Key Points
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HRQoL worsened 1 month after axi-cel infusion but recovered by 3 months and remained stable or improved by 12 months.
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HRQoL recovery for transplant-ineligible patients from ALYCANTE was similar to or better than for transplant-eligible patients from ZUMA-7.
Visual Abstract
Abstract
The phase 2 ALYCANTE trial aimed to evaluate the investigator-assessed complete metabolic response at 3 months from the axicabtagene ciloleucel (axi-cel) infusion as a primary end point in patients with high-risk relapsed/refractory large B-cell lymphoma who are ineligible for autologous stem cell transplantation (ASCT). This study showed a significant improvement in complete metabolic response rate at 3 months based on historical controls. This study reports the health-related quality of life (HRQoL) results as a secondary end point. HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) cancer-specific questionnaire, the Quality of Life Questionnaire high-grade non-Hodgkin lymphoma 29 (QLQ-NHL-HG29) , and the EuroQol Quality of Life Scale-5 dimensions-5 levels of severity (EQ-5D-5L) generic questionnaire at baseline and 1, 3, 6, and 12 months after axi-cel infusion. Among the 62 patients included, 60 (97%) completed a baseline and at least 1 postbaseline HRQoL assessment. At 1 month infusion, adjusted mean change in HRQoL scores from baseline showed a clinically significant deterioration (greater than the clinical threshold) in physical, role, social functioning, and fatigue. However, all HRQoL dimensions recovered by 3 months after infusion and remained stable or continued to improve by 12 months. In an exploratory analysis, adjusted mean change in HRQoL score from baseline in ALYCANTE was similar to or better than in ASCT-eligible patients who received axi-cel in the phase 3 ZUMA-7 trial. Finally, the global health status and fatigue scores of the ALYCANTE population improved to levels comparable to the general French population of similar age by 3 months after infusion. These findings indicate that axi-cel improves HRQoL regardless of transplant eligibility, supporting its use across a broad patient population. This trial was registered at www.clinicaltrials.gov as #NCT04531046.
Introduction
Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment landscape for patients with aggressive B-cell lymphomas. Axicabtagene ciloleucel (axi-cel) was the first autologous anti-CD19 CAR T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma (LBCL) who have progressed after 2 or more lines of systemic therapy, based on the pivotal phase 1/2 ZUMA-1 trial.1, 2, 3, 4 Subsequent to initial approval, axi-cel was approved for patients who were refractory to or had relapsed within 12 months after first-line chemoimmunotherapy, based on the phase 3 ZUMA-7 trial.4,5 In ZUMA-7, autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory LBCL were randomized to receive axi-cel or standard of care (SOC), which comprised chemoimmunotherapy followed by high-dose chemotherapy-ASCT in patients with a response to the chemoimmunotherapy. Patients in the axi-cel arm had a median event-free survival of 8.3 months (95% confidence interval [CI], 4.5-15.8) and an objective response rate of 83%, both of which were improved compared with those of the patients in the SOC arm. The median overall survival was not reached.5 Following the ZUMA-7 trial, axi-cel became a new SOC therapy option in the second-line setting for patients with LBCL that is refractory or has relapsed within 12 months.6
Building on the findings from the ZUMA-7 trial, the open-label phase 2 ALYCANTE trial (ClinicalTrials.gov identifier: NCT04531046) addressed an unmet need in the relapsed/refractory LBCL treatment landscape by evaluating the efficacy and safety of axi-cel in ASCT-ineligible patients who historically face poor prognoses and were excluded from the ZUMA-7 trial due to its randomized design and the use of ASCT in the SOC arm.7 The trial met its primary end point, with a complete metabolic response (CMR) rate of 71.0% (95% CI, 58.1-81.8) at 3 months after infusion. The investigator-assessed best objective response rate and best CMR were 90.3% and 79.0%, respectively. The median progression-free survival was 11.8 months (95% CI, 8.4 to not available) and the median overall survival was not reached. The results from the ALYCANTE trial support the use of axi-cel as a second-line therapy for patients with relapsed/refractory LBCL who are transplant-ineligible.
