Axicabtagene Ciloleucel (Axi-Cel) Large B-Cell Lymphoma (R/R LBCL): 2-Year Follow-up of ZUMA-1 Cohort 6
By Olalekan Oluwole, MD, MPH, MBBS
What is the ZUMA-1 Cohort 6 clinical trials in large b-cell lymphoma (R/R LBCL)? So my study is title Prophylactic Corticosteroid Use with Axicabtagene Ciloleucel (Axi-Cel), Axicabtagene Ciloleucel (Axi-Cel) also called Axu-Cell. It is FDA approved for the treatment of light cell lymphoma, and there are patients that develop cytokine release syndrome and neurological toxicity. And the question was whether this treatment that has been so effective can also be given in a safer way. In other words, maybe if we give a smaller dose of prophylactic corticosteroids, maybe we can prevent the higher grade toxicities, namely cytokine release syndrome (CRS) and neurologic events (NEs). And so what I’m presenting today is a longer term follow up of the patients that were treated on that study.
Could You Give Us The Standard of Care For Large B Cell Lymphoma Patients?
Patients with relapse or refractory large cell lymphoma, they are outcomes with chemotherapy, is not great. Less than a quarter will respond and half will be dead in 6 months, so CAR-T therapy with Axicabtagene Ciloleucel (Axi-Cel) was approved and we think it may curative in about half of these patients. So that is really when it is used in light cell lymphoma that is relapse or refractory. Also proof of follicular lymphoma after two or more lines of therapy.
Can You Please Explain About The Axi-Cel Cohort Design in Large B Cell Lymphoma?
The trial design is to use prophylactic corticosteroids, in a small dose, very early on in the treatment to see whether that will prevent patients developing higher grade cytokine release syndrome (CRS) or cytokine storm and some neurological toxicities. So Axicabtagene Ciloleucel (Axi-Cel) , when it was initially tested, 13% had grade 3 or higher CRS (cytokine release syndrome), and almost 30% had grade 3 or higher neurological toxicity. So whereas treatment is very effective.
We also were thinking about a way to improve the safety profile, and that’s why instead of giving a lot of corticosteroids on the back end after they developed toxicity, we were trying to preempt that by giving a small dose early on that we think should be tolerable and that will not affect the efficacy of the treatment.
Could You Highlight Some Data from the Axi-Cel Cohort in Large B Cell Lymphoma?
So unlike the pivotal studies, we have 13% had grade 3 or higher CRS or cytokine storm. In our study, none had that higher grade toxicity. What we also found out was that the neurological event was actually lower the higher grade and the time to the development of cytokine release syndrome (CRS) was also pushed out a little bit and it was not as rapid onset and was not as fluorid so that allowed time to give appropriate intervention and they didn’t get to higher grade to toxicity.
So the efficacy seems the same because the objective response rate in our study was 95%. One could argue that it was higher than 87%, but it’s not powered for that. So the efficacy seems to be preserved, but the toxicity was also moderated significantly by the adding of these prophylactic corticosteroids.
8 Key Takeaways From The Axi-Cel Cohort in Large B Cell Lymphoma
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The pivotal phase 1/2 ZUMA-1 study demonstrated the safety and efficacy of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimaeric antigen receptor CAR-T cells therapy, for the treatment of patients with relapsed/refractory large B-cell lymphoma ((LBCL) treated similarly to follicular lymphoma) after two or more prior lines of systemic therapy (NCT02348216).
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Cohort 6 investigated the impact of adding prophylactic corticosteroids to the management of toxicity in cohort 4 in an effort to build upon these findings.
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Patients in cohort 6 received levetiracetam and corticosteroid prophylaxis, whereas patients in cohorts 1 and 2 received corticosteroids and tocilizumab for toxicity control.
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In cohort 6, patients were eligible if they had histologically confirmed R/R LBCL after two or more lines of systemic therapy, were refractory to first-line therapy [defined as best response of progressive disease ((PD) disease progression) or stable disease (SD) to four or more cycles of first-line therapy with SD duration at most six months] or had PD or relapsed 12 months after autologous stem cell transplant (SCT). Data S1 contains additional inclusion and exclusion criteria.
