Authored by Brian Koffman, MDCM (retired), MSEd
Bottom Line:
By never freezing the locally produced CAR-T cells, disappointing response rates for relapsed / refractory CLL and Richter’s Syndrome patients are greatly improved. GLPG5201 is an experimental CD-19-directed CAR-T that was being studied for use in difficult-to-treat relapsed/ refractory (R/R) chronic lymphocytic leukemia (CLL) and Richter’s Syndrome or Transformation ((RT) patients who have few treatment options.
Who Performed the Research and Where Was it Presented:
Dr. Valentin Ortiz-Maldonado of Hospital Clinic de Barcelona, Barcelona, Spain, and colleagues presented the results in a poster session at the American Society for Hematology (ASH) Annual Meeting in 2024 in San Diego, CA.
Background:
CAR-T therapy is potentially lifesaving for Richter’s Transformation patients and for double refractory CLL patients who have progressed after failing both BTK inhibitors and venetoclax. These two groups of patients have been traditionally difficult to treat and have a poor prognosis. Unfortunately, CAR-T has not been as successful in CLL or RT patients compared to other lymphomas. This may be because CAR-T therapy’s success relies on the killing power of the patient’s own T cells that are harvested and then ex-vivo (outside of the body) genetically re-engineered to attack the cancer. The T cells of CLL and Richter’s patients often have an “exhausted” profile, making them less effective killers due to the late stage of the disease by the time they are going to be used and possibly from any damage caused by multiple prior therapies. Freezing the cells for transport to a central facility for manufacturing may further attenuate their efficacy. The manufacturing process can take weeks, allowing the disease to progress, especially worrisome in the case of the usually fast-moving RT. Worse yet, sometimes producing the CAR-T cells to the required specification
proves impossible.
GLPG5201 is an experimental fresh, never-frozen anti-CD19 CAR-T product produced locally in a self-contained unit near the patient being treated to address many of these concerns. CD19 is a marker found on the surface of all CLL cells and all normal B cells. The time from leukapheresis (the harvesting of the patient’s own T cells for manufacturing) to the time when the re-engineered CAR-T cells are injected back into the patient is only seven days. This is sometimes called “vein to vein” time.
Methods and Participants:
This is a Phase1/2 trial to study safety and efficacy in RT or CLL patients with at least two prior therapies.
Results:
- 15 patients were enrolled: six with R/R CLL and 9/15 with RT.
- The average age was 66, so it was younger than the usual CLL patient. Two-thirds were male, as expected.
- All CLL patients were double refractory to BTKi and BCL2i (venetoclax) therapy. 8 of 9 RT had had prior chemoimmunotherapy for their RT.
- The average vein-to-vein time was 7 days, ranging up to 14 days.
- Successful CAR-T cells meeting the required standards were produced for all 15 patients.
Adverse Events:
- The most severe side effects were low blood counts.
- Cytokine release syndrome (CRS), where excessive inflammation results from the release of inflammatory enzymes (cytokines), is a common complication with CAR-T and other immune therapies. GLPG5201 caused mild (grade 1 or 2) CRS in only 8 of the 15 patients and no neurotoxicity.
- Most severe (Grade ≥ 3) adverse events were low blood counts.
- Two RT patients died. One was from a viral (CMV) infection in the colon when in complete remission (CR) 14.5 months after the infusion; the other was from disease progression at day 110.
Outcomes:
- In total, 13 of 15 patients responded.
- Three of the 13 patients progressed after an initial response.
- Complete response or CR was achieved by 10 of 15 patients.
- At the data cut-off, 12 of 15 patients remain in the study for further follow-up.
Conclusions and Commentary:
The use of rapid, fresh, decentralized manufactured CAR-T, GLPG5201, produced very promising results in two difficult-to-treat situations: double refractory CLL or Richter’s Transformation. There was no severe CRS and no neurotoxicities. Very encouraging overall, but the manufacturer, Galapagos, made the decision in February 2025 to “deprioritize” GLPG5201 and instead concentrate on the development of GLPG5101, which has had strong results in diffuse large B-cell lymphoma (DCBL) and some slow-moving lymphomas related to CLL, but has not yet been trialed in CLL and there are less data in RT. There are plans to move forward to try to help those needy patients. At the time of publication, the RT trial in the US has been approved by the FDA and the CLL trial is being reviewed. Galapagos feels confident this choice will be better for all patients, including those with CLL and Richter’s. We look forward to those trials.
Links and Resources:
Watch the interview on the abstract here:
Read the full ASH abstract at Euplagia-1: A Phase 1/2 Trial of GLPG5201, a Fresh Stem-like Early Memory CD19 CAR T-Cell Therapy with a 7-Day Vein-to-Vein Time, in Patients with Relapsed/Refractory CLL and RT.
The company’s plans to switch development to GLPG5101 can be read about in this update.
