Early Steroids Can Result in Less Toxic CAR T-Cell Therapy
Cancer treatments have an array of adverse effects, ranging from skin irritation to more complex, life-threatening symptoms.
The same holds true for chimeric antigen receptor T-cell therapies that, in exchange for lasting remissions among a majority of patients, require most recipients to endure severe treatment-related effects that can easily reach critical status.
New evidence shows early use of steroids after administration of CAR T-cell therapy can reduce the severity of treatment-related toxicities, namely cytokine release syndrome (CRS) and neurotoxicity.
Furthermore, research has shown that steroids can be administered in concert with CAR T-cell therapy without diminishing its effectiveness and longevity.
Investigation in this area has been led by Max S. Topp, MD, head of hematology at University Hospital of Würzburg.
Topp and colleagues analyzed the safety expansion cohort of the phase 1/phase 2 ZUMA-1 trial, in which patients received early steroid intervention when grade 1 CRS or neurotoxicity developed after an infusion of axicabtagene ciloleucel (Yescarta; Kite, Gilead), an autologous anti-CD19 CAR T-cell therapy.
Researchers presented preliminary results of the safety expansion cohort at last year’s ASCO Annual Meeting. Topp shared data on 21 patients in the cohort that showed early steroid use reduced incidence of severe CRS and neurotoxicity without affecting the response rate.
A broader analysis presented at last year’s ASH Annual Meeting & Exposition compared results of the nonrandomized safety expansion cohort (cohort 4) with cohorts 1 and 2 in the ZUMA-1 trial.
“The purpose of the study was to introduce a new, revised risk-management profile in these patients by adding early steroids to mitigate cytokine release syndrome and neurotoxicity,” Topp told Cell Therapy Next.
Cohort 4 comprised 41 patients (median age 61 years; range, 19-77; 32% aged 65 years; 68% men) who received CAR T-cell therapy, with median follow-up of 8.7 months (range, 2.9-13.9). Disease types within the cohort included diffuse large B-cell lymphoma (63%), transformed follicular lymphoma (24%), high-grade B-cell lymphoma (7%) and primary mediastinal B-cell lymphoma (5%). Seventy percent of patients had stage III or stage IV disease, 63% had more than three previous lines of therapy, and 20% had relapsed disease after receiving an allogenic hematopoietic stem cell transplant.
Patients in cohort 4 more frequently received steroids (73% vs. 27%) and tocilizumab (Actemra, Genentech; 76% vs. 43%) to resolve treatment-related adverse events compared with cohorts 1 and 2.
“Overall, the study cohorts were quite comparable,” Topp told Cell Therapy Next.
Incidence of severe CRS or neurotoxicity served as the study’s primary endpoint.
“There was a clear reduction in cytokine release syndrome and neurotoxicity from the pivotal phase 1 cohorts 1 and 2, down to 10% in the patients being treated in cohort 4,” Topp said in describing the study’s key finding.
Patients who received early steroids in cohort 4 experienced less frequent high-grade CRS (2% vs. 11%) and neurotoxicity (17% vs. 32%) compared with cohorts 1 and 2. Further, response rates among patients who received early steroids appeared comparable to those of patients in cohorts 1 and 2 (see table).
Median duration of response was 8.9 months in cohort 4 vs. 8.1 months in cohorts 1 and 2.
“Importantly, the expansion of CAR T cells was not impacted by the use of steroids,” Topp told Cell Therapy Next.
The analysis showed the same amount of peak expansion, as well as the same area under the curve of CAR T cells in patients, Topp said.
“But, more importantly, we saw that cytokine levels in these patients were clearly reduced if they received steroids,” he added.
Perhaps the most important finding from the safety expansion cohort was that the early use of steroids after CAR T-cell infusion did not have a negative impact on overall response rates to therapy or long-term disease control, according to Topp.
“With this new risk-benefit management profile, we have a means of delivering CAR T cells more effectively to patients with less toxicity,” he said.
Early Steroids and CAR-T: Ready for Prime Time?
Clinical trials that evaluate the safety and effectiveness of CAR T-cell therapy each have their own protocol treatment algorithm for the initiation of steroids or tocilizumab to manage CRS or neurotoxicity, according to Peter A. Riedell, MD, a lymphoma expert, assistant professor of medicine and director of clinical research for the hematopoietic cellular therapy program at The University of Chicago.
A movement has developed within the field — bolstered by the results of studies conducted by investigators such as Topp and colleagues — to initiate steroids earlier to help resolve these treatment-related toxicities.
“There was a large amount of hesitancy about using [steroids] because it was thought that they were going to impair the CAR T cells and reduce its efficacy,” Riedell told Cell Therapy Next.
Riedell said the data presented by Topp and colleagues indicate a favorable toxicity profile when steroids are used early to treat CRS and neurotoxicity, and there is preliminary evidence that it may reduce the frequency of severe toxicities without obviously affecting treatment efficacy. However, the small study size is a limitation, and he would like to see further study in this area to confirm these results.
“This needs to be studied in a systematic fashion before I would be comfortable using this treatment strategy in current clinical practice,” Riedell said. “We need to explore this question in a larger number of patients with longer-term follow-up to confirm if there is a signal of a change in efficacy in these patients.”
Riedell said he believes the field of cell therapy and clinical trial protocols are moving toward earlier steroid use, but that much of this is based on expert opinion rather than evidence.
Evidence-based direction will come in the form of clinical practice guidelines, and Riedell told Cell Therapy Next that the American Society for Transplantation and Cellular Therapy (ASTCT) is working on guidelines to harmonize the nomenclature, grading and management of CAR T-cell-related toxicities. He said the data presented by Topp and colleagues are “intriguing” and will likely play a role in developing the management strategies recommended by ASTCT in its guidelines.
“The hope is that we will be able to compare toxicities between clinical trials and that we will all use the same grading system and compare them all on a more level playing field,” Riedell said. “The information gathered by Topp and colleagues is important and will likely have a role in the management algorithm that is eventually adopted by the ASTCT.” – by Drew Amorosi
- Topp MS, et al. Abstract 7558. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
- Topp MS, et al. Abstract 243. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
- For more information:
- Peter A. Riedell, MD, can be reached at email@example.com.
- Max S. Topp, MD, can be reached at firstname.lastname@example.org.
Disclosures: Riedell reports research funding from Juno Therapeutics, Kite/Gilead and Novartis; a consultant role with Novartis; a speakers bureau role with Kite/Gilead; and advisory board roles with Celgene/Bristol-Myers Squibb and Novartis. Topp reports research funding from Amgen, Kite, Regeneron and Roche; consultant roles with Amgen, Kite, Novartis, Regeneron and Roche; honoraria from Amgen; a speakers bureau role with Prime Therapeutics; and travel support from Amgen, Celgene and Gilead.