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All treated patients experienced AEs. The most common adverse events of any grade were fever (85%), hypotension (55%) and neutropenia (50%).
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The investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and CAR T-cells numbers in the blood were secondary goals.
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Since then, the median DOR and progression-free survival (PFS) have been attained (25.9 months [95% CI, not estimable] and 26.8 months [95% CI, not estimable], respectively).
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By Month 24, 70% of 14/20 patients with evaluable samples exhibited detectable CAR T cells, compared to 64% of 23/36 patients in Cohorts 1+.
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Were the Primary Endpoints Met in the Axi-Cel Cohort?
The primary endpoint was the safety profile and it was actually met in the sense that 13% had high grade CRS in the initial pre-pivotal to study, and there was zero percent. That is clearly significant.
What Common Questions Did You Receive From Your Colleagues on this Axi-Cel Data?
People worry about why would they want to use corticosteroids when we know that lymphoid cells can be affected by corticosteroids. So we just point them to the data that we are asked in the early studies where patients could develop this toxicity. They need a lot of steroids to minimize and to cause a reversal of the toxicity.
When we look at the cumulative dose of corticosteroids we used in our study, it was a third less than the ones used in the earlier studies. Again, supporting the argument that it is true that one has to be cautious with the use of corticosteroids, but when we give it in a prophylactic manner and we intervene earlier, overall, we use less than we would have if we waited for the higher grade toxicity.
Another question that I often get asked is, okay, why do you give it to everybody? Why not just in a select people that you think may have higher grade toxicity, and we have some data to that effect because when you look at patients with high LDH and high tumor burden, they tend to have the higher grade cytokine release syndrome (CRS) and neurological toxicities.
So in our study we found that at even, actually before I get to that, but when we look, when you look at this study, it’s not exclusive. In other words, the higher grade toxicity is not exclusive in those with the high tumor burden or LDH. Even those who don’t meet those criteria can still have the higher grade toxicity, I need to be of benefit include them. So in our study we did not discriminate with high LDH or tumor burden.
We looked at it, but that was not a stratification factor, and the FDA amended the label of the use of Axicabtagene Ciloleucel (Axi-Cel). And it was across the board that they were they allowed the use of corticosteroids prophylactically like we did in our study.
What Were Some of the Takeaways from the Axi-Cel Cohort in Large B-cell Lymphoma?
I know that prophylactic sometimes is better than a lot of care, so to speak, we believe that prophylactic use of corticosteroids can be of benefit in reducing the incidence of higher grade toxicity down the line.
And some may look at the data and say that it is not a randomized study, and I understand that they may want to preserve that only for those, with high LDH, and high tumor buren, but that is fair also.
Olalekan O. Oluwole, MD, MPH, MBBS – About The Author, Credentials, and Affiliations
Dr. Oluwole’s research focuses on Chronic Lymphocytic Leukemia (CLL), Hodgkin, and non-Hodgkin lymphomas. He is conducting clinical trials using targeted therapeutics to improve the treatment outcomes of individuals with hematologic (malignancies) cancers.
He also acts as a portfolio coach at the Vanderbilt University School of Medicine (VUSM), guiding individual medical students in the development of skills for self-evaluation and lifelong learning.
Dr. Oluwole obtained his MBBS from the University of Ibadan in Nigeria and his MPH from the University of Medicine and Dentistry of New Jersey. His residency at Morehouse was in Internal Medicine. Since completing his residency in Hematology/Oncology at Vanderbilt University Medical Center in 2011, he has been a member of the faculty.
He has authored or co-authored research articles in publications with peer review and a book chapter. He belongs to the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), and the American College of Physicians (ACP) (ACP).
Reference
Wiley Online Library – Prophylactic corticosteroid use in patients receiving axicabtagene ciloleucel for large B-cell lymphoma. Wiley Online Library, July 22, 2021