The CD19-directed CAR T-cell therapy lisocabtagene maraleucel demonstrated promising responses and a manageable toxicity profile in patients with high-risk chronic lymphocytic leukemia or small lymphocytic leukemia who have previously progressed on ibrutinib in the updated findings from the phase I/II TRANSCEND CLL 004 study.
Tanya Siddiqi, MD
The CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) demonstrated promising responses and a manageable toxicity profile in patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have previously progressed on ibrutinib (Imbruvica) in theupdated findings from the phase I/II TRANSCEND CLL 004 study.
Overall, 81.5% of patients had a response after 11 months of follow-up, which included 45.5% of patients who had either a complete response (CR) or CR with incomplete blood count recovery as the best overall response. The overall response rate was 89% in those who had failed on both ibrutinib and venetoclax (Venclexta) previously, whereas 67% of patients achieved a CR.
Investigators noted that 68% of patients achieved a response by day 30 (n = 15), and 27% of the responses deepened over time (n = 6). This included 3 patients who went from a partial response (PR) to CR. Out of 12 patients who achieved a CR or PR at 6 months, 10 remained in remission at 9 months (83%). Eight of the 10 patients remained in remission at 1 year or longer.
In terms of treatment-emergent adverse events (TEAEs), cytokine release syndrome (CRS) of any grade occurred in 74% of patients, while 9% had grade 3 CRS. There were no grade 4 or 5 CRS events. Approximately 39% of patients had neurological events of any grade, including 5 that were either grade 3 or 4 neurotoxicity. Grade 5 neurotoxicity did not occur.
The most common TEAEs of grade 3 or 4 included anemia (78%), thrombocytopenia (70%), neutropenia (56.5%), and leukopenia (43.5%). Grade 3 or greater tumor lysis syndrome also occurred in 17.4% of patients. Two patients experienced dose-limiting toxicities in the dose level 2 arm, though both were resolved.
TRANSCEND CLL 004 enrolled 23 patients with relapsed/refractory CLL or SLL who were ineligible for or failed a previous BTK inhibitor, and patients were divided into 2 dose level cohorts. Nine patients received liso-cel infusion at 50 × 106 total CAR+ T cells for dose level 1, and 14 patients received 100 × 106 total CAR+ T cells for dose level 2.
In an interview withTargeted Oncology, Tanya Siddiqi, MD, principal investigator of TRANSCEND CLL 004’s site at City of Hope and associate professor at City of Hope Medical Center, discussed the results from the phase I portion of the TRANSCEND CLL 004 trial. She also discussed the value of CAR T-cell therapy treatment.
TARGETED ONCOLOGY: What was the rationale for conducting this trial?
Siddiqi:There are a lot of novel agents that have come out for CLL within the last 5 years or so. The novel agents seem to be working extremely well in the frontline setting, but are less effective in the relapsed setting. We find that if people have failed ibrutinib or a BTK inhibitor and a couple of other lines of therapy, their prognosis does seem to be poorer, so there is still a need, even though there are so many novel agents out there. If people begin to fail novel agents, then we have nothing good left to treat them with. CAR T cells seemed to be a good fit in that space to see if we could treat patients so that they may never need treatment again if it works well. That’s the attraction.
TARGETED ONCOLOGY: Could you discuss the design of the trial?
Siddiqi:This is a phase I/II trial called TRANSCEND CLL 004. I presented the phase I portion of the study, in which we enrolled 23 patients. Patients with relapsed/refractory CLL were allowed. Patients needed to have failed a BTK inhibitor of some sort, which happened to be ibrutinib in all the patients who were enrolled. They also needed to have failed 2 or 3 other prior lines of therapy, depending on whether they had poor-risk cytogenetic features or not. The 23 patients were split between 2 dose levels, so 9 patients received dose level 1 and 14 received dose level 2.
TARGETED ONCOLOGY: What were the data that you presented?
Siddiqi:We found that the liso-cel CAR T cells were pretty well tolerated. Even though 74% of patients had some kind of cytokine release syndrome (CRS), only 2 out of the 23 patients had grade 3 CRS, which was manageable and reversible. There were no grade 4 or 5 CRS events.
As far as neurotoxicity events are concerned, which is another common CAR T cell side effect, we found that about 39% of patients had some grade of neurotoxicity, but only 5 of the 23 had grade 3 or 4 neurotoxicity. We found that it was very well-tolerated overall. The toxicities were not super concerning at this point.
The outcomes were superb. At day 30, we had the first assessment for all these patients. They underwent bone marrow biopsies, blood work, and scans. We found that 81% had already had an objective response, meaning CR or PR. About 45% were CRs already at the day 30 mark after CAR T cells. We did minimal residual disease (MRD) testing, and we found that 65% to 75% of patients were already in undetectable MRD as well.
We had looked at a sub-cohort of patients that were probably some of the most badly-behaving [cases of] CLL. They had failed ibrutinib and venetoclax before they came onto our study, and even in those patients, the response rate was 89%, and about 80% were undetectable MRD.
The data looks good, but what needs to be seen is how long the results are durable. We have 10 of 12 patients who are in a CR or PR at month 6. At month 9, 10 remained in remission, and now 8 of them are out 1-year maintaining their response. We had about 20% of patients who improved their response over time, so if the had stable disease, they went to into PR or if they were in PR, they went to into CR. This was seen as far out as 1 year later, so these cells continue to persist and do their work in the body, which is great.
TARGETED ONCOLOGY: What are potential implications of these findings?
Siddiqi:The phase II trial is now enrolling. That needs to finish so that the data can be analyzed, and we have more experience with the drug in CLL. Since liso-cel has already been tested in aggressive lymphoma and over 100 patients have already been treated, we already know what the toxicities look like, and they are fairly similar. We know what the response is in that is too, so I think it would be great to see it commercially available so that more patients could access it. That would be the goal.
Ultimately, it would be nice to be able to offer this to patients who haven’t failed so many lines of therapy already. If we can do it earlier, such as after the second-line, for example, then maybe it can potentially cure patients faster so they don’t have to cycle through so many medications. “Cure” is a relative term. We need to wait 10 years before we can call anything a cure in a disease like CLL, but we can hope.
TARGETED ONCOLOGY: Is there anything else you would like to emphasize about CAR T-cell therapy?
Siddiqi:One thing people forget when they are thinking about CAR T cells is that it is 1 dose, and then you’re done. It’s not something that you are taking forever. It is 1 dose of CAR T cells after 3 days of chemotherapy. If it works, it works extremely well, and you may never need treatment again. I usually tell patients to give me 1 month of their life so I can get them through CAR T cells, manage the toxicities, and then there should be no lingering side effects. If it works, it works great.