Beyond survival, health-related quality of life (HRQoL) is also an important concern, particularly for older patients who often have multiple comorbidities and are at high risk for treatment-related toxicities.8,9 Acute toxicities related to CAR T-cell therapies, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), can occur shortly after infusion and may be serious.7 Comorbidities and toxicities (ie, CRS, ICANS), along with other adverse events such as fatigue, may impair HRQoL in patients receiving intensive LBCL therapies,5,10 ultimately increasing their dependency with regard to daily activities. In the ALYCANTE trial, most patients were older and/or presented comorbidities, with a median age of 70 years (range, 49-81), and 88.7% of patients were aged ≥65 years.7 Understanding HRQoL in these older, frail patients treated with CAR T-cell therapies is imperative due to the potential impact of treatment-related toxicities on their overall well-being.
Although ZUMA-7 demonstrated that axi-cel improves HRQoL in patients who are ASCT eligible,11 comprehensive data on HRQoL outcomes are limited for patients who are ASCT ineligible. In this context, we report the impact of axi-cel therapy on HRQoL outcomes in ASCT-ineligible patients with high-risk relapsed/refractory LBCL from the ALYCANTE trial. For an exploratory analysis, we also compared these outcomes with those of patients who received axi-cel in the ZUMA-7 trial and with the general French population of similar age.
Methods
Study design
The ALYCANTE study was a prospective, single-arm, multicenter, open-label, phase 2 trial conducted in 18 centers in France. Eligible patients were required to be aged at least 18 years with histologically confirmed LBCL that was refractory to or had relapsed within 12 months of first-line chemoimmunotherapy. Patients had to be ineligible for high-dose chemotherapy/ASCT based on the physician’s assessment and with at least 1 of the following criteria: age ≥65 years, hematopoietic cell transplantation–specific comorbidity index score ≥3, and/or prior ASCT. All patients underwent lymphodepletion with cyclophosphamide and fludarabine, followed by axi-cel infusion at a target dose of 2 × 106 CAR T cells per kg. Full details of the ALYCANTE study design have been previously described.7
HRQoL assessments
HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) cancer-specific questionnaire,12 the Quality of Life Questionnaire high-grade non-Hodgkin lymphoma 29 (QLQ-NHL-HG29) module,13 and the EuroQol Quality of Life Scale-5 dimensions-5 levels of severity (EQ-5D-5L) generic questionnaire.14 The questionnaires were self-completed in paper form. Collected data were entered using the electronic data capture system from Ennov version 8.1.
HRQoL assessments were conducted at baseline and at 1, 3, 6, and 12 months after CAR T-cell infusion or until time of relapse or progression.
The QLQ-C30 includes 30 items that assess the global health status, 5 functional scales (physical, role, emotional, cognitive, and social functioning) and 9 symptomatic scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-NHL-HG29 module comprises 29 items that evaluate 5 symptomatic scales (symptom burden, neuropathy, physical condition/fatigue, emotional impact, and worries/fears about health and functioning). Scores vary from 0 (worst) to 100 (best) for global health status and functional scales and from 0 (best) to 100 (worst) for symptomatic scales.
The EQ-5D-5L questionnaire contains 5 items (mobility, autonomy, current activities, pain/discomfort, and anxiety/depression) used to calculate a utility score, and a visual analog scale (VAS) ranging from 0 (worst) to 100 (best) assessing the overall health status. The higher the score, the higher the patient’s health status/QoL.
Statistical analysis
Analyses were conducted on patients who received CAR T cells, with HRQoL scores available at baseline and at the follow-up time point of interest. Quantitative data were described as mean (standard deviation [SD]) and median (range) values or mean values with 95% CI, whereas qualitative data were summarized as absolute and relative frequencies. Completion rates for each questionnaire were reported at baseline and each follow-up time point. Baseline characteristics and HRQoL were described. For post hoc analyses and exploratory purposes, the analysis of missing data profile was conducted when the completion rate to HRQoL questionnaire was <70%. This analysis compared patients who completed HRQoL questionnaires with those who did not in terms of baseline characteristics reflecting patients’ health status (ie, global health status and physical functioning HRQoL scores, performance status, and disease stage) and according to clinical response to CAR T cells at 3 months. Quantitative data were compared using Student t test, whereas qualitative data were compared according to the χ2 or Fisher exact test.
