CAR T Toxicity Differences Seen in Transplant-Ineligible LBCL
During a live event, Nathan M. Denlinger, DO, MS, discussed the PILOT and ALYCANTE trials of CAR T-cell therapy in transplant-ineligible B-cell lymphoma.
Nathan M. Denlinger, DO, MS
Assistant Professor
Division of Hematology
The Ohio State University College of Medicine
Columbus, OH
This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted OncologyTM: What are the primary toxicities with chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL), based on the ZUMA-7 trial (NCT03391466) and TRANSFORM trial (NCT03575351)?
Nathan M. Denlinger, DO, MS:CRS [(cytokine release syndrome) leads to fevers and can] look like they have sepsis. We deal with this inpatient [in tertiary care centers]. It's not something [referring oncologists] will ever see, but it is something that affects patients significantly. Severe CRS was present in 6% of patients with axicabtagene ciloleucel [axi-cel; Yescarta] and 1% in lisocabtagene maraleucel [liso-cel; Breyanzi].1,2 We're a lot better at treating this today. It's very rare that it causes significant issues. The use of tocilizumab [Actemra] was more prevalent with axi-cel.
Grade 3 ICANS [immune effector cell–associated neurotoxicity syndrome], which is neurotoxicity, probably scares most patients. [It causes] confusion, tremors, and word finding difficulty. It's not like a stroke; it has its own presentation. It's [almost] always reversible. Some patients can get really sick with it, though.
In the axi-cel group [in the ZUMA-7 trial], there was 21% grade 3 ICANS.1 To me, that's severe. That means they are near comatose at some point or they're not speaking very well, so we have to [treat] them with high-dose steroids.
[In the TRANSFORM trial], having severe grade 3 ICANS with liso-cel of only 4% and only having to use steroids in 7% of cases was remarkable.2 There was no grade 5 toxicity; that was critical in the liso-cel group.
Severe infections, hypogammaglobulinemia, and cytopenias are the other main adverse events [AEs] of CAR T-cell therapy. Both [CAR T-cell therapies] had similar rates of infections, hypogammaglobulinemia—which we treat with IVIG [intravenous immunoglobulin] very routinely for patients with [immunoglobulin G (IgG)] levels lower than 400 mg/dL or patients with recurrent URIs [upper respiratory infections]—and cytopenias. These are all reasonably common.
We see cytopenias at day 30, 30% to 50% of the time. By day 90, it'll be down to about 10% of the time. We see these very commonly. Most of my patients [receiving] CAR T are on 5 different antibacterials, antifungals, [etc]. Their immune system recovers after 30 days to 60 days, and we wean them off those.
Do you need IVIG in the majority of patients with LBCL?
No, I wouldn't say that. I think the rate [was] somewhere around 30%. We’ll check an IgG level. If it's severely depleted, we'll consider using it empirically. Often, I just wait and see if they get sick. A lot of my patients never get sick. Some patients get recurrent sinopulmonary infections or URIs, and then I use IVIG. But right now, not everybody gets it. If they're older and frailer and they have low immunoglobulin levels, then I'm going to give it. It seems to work. It helps clear viruses. We often get patients who have COVID-19 for a couple months or respiratory syncytial virus for a while, and it can sometimes help with that.
What data support the use of liso-cel in transplant-ineligible patients?
This is the PILOT trial [NCT03483103] for transplant-ineligible patients. Given how tolerable liso-cel is, they did a phase 2 study of patients who are ineligible for autologous stem cell transplant [ASCT]. They could not go for ASCT either due to age or a variety of comorbidities. The age of 70 doesn't necessarily mean you can't get an ASCT but it's a combination of a couple of these things, I'm probably not going to take somebody to ASCT.
Instead of going the ASCT route, patients received liso-cel in the second line. This is for patients who are transplant ineligible. There were a few patients who were primary refractory, but it also had 25% of patients with relapse after 1 year. These may have been frailer, but you also had some patients that relapsed after 1 year. The median age was 74, 26% had ECOG performance status of 2, and there was median follow-up [of 23.1 months].3
In these patients, the response rates were not quite as high as that liso-cel second line eligible cohort. They were still impressive. The ORR was 80% with a complete response [CR] rate of 54%. They had good durability of responses, particularly in the CR group, with good flattening of the curves at 2 years out.
[In terms of] safety, this was in frailer and older patients. The AEs were similar [to TRANSFORM]. Importantly to me in this study is that there were no treatment-related deaths. There was no nonrelapse mortality. We're treating patients who are [over] 80 years old. They can't get a transplant, but you can give them liso-cel. They have great response rates, great durability responses, and they're not dying from it. When I talk to my patients…I'm usually quoting some small percent chance of mortality. You have to be [honest] with patients. You don't know what's going to happen. But based on these trial data, you would say that it is extremely rare. This was FDA approved for transplant-ineligible patients based on that study.
How was axi-cel investigated in transplant-ineligible patients?
ALYCANTE [NCT04531046] is a phase 2 study of axi-cel in the transplant-ineligible population. Ineligibility was based on physician's assessment [based on] at least one of the following: age greater than 65, which is a bit young to say they're excluded from ASCT; high hematopoietic cell transplantation-specific comorbidity index score greater than 3, which also, to me, doesn't make you transplant ineligible at all; or prior ASCT. They may have had a sicker population, but I don't know about their transplant ineligible [status].
They had good response rates.4 The ORR was 69% by the central review panel, and the CR rate was 66%. The progression-free survival and overall survival curves were [promising]. The main thing that I would point out is that they still had high rates of ICANS and neurotoxicity. Any-grade CRS was 93%; that means 93% of patients are getting a fever and they're going to be admitted to the hospital, and in 8% it was severe. That's going to cause a problem for those patients. For ICANS, there was 50% of any grade, so 50% of patients are getting neurotoxicity. Grade 3 or 4 [ICANS occurred in] 15%. In this transplant-ineligible population, having severe ICANS is dangerous to me, so I would hesitate to use this for that population personally. The nonrelapse mortality was 9.7%.
…The outcomes with the toxicity were rough, but it's good to know, too. Some people make a case saying some people did well with it. I'm probably going to go with liso-cel for that, and that's an easy choice. [Axi-cel] did not necessarily get FDA approval based on this yet.
DISCLOSURES: There were no known relevant disclosures.
