‘Wake-up call’: Cancer cachexia causes worse outcomes after CAR-T for lymphoma
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Key takeaways:
- Patients who developed cancer cachexia after CAR-T for lymphoma had poorer survival.
- They also had worse response and higher rates of relapse.
Historically, Jae H. Park, MD, has not paid much attention to his patients’ weight loss.
If an individual receiving treatment for cancer came in and had lost 10% of their body mass, Park likely would have considered it a “surrogate marker” of their disease.
“If it was a 30% drop, yes I would have noticed. That’s a pretty significant drop. “But 10% to 15%? Probably not,” Park, chief of the cellular therapy service and a hematologist/oncologist specializing in leukemia at Memorial Sloan Kettering Cancer Center, told Healio.
Results of a retrospective study have given Park a “wake-up call” to cancer cachexia, however, and he said other oncologists must take notice.
Patients with lymphoma who had cancer cachexia had worse response, OS and EFS following chimeric antigen receptor T-cell therapy than those who did not lose weight.
Cancer cachexia — per Fearon 2011 international consensus criteria — is defined as 5% or more weight loss over 6 months, or at least 2% for patients with a certain BMI or sarcopenia.
“These data should heighten the alert,” Park said.
Background
Multiple factors can be evaluated before CAR-T to determine how a patient may respond, according to study background. These include disease burden, prior treatments, response to bridging therapy, and laboratory measurements such as CAR-HEMATOTOX and InflaMix.
However, disease burden measurements by PET or CT scans require special tools and assessments by radiologists, and may not always be available, Park said.
Additionally, several patients do not get tested for inflammatory serum biomarkers such as C-reactive protein and ferritin prior to treatment. Those are needed for models such as CAR-HEMATOTOX.
Researchers wanted to determine if an “easily obtainable” factor such as weight loss could be a prognostic marker, Park said.
“We always get weight for creatinine clearance and drug dosing calculation and as part of their vital signs,” he added. “If patients report weight loss, we are concerned but we don’t know whether it impacts their response to CAR T cell therapy. This was one of the first studies to look at [that question].”
Methods
Park and colleagues evaluated 259 adults (64% men; 52% aged older than 65 years; 78% white) with lymphoma who received CAR-T between 2017 and 2023 at Memorial Sloan Kettering Cancer Center.
Patients received any of the following: axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences), tisagenlecleucel (Kymriah, Novartis), lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb) or brexucabtagene autoleucel (Tecartus, Kite Pharma/Gilead Sciences).
Patients had their first weight evaluation between 70 and 110 days prior to lymphodepleting chemotherapy (median, 94 days).
The impact of weight loss on OS served as the primary endpoint. The association of weight loss with response to CAR-T, EFS, cumulative incidence of relapse and nonrelapse mortality served as secondary endpoints.
Results
In all, 26% of individuals had greater than a 5% weight loss in the approximate 3-month leadup to lymphodepletion.
After median follow-up of 12.4 months, patients with cancer cachexia had significantly shorter OS than those who did not (10.5 months vs. not reached; P < .0001). They had worse EFS, as well.
Individuals who lost more than 10% of their weight had drastically shorter OS than the rest of the study population (4.1 months vs. 43.8 months; P < .001).
Results showed higher cumulative incidence of relapse with death (P = .02) and a trend toward higher nonrelapse mortality (11% vs. 6.7%) among those with cancer cachexia.
“It was surprising that weight loss was an independent prognostic factor in multivariable analysis, even when adjusted for tumor burden and other markers,” Park said. “They didn’t die of infectious complications. The reason their EFS and OS were low was due to their disease not responding well. It’s directly linked to their oncological outcome.”
Results showed worse rates of complete remission (49% vs. 75%; P <.001) and higher rates of progressive disease (28% vs. 15%; P < .001) among patients with weight loss.
Individuals with weight loss had increased rates of grade 3 or worse immune effector cell-associated neurotoxicity, or ICANS (P = .016) and grade 3 or worse early immune effector cell-associated hematotoxicity (P = .012); however, those differences did not remain statistically significant in multivariable logistic regression models.
Researchers did not observe any differences in cytokine release syndrome or any-grade ICANS among individuals with weight loss.
Patients with cancer cachexia had higher rates of infection during the first 100 days after infusion (63% vs. 45%).
Individuals with weight loss experienced worse cytopenia and increased inflammatory markers at apheresis, lymphodepletion and CAR-T infusion.
Next steps
Park highlighted several areas of future research, starting with an assessment of the type of weight that is being lost.
“Is it muscle mass loss? Is it fat from the adipose tissue? Is that important?” Park said.
Researchers also plan to investigate whether regaining lost weight can improve outcomes for patients, and if there is a mechanistic factor involved.
“Is it more due to the lymphoma cells themselves that led to the additional weight loss for this particular patient?” Park said. “If they were disease driven maybe there are some mechanisms that make [T cells] more ineffective.”
Cancer cachexia’s effect on patients with other malignancies who are treated with CAR-T, such as multiple myeloma, should be examined, too.
The data suggest clinicians should consider post-CAR-T consolidation strategies and additional therapies that could aid patients who have cancer cachexia.
“We should still offer CAR-T to these patients with weight loss because that is the best therapy for them. But maybe we have opportunity before and after treatment to maximize the response and minimize the risk for relapse,” Park said.
Additionally, clinicians should consider having nutrition consultations and exercise programs available for their patients to prevent further weight loss.
“CAR T cells are often given in the referral center,” Park said. “Our data suggests that weight changes should be monitored at the referring institutions. That’s probably the best setting to test future interventions to see if we can further improve outcome of these patients.”
For more information:
Jae H. Park, MD, can be reached at parkj6@mskcc.org.
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