The proportion of patients with deteriorated, stable, or improved HRQoL scores at 3 months compared with baseline were reported for each HRQoL score, using the minimal important difference (MID) to classify patients. Adjusted mean change in HRQoL level using mixed model for repeated measure was described at each follow-up time up to 12 months and compared with baseline with a 95% CI. QLQ-C30 global health status and fatigue scores were compared with data from the general French population of similar age.15 Analyses were also repeated in the subgroup of patients presenting CMR at 3 and 12 months.
Clinically relevant change or MID was defined as a change of at least 10 points in the QLQ-C30 and QLQ-NHL-HG29 questionnaires, 7 points in the EQ-5D-5L VAS, and 0.06 points in the EQ-5D-5L utility score.16,17
For an exploratory analysis, unadjusted comparisons of QLQ-C30 and EQ-5D-5L scores were conducted between the ALYCANTE and ZUMA-7 axi-cel arm at similar time points.7,11 HRQoL in ZUMA-7 was assessed at baseline, day 50, day 100, day 150, month 9, and every 3 months thereafter up to 24 months (from randomization) or time of an event-free survival event, whichever occurred first.11 In ZUMA-7, assessments were based on the time from randomization to axi-cel infusion, with a median duration of 29 days (interquartile range, 27-34). In ALYCANTE, assessments were based on the time from infusion, aligning day 50 after randomization in ZUMA-7 with month 1 after infusion in ALYCANTE and day 100 after randomization with month 3 after infusion. Three prespecified HRQoL dimensions were evaluated in ZUMA-7: QLQ-C30 global health status and physical functioning as well as EQ-5D-5L VAS.
All statistical tests were 2-sided and P values <.05 were considered statistically significant. Analyses were performed using SAS version 9.4 (SAS Institute Inc, Cary, NC) software.
The study protocol was approved by French Ethics Committee Est I (Dijon; number 20.07.08.66206) in accordance with the applicable French laws and regulations, and was conducted in accordance with the Declaration of Helsinki.
Results
Study population
Between 19 March 2021 and 4 May 2022, a total of 62 ASCT-ineligible patients with high-risk relapsed/refractory LBCL were enrolled and treated with a single axi-cel infusion.
Baseline characteristics are summarized in Table 1. The median age was 70 years (range, 49-81), and 47 patients (75.8%) were men. Most patients presented an Eastern Cooperative Oncology Group performance status of 0 to 1 (n = 61 [98.4%]) and an advanced Ann Arbor stage of III to IV disease (n = 46 [74.2%]). Twenty patients (32.3%) had a hematopoietic cell transplantation–specific comorbidity index score of ≥3.
Table 1.
Baseline characteristics of patients who received axi-cel
| Patients who received axi-cel (N = 62) | |
|---|---|
| Median age (range), y | 70 (49-81) |
| Sex, n (%) | |
| Female | 15 (24.2) |
| Male | 47 (75.8) |
| ECOG performance status, n (%) | |
| 0-1 | 61 (98.4) |
| 2 | 1 (1.6) |
| Ann Arbor stage, n (%) | |
| I-II | 16 (25.8) |
| III-IV | 46 (74.2) |
| International prognostic index, n (%) | |
| 0-1 | 7 (11.3) |
| 2 | 20 (32.3) |
| 3 | 23 (37.1) |
| 4 | 12 (19.4) |
| 5 | 0 (0.0) |
| HCT-CI score, n (%) | |
| <3 | 42 (67.7) |
| ≥3 | 20 (32.3) |
| CRS, n (%) | |
| Any | 58 (93.5) |
| Grade 3-4 | 5 (8.1) |
| ICANS, n (%) | |
| Any | 32 (51.6) |
| Grade 3-4 | 9 (14.5) |
| Intensive care unit transfer due to CAR T-cell toxicities, n (%) | 16 (25.8) |
| Best response after axi-cel infusion, n (%) | |
| Objective response | 57 (91.9) |
| Complete response | 51 (82.3) |
| Partial response | 6 (9.7) |
| Stable disease | 1 (1.6) |
| Progressive disease | 4 (6.5) |
| Survival, % | |
| Progression-free survival at 12 months | 48.8 |
| Overall survival at 12 months | 78.3 |
ECOG, Eastern Cooperative Oncology Group; HCT-CI, hematopoietic cell transplantation–specific comorbidity index.
