Axi-cel ‘can be curative’ for large B-cell lymphoma, but nonrelapse mortality a concern
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Key takeaways:
- Patients with large B-cell lymphoma who received axi-cel in a real-world setting derived similar benefit as those treated in trials.
- Results showed a higher rate of nonrelapse mortality than reported in trials.
A real-world evaluation of axicabtagene ciloleucel for individuals with relapsed or refractory large B-cell lymphoma showed 5-year OS, PFS and disease-specific survival rates comparable to those observed in clinical trials.
“Refractory or relapsed large B-cell lymphoma is an aggressive lymphoma. If left untreated, it’s fatal universally,” Saurabh Dahiya, MD, FACP, associate professor of medicine and clinical director of cancer cell therapy at Stanford Medicine, told Healio. “A single infusion [of axicabtagene ciloleucel] can be curative [for] a subset of patients. That was a pleasant surprise.”
However, Dahiya and colleagues also observed a higher risk for nonrelapse mortality — driven largely by infections and second primary neoplasms — in the standard-of-care real-world setting. Most nonrelapse mortality events occurred at least 1 year after CAR-T therapy.
We need to come up with a better plan [to address this],” Dahiya said. “How do we prevent infections in these patients? How do we better monitor and perhaps intervene early [for] patients to screen for some of these cancers?”
Background and methods
Axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences), often called axi-cel, is a CD19-directed chimeric antigen receptor T-cell therapy.
The FDA approved axi-cel for patients with relapsed or refractory large B-cell lymphoma after one line of treatment based on data from the ZUMA-1 and ZUMA-7 clinical trials.
After FDA approval, Dahiya and colleagues began evaluating axi-cel in the standard-of-care setting as part of the U.S. Lymphoma CAR T-cell Consortium, which consists of 17 academic centers.
“For many recently FDA-approved therapies that are not CAR T-cell therapies, reported outcomes in actual clinical practice are much worse than the outcomes reported from clinical trials. For axi-cel, reported clinical trial outcomes and our clinical practice outcomes were almost identical,” Michael D. Jain, MD, PhD, associate member and the immune and cellular therapy medical director at Moffitt Cancer Center, told Healio.
Researchers followed 275 patients with relapsed or refractory large B-cell lymphoma who had received at least two prior lines of treatment. Patients underwent leukapheresis followed by axi-cel infusion between Nov. 3, 2017, and Sept. 30, 2018.
Results
Median follow-up was 58 months.
Patients treated in standard-of-care settings and ZUMA-1 trial participants achieved comparable 5-year PFS (28.5% vs. 32%), OS (40.3% vs. 43%) and lymphoma-specific survival (53.3% vs. 51.1%).
In the standard-of-care cohort, researchers reported median PFS of 8.7 months and median OS of 34.9 months. Most (87%) progression events occurred in the first year.
These results are particularly exciting, Dahiya said, because 43% of the cohort treated in standard-of-care settings would not have been eligible for the registrational clinical trial.
“It only reaffirms our belief in the curative potential of CAR-T for lymphoma,” he said.
However, results showed a 16.2% nonrelapse mortality rate in the standard-of-care clinical setting. Twenty-one patients died due to infection and nine died of secondary malignancies.
In the standard-of-care clinical setting cohort, individuals aged at least 60 years had lower risk for relapse (P = .02) but significantly higher risk for nonrelapse mortality (OR = 4.5; 95% CI, 2.1-10.8) than those aged younger than 60 years.
In total, 9% of patients in the standard-of-care setting cohort developed subsequent malignant neoplasms, which included therapy-related myeloid neoplasms, solid tumors and unrelated lymphoid malignancies.
The nonrelapse mortality rate “was a lot higher than had been previously reported on the clinical trials,” Jain said.
“This is a remarkable therapy and, without it, these people would have died of their lymphoma,” he added. “Now, they’re living long enough for us to start considering these survivorship issues.”
‘The hottest topic’
Dahiya has adjusted care for his patients due to results of this study, particularly to avoid infections.
He said he routinely gives prophylactic antimicrobials and IV immunoglobulin to keep immunoglobulin G levels above 400 for passive immunity. He also emphasized the importance of vaccinations and infection prevention.
“These patients were the earliest recipients of FDA-approved commercial CAR-T therapy and likely were the sickest of the sick,” Dahiya said. “As CAR-T moves into earlier lines and [is used in] less-heavily pretreated patients, we will see fewer infections.”
Second primary malignancies following CAR-T are “the hottest topic” in the community, Dahiya said.
In November, the FDA issued a warning about risk for T-cell malignancies following CAR-T, but T-cell lymphomas after CAR-T therapy remain “super rare,” Dahiya said.
“What you see is a lot of secondary myeloid malignancies,” he added. “That’s the bulk of where the second primary malignancies are coming from. And then there’s solid tumors, too.”
Several studies have now showed the risk for second primary malignancies to be between 1.7% and 4.3%, Dahiya said.
“Why do these patients have these secondary events?” Jain asked. “Is it that these patients got a lot of chemotherapy and other therapies previously? Or is it the case that somehow the CAR T cells are speeding up this process? Is there anything that we can do to either screen for these cancers or prevent them from happening in their nascency?”
Immortal time bias as also could be a possible explanation, Dahiya said.
“You live long enough to realize the risk of dying from other causes than [the primary cancer],” he said.
Moving axi-cel into earlier lines of treatment could reduce the number of secondary malignancies, Dahiya said.
“[However], if the major driver is these mutations are due to aging or the dysregulated immune system that patients with lymphoma already have, then it may not have a great improvement simply by moving CAR T-cell therapy earlier,” Jain said.
Dahiya said he expects progress in the next 5-year report thanks to earlier use, better supportive care, multiantigen targeting and manufacturing modifications.
“I can only imagine that when the next 5-year report for large B-cell lymphoma comes out, we would be at PFS of 50% to 60% at 5 years,” he said. “I hope it’s better than that, but we will be much, much better.”
For more information:
Michael D. Jain, MD, PhD, can be reached at michael.jain@moffitt.org.
Saurabh Dahiya, MD, can be reached at sdahiya@stanford.edu.
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