In this video, Dr. Tanya Siddiqi, MD, a chronic lymphocytic leukemia (CLL) specialist, at the City of Hope Comprehensive Cancer Center in Duarte, CA, is interviewed by CLL Society founder and Chief Medical Officer, Dr. Brian Koffman, MDCM, a retired family physician and CLL patient. This video was recorded at the 61st Annual Meeting of the American Society of Hematology in 2019, in Orlando, FL.
CAR-T (chimeric antigen receptor T-cell) therapy is a revolutionary treatment for CLL and other B-cell malignancies. This therapy harnesses the immune system to fight cancer, rather than infections. The procedure involves removing healthy T-cells from the patient. These cells are prepared and frozen at the collection site, and then sent to the laboratory of the manufacturer. In the laboratory, scientists genetically modify the T-cells so they recognize and target malignant B-cells.
The FDA has approved only two CAR–T therapies: tisagenlecleucel (Kymriah®) and axicabtagene ciloleucel (Yescarta®). Kymriah® received approval for use in pediatric and young adult patients with acute lymphoblastic leukemia (ALL) in August 2017, and for use in appropriate patients with large B-cell lymphoma (DLBCL) in May 2018. Yescarta® was the first CAR-T therapy to receive FDA approval for DLBCL in October 2017. At present, neither of these products has received approval for CLL or small lymphocytic lymphoma (SLL). MD Anderson has conducted one ongoing clinical trial with Kymriah®, but it is not currently recruiting new patients.
During ASH 2019, Dr. Siddiqi gave an oral presentation discussing the TRANSCEND CLL 004 study. TRANSCEND CLL 004 is a Phase I/II clinical trial that evaluates an investigational CAR-T therapy known as JCAR017 (lisocabtagene maraleucel) or Lisocel®. Lisocel®, developed by Juno Therapeutics, targets CD-19, a protein expressed during B-cell development of both healthy and malignant B-cells. Celgene, a Bristol Myers Squibb company, subsequently obtained the rights to this product. Dr. Siddiqi reported on the results of the Phase I portion of the trial. Like all Phase I trials, this trial assessed the safety of Lisocel® as a primary focus, with a secondary emphasis on efficacy. Phase II will include two arms. Patients in the first arm will receive Lisocel® monotherapy; patients in the second arm will receive ibrutinib in addition to Lisocel®.
- Lisocel® is a one-time treatment using the patient’s own genetically modified T-cells to kill malignant B-cells. Unlike other CAR-T products in which the number of T-cells varies from dose-to-dose as a result of patient variability, Lisocel® delivers a fixed amount of cells per dose.
- Phase I included 23 patients with relapsed or refractory (R/R) CLL or SLL. To be eligible, a patient needed to have failed two to three prior treatments, including at least one Bruton’s tyrosine kinase inhibitor (BTKi), such as ibrutinib (Imbruvica®) or acalabrutinib (Calquence®). The median number of prior lines of treatment was five.
- All 23 patients in this trial had advanced disease, either stage 3 or 4 using the RAI staging scale. Eighty percent had high-risk factors, such as deletion 17p, TP53 mutation, complex karyotype, or unmutated IGHV. Nine patients had failed both ibrutinib and venetoclax (Venclexta®).
- Thirty days after receiving Lisocel®, 81% achieved a response, with 45% reaching a complete response (CR), and 36% achieving a partial response (PR). Interestingly, the group of patients who had failed both ibrutinib and venetoclax had a higher overall response (OR) at 89%, with 67% reaching a CR.
- Of the 15 patients who reached undetectable minimal residual disease (uMRD), 12 (80%) maintained uMRD at 1-year or beyond, but unfortunately, 3 (20%) experienced Richter’s transformation. All three Richter’s patients were from the group that had failed both ibrutinib and venetoclax.
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 of five prior therapies.
This trial adds another potential treatment option for heavily pre-treated patients who currently have poor prognoses.
CAR-T is an inspiring example of cellular therapy for CLL. Dr. Koffman is the beneficiary of CAR-T treatment, and he chronicles his experience in a dedicated blog that you can access here.
The TRANSCEND CLL 004 trial is recruiting patients for phase II. This trial is available at 34 sites in the US. To learn more about this trial, please click here.
Thanks for reading this summary and viewing this interview.
Stay strong; we are all in this together!
Thomas. E. Henry III, MBA, RPh, CPh