Among the 62 patients who received axi-cel, 60 patients (97%) completed baseline and at least 1 postbaseline HRQoL assessment (supplemental Table 1). Question completion rates remained high from baseline (97%) to month 3 (72%) but decreased over time and was <70% at subsequent time points at month 6 (65%) and month 12 (60%). Baseline HRQoL scores are provided in supplemental Table 2. Among the 60 patients who completed the baseline QLQ-C30 questionnaire, the mean global health status score was 66.67 (SD, 18.73) and the mean physical functioning score was 84.83 (SD, 16.04). Among the 57 patients who completed the baseline EQ-5D-5L questionnaire, the mean VAS score was 63.49 (SD, 18.05).
Due to the low completion rate at months 6 and 12, we compared patients who completed HRQoL questionnaires with those who did not in terms of baseline characteristics and clinical response to CAR T cells at 3 months (supplemental Tables 3 and 4). There was no difference in baseline characteristics between HRQoL completers vs noncompleters at months 6 and 12, except for disease stage, which showed more advanced stage III to IV among noncompleters at month 12 (P = .021). The proportion of patients not achieving a CMR at month 3 was higher among noncompleters than HRQoL completers at month 6 (P < .001) and 12 (P = .002).
Change in HRQoL over time after axi-cel infusion
Longitudinal analyses of adjusted mean changes in HRQoL scores after axi-cel infusion showed an initial clinically significant deterioration in 4 of 22 dimensions at 1 month after infusion, followed by clinically significant improvement or stable states in all 22 dimensions by 3 to 12 months (supplemental Table 5). Results in the subgroup of patients with complete response showed similar results (supplemental Tables 6 and 7).
At 1 month after infusion, 4 QLQ-C30 dimensions showed clinically significant deterioration from baseline, with mean change exceeding the MID. Specifically, patients presented a clinically significant deterioration for physical functioning (adjusted mean change, −14.18; 95% CI, −19.67 to −8.68), role functioning (−21.14; 95% CI, −27.93 to −14.36), social functioning (−16.26; 95% CI, −23.22 to −9.31), and fatigue (19.25; 95% CI, 13.31-25.20). The remaining 18 HRQoL dimensions were stable compared with baseline, with mean change within the MID. Patients presented stable states for global health status (−5.87; 95% CI, −10.29 to −1.46) and EQ-5D-5L VAS (0.35; 95% CI, −3.96 to 4.67) compared with baseline.
At 3 months after infusion, the 4 dimensions that initially deteriorated at 1 month after infusion recovered to baseline levels. In addition, a clinically significant improvement from baseline in EQ-5D-5L VAS scores was observed (12.59; 95% CI, 8.04-17.14). The remaining 21 dimensions were stable compared with baseline, with mean change within the MID. Patients presented stable states for global health status (6.67; 95% CI, 1.91-11.43) and physical functioning (−2.51; 95% CI, −8.34 to 3.32) compared with baseline.
At 12 months after infusion, a clinically significant improvement in HRQoL was observed for 4 of 22 dimensions compared with baseline: constipation (−12.90; 95% CI, −19.95 to −5.86), worries/fears about health and functioning (−11.40; 95% CI, −16.93 to −5.86), VAS (15.41; 95% CI, 10.21-20.61), and utility (0.07; 95% CI, 0.00-0.13). The remaining 18 dimensions remained stable compared with baseline.
Trends in adjusted mean change in scores from baseline for the QLQ-C30 questionnaire are shown in supplemental Figures 1 and 2; QLQ-NHL-HG29, supplemental Figure 3; and EQ-5D-5L, supplemental Figure 4. The steady improvement over time in worries/fears about health and functioning score from the QLQ-NHL-HG29 questionnaire are also illustrated in Figure 1. Patients presented a clinically significant improvement for worries/fears about health and functioning score at 6 months (−10.17; 95% CI, −15.17 to −5.17) and 12 months (−11.40; 95% CI, −16.93 to −5.86) after infusion compared with baseline.
Figure 1.
Adjusted mean change from baseline for worries/fears about health and functioning score from the QLQ-NHL-HG29 questionnaire. Change is considered significant when reaching the MID threshold, represented by the dotted lines. ∗P < .05.
