Further Promise for CAR T-cell Therapy Use in R/R MCL Observed with Liso-Cel

March 24, 2021
Sara Karlovitch

In an interview with Targeted Oncology, Maria Lia Palomba, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, discussed the efficacy and safety of liso-cel in patients with R/R MCL as observed in the phase 1 TRANSCEND NHL 001 study.

Most patients with mantle cell lymphoma (MCL), an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL), relapse after first-line immunotherapy. Many of these patients also have a poor response to salvage therapy. However, chimeric antigen receptor (CAR) T cell therapy has shown some clinical efficacy in patients with relapsed/refractory (R/R) MCL and other NHLs. 

The use of the investigational CD19-directed, defined composition, 4-1BB CAR T-cell product, lisocabtagene maraleucel (liso-cel) is being investigated in the ongoing phase 1 TRANSCEND NHL 001 (NCT02631044). The study aims to determine if liso-cel is a safe and effective treatment for R/R MCL.

Eligible patients had confirmed MCL and at least 1 or more prior line of therapy. Of the patients who received liso-cel, the median age was 67, and 84% of the participants were male. Of the patients, 37.5% had blastoid morphology, 72% had documented Ki67 of 30% or greater, 11% had a complex karyotype, and 22% had a TP53 mutation. Additionally, most patients had a median of 3 prior systemic therapies and 72% were refractory to their last prior therapy. Most patients, 87.5% had received a prior Bruton tyrosine kinase (BTK) inhibitor. Of these patients, 34% were refractory to the therapy. Over half, 53% of patients had received bridging therapy. At the time of data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel. 

During the trial, patients received liso-cel infusions at 1 of 2 dose levels. Dose level 1 was at 50 × 106 CAR T cells while dose level 2 was at 100 × 106 CAR T cells. Primary end points included safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration do response, and progression-free survival.

Of the patients, 56% had serious treatment-emergent adverse events (TEAEs) while 84% had TEAEs of grade 3 or higher, primarily neutropenia and anemia. Grade 3 or higher thrombocytopenia was more frequent at dose level 2. Sixteen patients had cytokine release syndrome (CRS), according to the study results. There were no grade 3 or 5 incidents of CRS.

Additionally, 84% of the patients responded to liso-cel and 59% achieved a CR. Of the 12 patients who had blastoid morphology, 9 had a response of which 7 achieved a CR.

In an interview with Targeted Oncology, Maria Lia Palomba, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, discussed the efficacy and safety of liso-cel in patients with R/R MCL as observed in the phase 1 TRANSCEND NHL 001 study.

TARGETED ONCOLOGY: What set the stage for the evaluation of CAR T-cell therapy in MCL?

PALOMBA: MCL is a difficult to treat disease, particularly for patients that are refractory to BTK inhibitors, and the ones who have very high-risk histology, like p53 mutations, pleomorphic, or blastoid morphology, and so on.

TARGETED ONCOLOGY: Acknowledging that we don't have any head-to-head on brexucabtagene autoleucel (Tecartus) and liso-cel, how do the agents seem to differ?

PALOMBA: The only thing that appears to be a real difference between the studies is the toxicity. Liso-cel seems to have a lower toxicity than the 2 approved products for diffuse large B-cell lymphoma or the KTE-X19 for MCL. So, I think that is the only thing we can say right now. I don't think we can compare efficacy in any way.

TARGETED ONCOLOGY: What did we observe with lis-cel in terms of efficacy during your analysis?

PALOMBA: In terms of efficacy, we see that there was an ORR 84%, and a CR rate of 66% in these patients. We have a few patients that have reached the end of the study in a CR. The study was completed at 2 years, so obviously, it very successfully.

TARGETED ONCOLOGY: In terms of toxicity, could you elaborate the profile you saw during the study?

PALOMBA: About a half of the patients had CRS of any grade, but only 1 patient developed grade 3 CRS. In terms of neurotoxicity, about 34% of the patients had any grade neurotoxicity with only 4 patients developing grade 3 or higher neurotoxicity. The onset of toxicity is quite early. It happens around day 8. It also does seem to be resolving very quickly. It resolves on average, around 4 days after the onset of CRS and around 8 days for neurological events.

TARGETED ONCOLOGY: Was there anything about the analysis that surprised you?

PALOMBA: I can't think of much that was unexpected. To tell you the truth. I have to say the rate of infections was quite low. So, that was unexpected, considering the fact that the patients were usually heavily pretreated and had received BTK inhibitors. For instance, we didn't see increased rates of fungal infections. We only saw 1 grade 5 fungal infection.

I think the product has shown to be very effective with a low incidence of CRS neurotoxicity. It might have to do with the costimulatory domain, which in this case is 4-1BB, might also have to do with the fact that it's a product that is given at a 1:1 ratio rate of CD4-positive and CD8-positive T cells. That might have a little bit of influence on the specific toxicity profile.

TARGETED ONCOLOGY: What are the next steps for the research?

PALOMBA: The next step is to wait for the data to mature. I think that we have to prove that these responses are durable. So, you'll see waiting a year or 2 to see if we can prove that. That would be wonderful. I think that we have proven that CAR T-cell therapy is a valid option for patients with MCL. We also know from data that I didn't present, but patients who didn't require bridging therapy did a little bit better. So, we know that having less disease or having controlled disease prior to receiving the product is important. Maybe it is necessary to bring this therapy earlier on into the sequence of therapy for these patients.

TARGETED ONCOLOGY: In anticipation of further positive data with this product, how do you imagine that we're going to approach patient selection between brexucabtagene autoleucel and liso-cel?

PALOMBA: If one is better than the other, it becomes clear which one should be used. Right now, we can't tell if one will be better than the other. In terms of toxicity, there is a definite difference. If we can select patients based on their comorbidities and extent of disease at the time of referral, I think that’s how we select patients. That is pretty much the way we select patients currently, and how we select a product for a certain patient at this time for DLBCL.

Palomba, M., Gordon, L., Siddiqi, T., et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in transcend NHL 001. Blood. 2020; 136 (suppl 1): 10-11. doi: 10.1182/blood-2020-136158