Authored by Dr. Brian Koffman
The Bottom Line:
Liso-cel (Lisocabtagene Maraleucel) is the CAR-T therapy closest to approval for relapsed / refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), primarily based on the Transcend CLL004 results that showed a high rate of undetectable measurable (minimal) residual disease (uMRD) in both the blood and the marrow, with a duration of response (DOR) averaging almost three years overall and not reached for the 18% that has a complete remission (CR). However, the average progression-free survival (PFS) was less than a year. Side effects, including cytokine release syndrome (CRS) and neurotoxicity, were common but usually mild and manageable.
DOR is the interval from response initiation to progression or death, so it only includes those who respond. PFS includes everyone.
Patients who have been failed by a BTKi and venetoclax have few options and a poor prognosis. Cellular therapy, including CAR-T, seems largely agnostic to high-risk features, and a number of prior treatments offer a good choice for those with few choices.
- 137 were leukapheresed to collect cells, and 117 received liso-cel.
- 83% had high-risk features
- Median lines of prior therapy were 5 (range 2–12), and all had prior BTKi. This was a tough group to treat.
- 18.4% had a complete response (CR)
- The overall response rate (ORR) was 42.9%
- The uMRD rate was 63.3% in blood and 59.2% in marrow. This is much higher than the CR rate, where all nodes and the spleen must shrink to normal.
- The median DOR was 35.3 months. DOR was only measured in those 42.9% who responded.
- Median DOR for those reaching CR was not reached, suggesting the deeper the remission, the longer it lasts.
- PFS was only 11.9 months, which reflects the average time for all until progression, including all the responders and non-responders.
- Cytokine release syndrome (CRS) was seen in 84.6% with no deaths. It was all grade 1-3, so milder.
- Neurological events (NE) were present in 45.3% with no deaths.
- 69.2% needed tocilizumab and/or corticosteroids to control CRS / NEs.
- The rate of grade ≥3 (serious) infections, low immunoglobulins, and prolonged low blood counts was 17.1%, 15.4%, and 53.8%, respectively.
- One death related to liso-cel was due to hemophagocytic lymphohistiocytosis, a very rare blood disorder seen with profound immune dysregulation.
- Liso-cel exhibited rapid in vivo expansion and was detected in patients’ blood up to 36 months after infusion.
Sadly, CAR-T therapies have been less successful in CLL / SLL than in many other lymphomas, likely due to the exhausted T cells and the generally impaired immunity seen in CLL. Still, liso-cel works very well in some tough-to-treat patients. Still, it is yet to be determined whether an average time to progression of less than a year will be enough to convince the FDA to approve it and patients to take it, especially with its high rate of manageable but unpleasant side effects.
On a personal note, I received JCAR-014, which is very closely related to liso-cel, and enjoyed an excellent 5½ years of remission, clearly worth my one month of misery from CRS and NE. Everyone will respond differently, but for me, it was amazing. If the numbers achieving a CR can climb, perhaps by adding a BTKi to enhance T cell function, I think CAR-T becomes an even stronger option for those with few good choices.
Links and Resources:
Watch Dr. Brian Koffman’s monologue on the abstract:
You can read the actual International Conference on Malignant Lymphomas (ICML) 2023 abstract here: LISOCABTAGENE MARALEUCEL (LISO-CEL) IN R/R CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL): PRIMARY ANALYSIS OF TRANSCEND CLL 004
Stay strong; we are all in this together.
Brian Koffman, MDCM (retired), MSEd
Co-Founder, Executive VP, and Chief Medical Officer
CLL Society, Inc.