Proportion of patients with deteriorated, stable, or improved scores at 3 months
The proportions of patients with deteriorated, stable, or improved HRQoL scores at 3 months after infusion compared with baseline are illustrated in supplemental Figures 5-7. Regarding the QLQ-C30 questionnaire, the highest proportions of improvement among patients were in fatigue and pain (both 44%), whereas cognitive functioning exhibited the highest proportion of deterioration (38%). Regarding the QLQ-NHL-HG29 questionnaire, physical condition/fatigue showed the highest proportion of improvement (49%), whereas neuropathy had the highest proportion of deterioration (32%). Finally, regarding the EQ-5D-5L questionnaire, VAS improved among 58% of patients and deteriorated among 11% of patients, whereas utility improved among 21% of patients and deteriorated only among 3% of patients.
Comparison of ALYCANTE vs ZUMA-7 axi-cel arm
In the exploratory analyses, baseline HRQoL level was generally comparable between ALYCANTE and ZUMA-7 axi-cel arm, with the exception of EQ-5D-5L scores (Figure 2; supplemental Table 8). The mean VAS was 63.5 (95% CI, 58.7-68.3) in ALYCANTE vs 72.4 (95% CI, 69.5-75.2) in ZUMA-7, with the difference exceeding the 7 points MID in favor of ZUMA-7 patients. In contrast, the mean EQ-5D-5L utility score was 0.87 (95% CI, 0.82-0.92) in ALYCANTE vs 0.80 (95% CI, 0.77-0.84) in ZUMA-7, with the difference exceeding the 0.06 point MID in favor of ALYCANTE.
Figure 2.
Radar charts of ALYCANTE and ZUMA-7 axi-cel arm for QLQ-C30 scores at baseline. Values are expressed in means. Symptomatic scores were reversed to have all scores in the same direction. Scores range from 0 to 100, with a high score indicating a high global health status, high functional level, and low symptomatic level. AP, appetite loss; CF, cognitive functioning; CO, constipation; DI, diarrhea; DY, dyspnea; EF, emotional functioning; FA, fatigue; FI, financial difficulties; GHS, global health status; NV, nausea and vomiting; PA, pain; PF, physical functioning; RF, role functioning; SF, social functioning; SL, insomnia.
For the 3 prespecified dimensions (EORTC QLQ-C30 global health status, EORTC QLQ-C30 physical functioning, and EQ-5D-5L VAS), outcomes over time were similar or better for ALYCANTE compared with those for the ZUMA-7 axi-cel arm (Figure 3). Both trials demonstrated a clinically significant deterioration in physical, role, social functioning, and fatigue at 1 month, with all adjusted mean changes surpassing the 10 points MID (supplemental Figures 8 and 9). In ZUMA-7, appetite loss score also worsened and the adjusted mean change reached the MID. At 12 months, both trials demonstrated clinically significant improvements in adjusted mean change for VAS, reaching the 7 points MID (supplemental Figure 10).
Figure 3.
Change over time in selected health-related quality of life scores for both ALYCANTE and ZUMA-7 axi-cel arm. Adjusted mean change from baseline for (A) global health status, (B) physical functioning QLQ-C30 scores, and the (C) EQ-5D-5L VAS in ALYCANTE and ZUMA-7 axi-cel arm. In the ZUMA-7 axi-cel arm, P values are only calculated for month 3 (day 100) and only for subsequent visits when the previous visit was statistically significant. Change is considered significant when reaching the MID threshold, represented by the dotted lines. ∗P < .05.
Comparison of ALYCANTE vs the general French population
At baseline, mean global health status in ALYCANTE was comparable with that in the general French population (66.67 in ALYCANTE vs 69.8 in patients aged 60-69 years and 67.8 in patients aged >70 years in the general French population; Figure 4). Consistent with the timing of well-described toxicities associated with CAR T-cell therapies, global health status (Figure 4) and fatigue scores (Figure 5) worsened 1 month after infusion before improving and stabilizing by 3 months to a level comparable with the general French population of similar age.
Figure 4.
Mean global health status score over time for ALYCANTE vs the general French population. The general French population mean scores are represented by the black dotted lines for those aged ≥70 years and the gray dotted lines for those aged 60 to 69 years.15
Figure 5.
