Recent exposure to chemotherapy drug linked to worse outcomes among CAR-T recipients
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NEW ORLEANS — Patients recently treated with bendamustine had significantly lower response rates to subsequent chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma, data presented at ASH Annual Meeting and Exposition showed.
Results from the retrospective analysis revealed surprisingly shorter survival among patients who received bendamustine in the 9 months prior to cellular therapy apheresis, indicating a possible lymphotoxic effect on CAR T-cell production.
However, researchers did not observe significant differences in safety or durability when comparing those with previous bendamustine exposure vs. bendamustine-naive patients, suggesting that any toxic effect on CAR T cells could be limited.
Background
The final composition of each commercially approved CAR-T product varies based on the fitness of a patient’s lymphocytes, according to Gloria Iacoboni, MD, hematologist at Vall d’Hebron University Hospital in Barcelona, Spain.
Further, previous research suggested a negative impact of bendamustine — a nitrogen mustard-derived alkylating agent — on CAR T-cell production due to potential lymphotoxic effects, she added.
“Consensus documents suggest avoiding use of bendamustine in CAR-T candidates,” Iacoboni said during a presentation. “However, there is scarce data regarding the impact of previous bendamustine exposure on T-cell kinetics and outcomes [of] patients treated with CD19-targeted CAR T cells.”
Methodology
Iacoboni and colleagues conducted a multicenter retrospective study to determine the effects of bendamustine exposure on patients who received commercial CAR T cells for relapsed or refractory large B-cell lymphoma.
The analysis included 370 patients (median age, 62 years; interquartile range [IQR], 52-69; 60% males) who received either axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) — commonly called axi-cel — or tisagenlecleucel (Kymriah, Novartis) at one of seven Europe-based centers between January 2019 and June 2022.
Seventy-four study participants (20%) had previous exposure to bendamustine.
Median time from last bendamustine dose was 6.5 months (IQR, 1.9-19.1), with a median total dose of 1,050 mg (IQR, 277-1,800).
Researchers collected baseline characteristics, response rates and survival outcomes.
They conducted a univariate regression analysis to evaluate associations with previous bendamustine therapy. They also performed an assessment of the time interval from last bendamustine dose to CAR-T apheresis and its impact on treatment outcomes.
Primary study outcomes included best overall response, PFS, OS and CAR T-cell kinetics.
Key findings
Median follow-up from CAR-T infusion was 19.4 months (95% CI, 13.7-30.8).
The investigators reported a 72% overall response rate among patients who did not receive bendamustine prior to CAR-T apheresis compared with 57% among those who did (P = .018). They also noted higher complete response (CR) rates in the bendamustine-naive group (51% vs. 41%).
Multivariate analysis showed prior bendamustine exposure had a significant impact on overall response (OR = 2.13; 95% CI, 1.18-3.85).
Safety results showed no significant differences in cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) based on previous bendamustine exposure. Researchers reported comparable rates of CRS (86% vs. 84%) and ICANS (38% vs. 34%) among bendamustine-naive patients vs. those previously exposed to the agent. Rates of grade 3 or higher CRS and ICANS also appeared comparable.
Researchers reported median OS of 18.6 months for the entire study cohort, 22.54 months (95% CI, 14.82-not reached) for the bendamustine-naive group and 10.12 months (95% CI, 5.55-not reached) for those with prior bendamustine exposure.
Investigators reported median PFS of 4.4 months for the entire study cohort, 3.2 months (95% CI, 1.97-7) for the bendamustine-exposed group and 6.21 months (95% CI, 3.61-11.9) for the bendamustine-naive group.
Iacoboni and colleagues reported significantly higher ORR based on timing of last bendamustine dose, with ORRs of 46% among those exposed in previous 9 months and 71% among those exposed more than 9 months before CAR-T apheresis.
Multivariate analysis showed a significant association between bendamustine exposure in the 9 months before CAR-T apheresis and lower ORR (OR = 2.78; 95% CI, 0.9-9.1).
Researchers also noted significantly lower median PFS among those with bendamustine exposure in the previous 9 months than those who received the drug beyond 9 months from CAR-T apheresis (1.45 months vs. not reached; HR = 2.95; 95% CI, 1.54-5.67).
