Growing Body of Evidence Underscores the Activity and Safety of CAR T-cell Therapy in ALL
Since the publication of the pivotal ELIANA trial in pediatric patients with acute lymphoblastic leukemia, the field of CAR T-cell therapy has grown significantly and left providers better equipped to understand and manage treatment-related adverse effects, such as cytokine release syndrome.
Stephan A. Grupp, MD, PhD
Since the publication of the pivotal ELIANA trial in pediatric patients with acute lymphoblastic leukemia (ALL), the field of CAR T-cell therapy has grown significantly and left providers better equipped to understand and manage treatment-related adverse effects, such as cytokine release syndrome (CRS), explained Stephan A. Grupp, MD, PhD, in a presentation during the 25th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma, a program hosted by the Physicians Education Resource®, LCC.
The phase 2 ELIANA trial evaluated tisagenlecleucel (Kymriah) in pediatric and young adult patients with relapsed/refractory ALL.
“These were really the first, second, or third CAR T-cell therapy patients that any of these centers had ever treated, so [ELIANA] really [gave us] a sense of what it was like to roll this [therapy] out,” said Grupp, section chief of the Cellular Therapy and Transplant Section, director of the Cancer Immunotherapy Program, and medical director of the Cell and Gene Therapy Laboratory at the Children’s Hospital of Philadelphia (CHOP), during the virtual presentation.
In this population (n = 65), the CD19-targeted CAR T-cell therapy demonstrated sustained rates of relapse-free survival (RFS) and overall survival (OS) at 24 and 18 months.1
The 24-month RFS rate with tisagenlecleucel was 62% (95% CI, 47%-75%). At months 12 and 18, the RFS rate was 66% (95% CI, 52%-77%). Additionally, the 12-month OS rate was 76% (95% CI, 65%-85%), and the 18-month OS rate was 70% (95% CI, 58%-79%). The complete response (CR) rate and CR with incomplete hematologic recovery (CRi) rate was 82% (95% CI, 72%-90%). Additionally, 98% of patients were minimal residual disease (MRD) negative by flow cytometry.
Tisagenlecleucel is the only FDA-approved CAR T-cell therapy in ALL, but other products are in development, said Grupp.
For example, the ongoing phase 1/2 ZUMA-3 trial (NCT02614066) is evaluating brexucabtagene autoleucel (Tecartus; KTE-X19) in adult patients with relapsed/refractory ALL. Preliminary results, which were presented at the 2019 ASCO Annual Meeting, demonstrated a CR + CRi rate of 68% in the overall patient population (n = 41) and an MRD-negativity rate of 100% among evaluable patients (n = 30) with any remission.2
Across the 3 dose levels that were evaluated with brexucabtagene autoleucel––2 x 106, 1 x 106, and 0.5 x 106––the median disease control rate was 4.0 months (95% CI, 2.4-24.5), 12.9 months (95% CI, 5.8-not evaluable [NE]), and not reached (95% CI, NE-NE), respectively.
“We’re seeing a reasonable response rate, a reasonable duration of remission, and tolerable toxicity. We’ll see where that goes in terms of making a product available for adult ALL, which all of us want very much,” said Grupp.
Regarding safety, neurotoxicity has not been a significant issue with tisagenlecleucel, said Grupp.
“We see some confusion, but we don’t see cerebral edema,” Grupp said. Moreover, because neurotoxicity is not a concern with tisagenlecleucel, steroids are less heavily employed early on than in a lymphoma population, added Grupp.
In terms of CRS, literature cite symptom onset within 1 to 14 days, said Grupp, who added that the symptoms that present typically do so within the first few days of infusion and tend to be marked by fever before other symptoms.
Encouragingly, real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) indicate that the incidence of grade 3 or greater CRS occurred less frequently than was reported in the ELIANA trial, at 16.1% vs 48.1%, respectively,3 which Grupp attributed to “slightly better CRS management and earlier referrals [in practice].”
Moreover, disease burden has been shown to be highly predictive of severe CRS, whereby patients with a bone marrow blast of 95% are much more likely to be admitted to the intensive care unit (ICU) vs those with 5% blasts, said Grupp.
In terms of treatment, CRS is associated with high levels of interleukin-6 (IL-6) and interferon-gamma, which is why the IL-6 receptor antagonist tocilizumab (Actemra) is the mainstay and only FDA-approved treatment for this treatment-related toxicity, said Grupp.
In order to evaluate the effect of preemptive tocilizumab on CRS, investigators conducted a study that compared a single dose of tocilizumab after patients with high tumor burden (≥ 40% blasts) developed a fever with standard CRS management in patients with low tumor burden, followed by standard CRS management.
The primary end point of the study was the occurrence of grade 4 CRS in less than 5 patients with high tumor burden.
The incidence of grade 1, 2, 3, and 4 CRS in the high tumor burden cohort (n = 15) was 0%, 40% (n = 6), 33% (n = 5), and 27% (n = 4), respectively, meeting the primary end point of the study.4 The results also compared favorably to historical experiences at CHOP, in which ICU admissions were more than double those seen in the trial, said Grupp.
In the lower tumor burden cohort (n = 55), the incidence rates were 7% (n = 4), 55% (n = 30), 2% (n = 1), and 4% (n = 2), respectively.
Notably, no impact on CR rate, CAR expansion, or CAR persistence or immune effector cell–associated neurotoxicity syndrome was reported, said Grupp.
Finally, Grupp emphasized The American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading for CRS.
“We hope the ASTCT Consensus Grading for CRS will be a very straightforward CRS grading approach that [is] adopted [in practice]. As all of you develop your studies and work with new companies, we all hope to use this consensus grading scale, so we can get a better comparison from study to study,” concluded Grupp.
References
- Grupp SA, Maude SL, Rives S, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood. 2018;132(suppl 1):895. doi:10.1182/blood-2018-99-112599
- Shah BD, Bishop MR, Oluwole OO, et al. End of phase I results of ZUMA-3, a phase 1/2 study of KTE-X19, anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in adult patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). J Clin Oncol. 2019;37(suppl 15):7006. doi:10.1200/JCO.2019.37.15_suppl.7006
- Pasquini MC, Hu ZH, Curran K, et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 2020;4(21):5414-5424. doi:10.1182/bloodadvances.2020003092
- Kadauke S, Myers RM, Li Y, et al. Risk-adapted preemptive tocilizumab to prevent severe cytokine release syndrome after CTL019 for pediatric B-cell acute lymphoblastic leukemia: a prospective clinical trial. J Clin Oncol. 2021. [published online January 8, 2021]. doi:10.1200/JCO.20.02477
Evaluating Allogeneic CAR-T P-BCMA-ALLO1 in R/R Multiple Myeloma
November 21st 2024Bhagirathbhai R. Dholaria, MD, an associate professor of medicine in malignant hematology & stem cell transplantation at Vanderbilt University Medical Center, discussed interim data from the phase 1/1b clinical trial evaluating Poseida's CAR-T.
World Pancreatic Cancer Day 2024: Looking Back at Progress in Cell and Gene Therapy
November 21st 2024In observance of World Pancreatic Cancer Day, held on the third Thursday of November each year, we took a look back at the past year's news in cell and gene therapy for pancreatic cancer indications.