Mean fatigue score over time for ALYCANTE vs the general French population. The general French population mean scores are represented by the black dotted lines for those aged ≥70 years and the gray dotted lines for those aged 60 to 69 years.15
Discussion
The ALYCANTE trial addressed an unmet need in the LBCL landscape because it was the first trial to evaluate axi-cel as a second-line therapy in ASCT-ineligible patients with high-risk relapsed/refractory LBCL, a population that often faces poor outcomes.7 This HRQoL analysis based on ALYCANTE revealed that despite an initial deterioration in 4 HRQoL dimensions at 1 month after axi-cel infusion (EORTC QLQ-C30 physical, role, social functioning, and fatigue), all HRQoL dimensions recover by 3 months after axi-cel infusion and remain stable or continue to improve by 12 months. In addition, HRQoL improvement was equal or better than that in ASCT-eligible patients from ZUMA-7. Moreover, global health status and fatigue scores improved to levels comparable with those in the general French population of similar age. These findings demonstrate that axi-cel not only extends survival (ie, quantity of life) but also preserves and improves HRQoL with benefits in transplant-ineligible patients, suggesting that this older adult population is not significantly affected by long-term sequelae of CAR T-cell therapy.
An exploratory analysis comparing 60 ASCT-ineligible patients from ALYCANTE with 165 ASCT-eligible patients in ZUMA-7 axi-cel arm revealed similar or better HRQoL scores in ALYCANTE,5,7 suggesting that axi-cel offers HRQoL benefits for relapsed/refractory LBCL irrespective of transplant eligibility, with similar or potentially greater HRQoL improvements in ASCT-ineligible patients. Furthermore, HRQoL improvements and stabilization in ALYCANTE were reported at 3, 6, and 12 months after infusion, and in ZUMA-7, clinically meaningful HRQoL improvements were reported at days 100 and 150 compared with those with SOC,11 highlighting HRQoL benefits over time with axi-cel in both trials. Specifically, in ALYCANTE, patients demonstrated stabilized or improved metrics in all HRQoL dimensions compared with baseline scores 3 to 12 months after infusion and had global health status and fatigue levels comparable with those in the general French population by 3 months. In ZUMA-7, for the prespecified end points of physical functioning, global health status, and VAS, the mean estimated scores for the axi-cel arm recovered and were comparable with or improved relative to baseline levels by day 150.11 Therefore, HRQoL benefit should be expected by ∼3 months in both ASCT-eligible and -ineligible patients.
Baseline characteristics and safety were generally similar between ALYCANTE and ZUMA-7, consistent with largely comparable HRQoL outcomes in our study, although the ALYCANTE population was older with a median age of 70 years (range, 49-81) and 88.7% of patients aged ≥65 years and the ZUMA-7 population had a median age of 58 years (range, 21-80) and only 28% of patients were aged 65 years or older.5,7 In regard to safety, CRS was reported in over 90% of patients in both trials and the rates of ICANS in ALYCANTE was similar to the rate of neurological events in ZUMA-7, with both exceeding 50%. Any differences in baseline HRQoL scores between the 2 trials may have the potential to affect the relative degree of change from baseline (ie, based on more or less room for improvement). However, baseline HRQoL scores in ALYCANTE and ZUMA-7 were comparable across most dimensions despite a higher median age and ASCT-ineligible status in ALYCANTE. A large difference in baseline HRQoL scores was observed in EQ-5D-5L VAS, which were worse in ALYCANTE vs ZUMA-7, and patients in ALYCANTE demonstrated significant improvements in VAS over those in ZUMA-7. However, compliance in the ALYCANTE study decreased over time and was <70% beyond month 6, whereas in ZUMA-7, compliance remained high with still 89.9% of patients in the axi-cel arm who completed questionnaire at month 12. Comparison between patients who completed HRQoL questionnaires and those who did not complete them showed that noncompleters presented lower health status, with more patients not achieving a CMR at month 3. Therefore, the results should be interpreted with caution due to this attrition bias and potentially missing not-at-random data. Additional factors not examined in this analysis may have also affected the HRQoL findings.
