosome contains the TP53 gene.
2. The TP53 gene is present but is mutated and therefore dysfunctional.

We have two copies of every chromosome so that a patient can have both deletion (17p) and a P53 mutation.

Your CLL team determines the most common chromosomal abnormalities found in CLL, including deletion (17p) and other chromosomal abnormalities using the Fluorescence in Situ Hybridization (FISH) test. TP53 mutations are found through a different test, next generation sequencing (NGS), that looks at individual genes rather than whole chromosomes. Unfortunately, those treated in the community infrequently receive this testing as demonstrated by Mato in the inform Registry. This dismal lack of testing in the community is the focus of CLL Society’s educational program called Test Before Treat™.

We know that patients with dysfunction of the TP53 gene should not receive chemoimmunotherapy because of historically poor outcomes. Despite the overall prognosis improvements of treatment with targeted agents, we know that patients with aberrant P53 (the protein produced by the TP53 gene) function often have inferior outcomes compared to patients with intact TP53.

A new small-molecule drug, APR-246 (eprenetapopt), was recently granted “Breakthrough” status for treating another blood cancer known as myelodysplastic syndromes (MDS). APR-246 reactivates the mutant and inactivated p53 protein by restoring p53 conformation and function, thereby re-inducing programmed cell death in cancer cells.

Given the encouraging data from this agent’s use in MDS patients with P53 mutation, researchers are interested in studying it to treat CLL patients.

Take-Aways:

• This upcoming study is a Phase I (3+3 dose escalation design) trial, built upon two existing approved therapies. Up to ten sites will participate in this multicenter trial (NCT04419389). At present, MD Anderson in Houston has joined Memorial Sloan Kettering in offering this clinical trial. Patients should check the study using the link above to find additional sites as they enter.
• To qualify for this clinical trial, patients must have the TP53 mutation and have received at least two prior therapies. Patients with deletion (17p) will not be eligible for this trial. It cannot fix what isn’t there.
• As with all Phase I trials, the primary focus will be safety. Two cohorts will be studied. In cohort #1, patients will receive ibrutinib + APR-246. The second group will receive venetoclax, rituximab, and APR-246. In each group, the dose of APR-246 will increase over time to arrive at the maximum tolerated dose or the dose that produces the highest positive effect with manageable side effects. Each cohort in the Phase I portion will have 20 patients or a total of 40. If deemed safe by Phase I, the next phase will enroll more patients.

Conclusions:

Based on this drug’s success in reversing TP53 dysfunction in other blood cancers, there is great hope that this agent will have similar efficacy in CLL.

Although it is early, this is a study that I and others in the CLL community will be following with interest.

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

Here is the ASH abstract: Phase 1 and Dose Expansion Study of APR-246 in Combination with Ibrutinib or Venetoclax-Based Therapy in Subjects with TP53-Mutant Relapsed and/or Refractory Non-Hodgkin Lymphomas (NHL) Including Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma

Thanks for reading 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).