Timing of bendamustine exposure did not have an effect on CRS or ICANS rates or severity of these treatment-related adverse events.
Clinical implications
The results show patients with large B-cell lymphoma exposed to bendamustine before CAR-T apheresis have lower response rates and shorter treatment durability than those who have not received the drug, Iacoboni said.
Bendamustine given as part of treatment regimen prior to CAR-T can have a negative impact on the T-cell quality and platelet count of the product that is produced after apheresis, she added.
“The impact of bendamustine on CAR T-cell outcomes seems to be time-dependent,” Iacoboni said. “Patients with recent exposures — during the previous 9 months in our study — have worse outcomes after CAR T-cell therapy.”
Perspective
Back to TopDavid L. Porter, MD, and Nasheed Hossain, MD
Can previous chemotherapy exposure impact CAR T-cell fitness and outcomes? Iacoboni and colleagues provide insights on this question. Their analysis suggests that prior bendamustine exposure — within 9 months of T-cell apheresis — results in decreased T-cell yield and health at apheresis and negatively affects response rates.
This study raises issues about therapies used prior to T-cell collection for CAR-T manufacturing. However, certain caveats must be acknowledged and considered when reviewing the study results.
For example, decreased absolute lymphocyte, CD3+ and platelet counts were noted in the bendamustine-exposed cohort and — in turn — CAR T cells showed slower and decreased peak expansion. However, the bendamustine group comprised older patients (median age, 66 years vs. 61 years) with poorer performance status and more lines of prior therapy. These factors may have affected overall T-cell characteristics, the CAR-T product produced and its cell dynamics — including persistence — which were not reported.
Further, the phenotypic analysis of CAR T cells was conducted on a small subgroup of 15 patients. Also, there is no description of the treatment patients received instead of bendamustine. It is possible a decision to use bendamustine instead of other agents may represent selection for sicker, more frail patients. The investigators report a higher portion of the bendamustine-naive patients received axi-cel (57%); given a favorable toxicity profile, many physicians select tisagenlecleucel for older and more frail patients.
Additionally, tisagenlecleucel is thought to have slower expansion, which may have skewed the cell expansion characteristics between the two cohorts. It would be useful to know whether tisagenlecleucel recipients were more likely to receive bendamustine. Product selection based on other characteristics could skew results.
It is also notable that, although the investigators reported an improved response/CR rate with no prior bendamustine, there is no mention on durability of response. The lack of statistically significant differences in median PFS and OS suggests that the initial differences in response rates are transient. Thus, this important study highlights that recent (within 9 months) bendamustine exposure prior to apheresis may negatively affect outcomes, although this needs to be assessed in the context of patient-specific variables that may influence the observations.
Perspective
Back to Top
Fateeha Furqan, MD
Bendamustine is known to cause severe bone marrow depression leading to leukopenia — particularly grade 3 or higher lymphopenia — in 50% to 90% of patients. This multicenter study by Iacoboni and colleagues adds to the available data showing that bendamustine use — especially within 9 months of apheresis — can adversely affect the expansion and composition of CAR T cells. Clinically, this translated into worse ORR and PFS, whereas OS and incidences of CRS and ICANS appeared similar between these groups.
Although the study was controlled for International Prognostic Index score, patient age and type of CAR, the study neither specifies previous lines and types of therapy nor baseline cell counts, all of which could adversely affect CAR T-cell expansion and response rates.
Despite safe use of bendamustine as lymphodepletion therapy, especially in the current era of fludarabine shortage, the cumulative dose and duration is much shorter.
This study further adds to the data that bridging therapy prior to CAR T-cell therapy needs to be optimized, because real-world evidence shows that outcomes for patients requiring bridging chemotherapy remain dismal.
References:
Bharadwaj S, et al. Abstract 4657. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
Ghilardi G, et al. Ann Oncol. 2022;doi:10.1016/j.annonc.2022.05.521.
Pinnix CC, et al. Blood Adv. 2020;doi:10.1182/bloodadvances.2020001837.
Svoboda S, et al. Blood. 2019;doi:10.1182/blood-2019-131482.
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Iacoboni G, et al. Abstract 763. Presented at: ASH Annual Meeting and Exposition; Dec. 10-13, 2022; New Orleans.
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