The open-label, phase 2 PILOT trial evaluated lisocabtagene maraleucel, another CAR T-cell product, as a second-line therapy in 61 patients with relapsed/refractory LBCL who were not intended for ASCT due to an age of ≥70 years, an Eastern Cooperative Oncology Group performance status of 2, and/or altered lung, heart, renal, or liver function.18 To evaluate HRQoL, the PILOT study used EORTC QLQ-C30, FACT-LymS (Functional Assessment of Cancer Therapy–Lymphoma “Additional Concerns” Subscale, a 15-item assessment with higher scores indicating better HRQoL), and EQ-5D-5L questionnaires.19 The study found that lisocabtagene maraleucel was associated with significant improvements in EORTC QLQ-C30 fatigue, pain, appetite loss, FACT-LymS, and EQ-5D-5L VAS scores, with clinically meaningful improvements in EORTC QLQ-C30 fatigue and FACT-LymS scores. Despite differences in study design, comparable outcomes in ALYCANTE and PILOT support the use of CAR T-cell therapy for enhancing HRQoL in patients not intended for transplant.
Variability in HRQoL questionnaires used in CAR T-cell trials has been highlighted in recent reviews.20,21 This heterogeneity makes it difficult to compare results across trials. Therefore, it is important to use tools adapted to capture specific symptoms of CAR T cells, which should also be adapted to the control arm. Recently, the Survivorship Special Interest Group of American Society for Transplantation and Cellular Therapy recommended using the Patient-Reported Outcomes Measurement Information System instruments in complement to Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events.22 Standardization of HRQoL questionnaires in future CAR T-cell trials would be useful to improve the comparison between trials.
Notably, our analysis of the ALYCANTE study has limitations, mostly associated with the single-arm, open-label design of ALYCANTE and lack of a randomized control group. In addition, indirect cross-trial comparisons are exploratory and are limited due to differences in study design, eligibility criteria, reporting practices, data interpretation, and patient populations.7,23,24 In addition, trials conducted at later times may reflect evolving treatment practices. Pertinent to this analysis, ALYCANTE and ZUMA-7 had different HRQoL assessment schedules. Furthermore, this study had a modest sample size of 62 patients and questionnaire completion rates declined over time, introducing potential attrition bias from potential differences between patients still in the study compared with those who dropped out for reasons that may be negatively associated with HRQoL (eg, disease progression).25 ALYCANTE is ongoing with a planned minimum follow-up of 3 years. In this analysis, there was a relatively short follow-up duration of 12 months, although HRQoL appeared to plateau beyond 3 months after infusion. Finally, although severe neurological events in patients with relapsed/refractory LBCL receiving axi-cel are rare, reversible, and typically resolve, CAR T-cell therapy may lead to long-term cognitive impairments and there is a need for HRQoL scales that are designed to assess CAR T-cell therapy–specific events and general long-term neurocognitive dysfunction.
Overall, the findings of this analysis highlight the consistent and meaningful impact of axi-cel on HRQoL irrespective of transplant eligibility. Patients experienced an initial HRQoL deterioration, followed by recovery to baseline or improvement, with global health status and fatigue scores reaching levels comparable with those in the general French population by 3 months. Confirmation of these results in other countries should be performed to allow generalization of these results. These results further support the use of axi-cel as a second-line therapy for ASCT-ineligible patients with relapsed/refractory LBCL, expanding the applicability of CAR T-cell therapies across a broader patient population.
