A single infusion of tisagenlecleucel (Kymriah, Novartis), an anti-C19 chimeric antigen receptor (CAR)-T cell product, produced durable anti-tumor responses in relapsed or refractory aggressive B-cell lymphoma patients provided they achieved a complete response (CR) at 3 or 6 months post-infusion, a long-term analysis of the phase II JULIET study has shown.
At a median follow-up of 40.3 months (Interquartile range [IQR], 37.8-43.8 months), the overall response rate was 53% (95% CI, 43.5-62.4%), with 39% of patients achieving a complete response (CR) as their best overall response, Stephen Schuster, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues reported in the Lancet Oncology.
These results were actually very similar to the previous JULIET report in which the best overall response rate was 52% (95% CI, 41-62%) and the CR rate was 40% at a median follow-up of 14 months, investigators noted.
For patients who achieved a CR at 3 months, event-free survival rates with longer-term follow-up reached 78.8% (95% CI, 60.3-89.4%) and for patients who achieved a CR at 6 months, the event-free survival rate reached 86.5% (95% CI, 67.7-94.7%), the authors observed.
Toxicities, largely hematologic in nature, were deemed to be manageable and there were no new safety signals with the longer-term follow-up and no treatment-related deaths.
“The findings reported by Schuster and colleagues show the long-term benefit of CD19-directed CAR T cells as a standalone therapy for some patients with non-Hodgkin lymphomas,” Elad Jacoby MD, Sheba Medical Center Tel Hashomer, Israel, and Abraham Avigdor, MD, Tel Aviv University, Tel Aviv, Israel, wrote in an accompanying editorial.
“Moreover, emerging [but] not yet peer-reviewed, results showing the superiority of CD19-directed CAR T-cell therapies over standard-of-care autologous haematopoietic stem-cell transplantation in the second line will most likely change the treatment paradigm for patients with relapsed or refractory aggressive B-cell lymphomas in the near future,” they added.
JULIET is a multicenter, open-label, single-arm trial that originally enrolled 167 patients from 27 different treatment sites.
As of Feb, 2020, 115 patients had received tisagenlecleucel infusion and were included in the analysis.
Patients had received at least two lines of previous therapy including ritiximab (Rituxan, Biogen/Genentech) and an anthracycline and had either relapsed after, were ineligible for, or did not consent to undergo autologous hematopoietic stem-cell transplantation (HSCT), researchers pointed out.
Following leukaphereis, bridging chemotherapy was permitted and patients could receive one cycle of lymphodepleting chemotherapy prior to receiving their infusion with the CAR-T cell therapy as well.
“Patients received a single intravenous infusion of tisagenlecleucel at a dose ranging from 0.1 x 108 viable CAR T cells to 6.0 x 108 viable CAR T cells (target dose 5 x 108 viable CAR T cells) in either the inpatient or outpatient setting,” Schuster noted.
The primary endpoint was overall response rate, namely the proportion of patients with achieved either a CR or a partial response (PR).
“Notably, our analyses showed that patients who had a complete response at any time had long-term durability of response and survival benefits,” the researchers wrote.
Indeed, the median duration of response was not estimable in the full analysis set, however, the estimated proportion of patients with a response at 36 months after response onset was 60.4% (95% CI, 46.1-72%).
Interestingly, of the 8 patients who achieved either a partial response or stable disease at 3 months, 5 of the 8 patients converted to being complete responders during longer-term follow-up.
While on study 62% (72 of 115) of patients had disease progression or died, the median progression-free survival (PFS) was 2.9 months (95% CI, 2.3-5.2 months), the investigators reported. However, a post-hoc analysis showed that the median PFS was not reached for patients who achieved a CR at either 3 or 6 months after infusion, they also noted.
The median overall survival (OS) was 11.1 months (95% CI, 6.6-23.9 months), but again, median OS was not reached for those who achieved a CR at either 3 or 6 months as their best overall response.
And in a separate analysis of patients with DLBCL, OS were equivalent to that of age and sex-matched individuals from the general population if patients made it out to 24 months after their diagnosis without experiencing any disease-related event.
The most common grade 3-4 adverse events (AEs) that occurred any time after patients had received their tisagenlecleucel infusion were as follows:
- Anemia: 39%.
- Decreased neutrophil count: 34%.
- Decreased white blood cell count: 32%.
- Decreased platelet count: 28%.
- Cytokine release syndrome: 23%.
- Neutropenia: 20%.
- Febrile neutropenia: 17%.
- Hypophosphatemia: 13%.
- Thrombocytopenia: 12%.
On the other hand, the most serious treatment-related serious AEs occurring any time after infusion were cytokine release syndrome in 27%; febrile neutropenia in 6%; pyrexia in 5%; pancytopenia in 3%, and pneumonia again in 3% of patients.
As the authors observed, lactate dehydrogenase levels were found to significantly predict both response and the development of severe cytokine release syndrome. In addition, the presence of severe thrombocytopenia and high lactate dehydrogenase levels prior to infusion were associated with poor outcomes.
They also noted that severe neurological events appeared to be associated with the development of severe cytokine release syndrome—”supporting previously suspected findings that cytokine release syndrome and neurological events tend to occur concurrently in patients treated with CAR T-cell therapy.”
The final analysis of the JULIET trial will be done when the last patient to receive their infusion completes 5 years of follow-up.
Commenting further on the study, Jacoby and Avigdor point out that the FDA has actually approved 3 CAR T-cell products for the treatment of relapsed or refractory aggressive B-cell lymphomas: tisagenlecleucel, axicabtagene ciloleucel (Yescarta, Kite Pharma) and lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb).
“All three showed high rates of complete responses in patients with refractory disease in pivotal trials,” the editorialists noted, and added, “In parallel, real-world data have emerged for these products showing similar overall responses.”
Real-world studies have also supported the safety and efficacy of CD19-directed CAR T-cell therapies in many patients who would not have been eligible for the pivotal clinical trials, as Jacoby and Avigdor noted.
On the other hand, one major disadvantage to the use of CAR T-cell therapy is the need to produce the product on an individual basis from heavily pre-treated patients.
This is not as readily done as it might sound—in the JULIET study, for example, only 69% of patients who were apheresed for CAR T-cell production actually received tisagenlecleucel, the editorialists pointed out
Thus, future studies need to help identify which patients are most likely to benefit from CD19-directed CAR T-cell therapy in an effort to help clinicians select the right therapy for the right patient at the right time, as they emphasized.
- Single infusion of CAR T-cell therapy produced durable anti-tumor responses in relapsed/refractory aggressive B-cell lymphoma patients provided they achieved at CR at 3 or 6 months following the infusion.
- The superiority of CAR T-cell therapies over standard-of-care HSCT will most likely change the treatment paradigm for patients with relapsed/refractory aggressive B-cell lymphomas in the near future.
The study was funded by Novartis Pharmaceuticals
Schuster reported serving as an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics and has received honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics. He has also participated in steering committees for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer and has received research support from AbbVie, Acerta, Celgene (Juno), DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics. He also reported having a patent with Novartis
Jacoby reported receiving honorarium or having participated on advisory boards for Amgen, Novartis and Lonza while Avigdor reported having served on advisory boards for Roche, Nanssen, Sanofi and Takeda.
Pam Harrison, Contributing Writer, Physician’s Weekly partner, BreakingMED™