Conflict-of-interest disclosure: E.C. reports travel reimbursement from Kite/Gilead. A.A. reports consulting fees from Amgen, Astellas, Janssen, and Kite/Gilead. E.B. reports honoraria from AbbVie, AstraZeneca, Janssen, Kite/Gilead, Novartis, Roche, and Takeda; research funding from Amgen and BMS; membership on scientific advisory boards of AbbVie, Antibody Drug Conjugates (ADC) Therapeutics, BeiGene, Incyte, Kite/Gilead, Novartis, and Roche; and travel reimbursement from Kite/Gilead, Novartis, and Roche. G.C. reports consulting fees from AbbVie, BeiGene, Celgene–BMS, Miltenyi, and Roche; honoraria from AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Sanofi, and Takeda; and membership on scientific advisory boards of Emercell, Mabqi, MedXCell, and Onward Therapeutics. F.-X.G. reports consulting fees from BMS, Gilead, Miltenyi, and Novartis; and travel and accommodation expenses from Gilead and Novartis. F.M. reports consulting fees from AbbVie, BMS, Genmab, Gilead, Novartis, and Roche; and honoraria for advisory boards from Gilead, Miltenyi, and Roche. L.O. reports consulting fees from Roche; honoraria from BMS, Incyte, and Kite/Gilead; and travel and accommodation expenses from AstraZeneca and Roche. T.G. reports consulting fees from Kite/Gilead and Takeda; honoraria from Kite/Gilead; and travel and accommodation expenses from Kite/Gilead, Roche, and Takeda. P.F. reports consulting fees from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen; honoraria from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen; and travel and accommodation expenses from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen. R.D. reports honoraria from Novartis and Takeda; nonfinancial support from Kite/Gilead; and research funding from Arthur Sachs, Dyskinésie Ciliaire Primitive Assistance Publique Hôpitaux de Paris (DCP AP-HP), Ligue Contre Le Cancer, Monahan Foundation, Philippe Foundation, and Servier Foundation. C.T. reports honoraria for advisory boards from AbbVie, AstraZeneca, BeiGene, BMS, Kite/Gilead, Novartis, Roche, and Takeda; institutional research funding from Kite/Gilead and Roche; and travel and accommodation expenses from AbbVie, BMS, Kite/Gilead, Novartis, Roche, and Takeda. F.J. reports honoraria from BMS, Gilead, Janssen, and Roche; honoraria for advisory boards from Roche; and travel and accommodation expenses from Gilead and Roche. S.C. reports consulting fees from AbbVie, AstraZeneca, Atara, Kite/Gilead, Novartis, Pierre Fabre, and Takeda; honoraria for advisory boards from AbbVie, Kite/Gilead, Novartis, Takeda, and Viatris; institutional funding from Janssen; and travel and accommodation expenses from AbbVie, Novartis, and Pierre Fabre. O.C. reports honoraria from AbbVie, ADC Therapeutics, BMS, Kite/Gilead, Merck, Roche, and Takeda; and research funding from Kite/Gilead, Roche, and Takeda. G.B. reports honoraria for advisory boards from BMS, Incyte, Kite/Gilead, and Novartis; and travel and accommodation expenses from BMS, Incyte, Kite/Gilead, and Novartis. M.C. reports honoraria from Amgen and CSL Behring; institutional research funding from AP-HP, Consortium de Recherche Contre le Lymphome, Fondation ARC pour la Recherche sur le Cancer, INSERM, and Institut National du Cancer; research funding from Innate Pharma and Servier; and travel and accommodation expenses from CSL Behring, Gilead, Grifols, and Pfizer. F.L.G. reports honoraria from Rennes University Hospital. E.I. reports honoraria from Janssen-Cilag and Pfizer. R.H. reports honoraria from AbbVie, Amgen, Celgene–BMS, Incyte, Janssen, Kite/Gilead, Merck Sharp & Dohme, Novartis, Roche, and Takeda; and is a member on the board of directors or advisory committees of AbbVie, Celgene–BMS, Kite/Gilead, Novartis, Roche, and Tessa Therapeutics. The remaining authors declare no competing financial interests.
Acknowledgments
The authors thank the patients who participated in this trial and their families, caregivers, and friends, along with the trial investigators, coordinators, and health care staff at each study site. Medical writing support was provided by Flora Gao of Avalere Health, and funded by Kite, a Gilead company. Kite also conducted a courtesy review of the manuscript draft.
This study was sponsored by The Lymphoma Academic Research Organisation.
Authorship
Contribution: F.L. and R.H. conceived and designed the study; E.C., A.A., C.P., F.L., and R.H. performed the data analysis and interpretation; E.B., G.C., F.-X.G., F.M., L.O., T.G., P.F., R.D., C.T., M.J., F.J., S.C., O.C., G.B., M.C., J.-O.B., F.L.G., E.I., X.P.-N., P.B.-D., Y.A.T., C.B., C.L., F.L., and R.H. provided the study materials or patients; E.C., A.A., F.L., and R.H. prepared the manuscript draft; and all authors reviewed and provided final approval of the manuscript.
Footnotes
F.L. and R.H. contributed equally to this study.
Data sharing is limited by national and European regulations. Participants did not consent to share their personal data.
The full-text version of this article contains a data supplement.
Supplementary Material
References
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