Longitudinal patient-reported outcomes and quality-of-life trajectories over 2 years in CAR-T therapy recipients.

Introduction

Chimeric antigen receptor T-cell (CAR-T) therapies have transformed the treatment of patients with relapsed and refractory lymphoma, myeloma, and certain leukemias, 1 , 2 , 3 leading to improved progression-free survival (PFS) and durable responses, 3 , 4 , 5 , 6 , 7 as well as cure in some patients. 8 , 9 , 10 , 11 Despite these advantages, CAR-T therapies have a substantial impact on health-related quality of life (HRQoL). Short-term hospitalization and monitoring for life-threatening adverse events after CAR-T therapy may be required, affecting both patients and caregivers. 12 , 13 , 14 , 15 In the long term, many CAR-T recipients will have progression or relapse of disease, which can worsens HRQoL. 13 Fatigue, specifically, is a significant contributor to inferior HRQoL for CAR-T recipients, but the long-term impact of CAR-T therapies on fatigue remains unclear. Current understanding of HRQoL outcomes after CAR-T therapy remains limited, with most studies reporting outcomes within the first year after CAR-T. 16 , 17 , 18 Data describing long-term, patient-centered outcomes after CAR-T are vital to counseling patients with hematologic malignancies who may achieve durable post–CAR-T therapy remissions. 19 , 20

Patient-reported outcome (PRO) measures are used to assess HRQoL and the tolerability of anticancer therapies, including CAR-T. 13 PROs are understudied in real-world patients with hematologic malignancies, and only recently have PROs been incorporated regularly into clinical trials and prospective cohort studies 19 , 21 despite their patient-centered value. 21 , 22 , 23 Although ∼75% of clinical trials collect PRO data, most do not publish these results, 19 and the changes in HRQoL experienced by patients receiving CAR-Ts warrant dedicated study. Furthermore, heterogeneity in the types of PRO instruments collected in CAR-T studies complicates their interpretation and translation into clinical practice. 24 , 25 , 26 To address this problem, an American Society for Transplantation and Cellular Therapy expert panel has recommended the use of Patient-Reported Outcomes Measurement Information System (PROMIS) instruments in CAR-T recipients to harmonize HRQoL measurements and facilitate comparative effectiveness studies. 27 Specifically, the PROMIS Profile-29 instrument is recommended because it measures multiple dimensions of HRQoL, including physical function, social role functioning, fatigue, anxiety, depression, pain, and sleep, and can be used to compare HRQoL with that of the general population as well as disease cohorts receiving different anticancer therapies. 24 , 25 Furthermore, PROs are predictive of treatment response and overall survival (OS) in the frontline setting for aggressive lymphomas 22 , 23 and of OS in hematopoietic stem cell transplant recipients, 28 but data regarding the predictive potential of PROs in CAR-T recipients remain limited.

In this prospective study, we model the short- and long-term trajectories of HRQoL at multiple time points over a 2-year period after receipt of CAR-Ts in patients with hematologic malignancies. We used PROMIS instruments to evaluate multiple aspects of HRQoL, which serve as a benchmark for future PRO studies. 24 , 29 Finally, given the significant deleterious effect of fatigue on HRQoL after CAR-T therapy, we have modeled changes in fatigue PRO measures over the acute and long-term phases of CAR-T treatment.

Methods

Patient enrollment and inclusion criteria

All adult patients (aged ≥18 years) planning to receive CAR-T therapies at The University of Chicago were approached to enroll in The University of Chicago Cellular Therapy Biobank, which includes serial administration of PRO instruments before and after CAR-T infusion. We included all patients in The University of Chicago Cellular Therapy Biobank who successfully received infusion with a CAR-T product and completed a minimum of 2 PRO surveys at 2 distinct time points before and after infusion. This study was approved by The University of Chicago Division of Biological Sciences and University of Chicago Medical Center (BSD/UCMC) institutional review board. Supplemental Figure 6 displays a CONSORT diagram describing patients screened and excluded from final analysis. This study was conducted in accordance with the Declaration of Helsinki.

PRO measures and longitudinal assessment time points

The University of Chicago Cellular Therapy Biobank prospectively administers the PROMIS Scale version 1.2 Global Health-10 and PROMIS-29 Profile version 2.1 instruments at the following time points anchored to the day of CAR-T receipt: baseline (before CAR-T infusion at either apheresis and/or lymphodepletion chemotherapy), and on the day of CAR-T infusion, and days 1, 7, 15, 30, 60, 90, 180, 270, 360, 540, and 720 after infusion. The PROMIS-29 Profile is a 29-item assessment of 7 HRQoL domains (physical function, fatigue, anxiety, depression, sleep disturbance, social role function, and pain interference) plus a single-item measure of pain intensity. The PROMIS Scale version 1.2 Global Health-10 is a 10-item assessment of global general health, physical health, mental health, and social activities and roles. 30

PROMIS scores are converted from raw scores into T-scores using a normalized distribution scale with a mean of 50 and standard deviation of 10, compared with the general US population in each subscale. 31 A higher PROMIS T-score indicates more of the concept being measured: for symptom subscales (anxiety, depression, sleep disturbance, pain, and fatigue), a higher score indicates worse symptoms; for functional subscales (global mental health, global physical health, physical function, and social role function), a higher score indicates better function. For this study, minimally important differences between mean subgroups scores were not analyzed for intergroup comparisons.

Clinical outcome assessments

Demographic and clinical data were extracted from the electronic health record and collected at the time of study enrollment. Variables collected included age, sex, race, ethnicity, hematologic malignancy diagnosis, number of lines of previous therapy, disease response, and survival data. For patients with lymphoma, Lugano response criteria were used for response assessments. 32 For patients with multiple myeloma, International Myeloma Working Group standardized response criteria were used for response assessment, 33 with overall response rate defined as partial response (PR) or better. We defined responders to CAR-T therapy as the following disease responses at any time point after CAR-T infusion: complete response (CR) or PR for lymphoma and acute lymphoblastic leukemia; and CR, stringent CR, very good PR, or PR for myeloma. Disease response assessments were conducted at days 30 and 90 after CAR-T infusion. Cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were evaluated using consensus American Society for Transplantation and Cellular Therapy criteria. 34

Statistical analysis and PRO modeling

Patient characteristics were summarized using frequencies, percentages, and medians. Distributions of time to death and time to progression/relapse were summarized using medians and interquartile ranges (IQRs), with individuals who had not experienced an event considered censored at time of last contact. PROMIS scores were grouped into 13 distinct time intervals relative to day 0, defined as the day of infusion: days −7, +0, +1, +7, +15, +30, +60, +90, +180, +270, +360, +540, and +720. For each individual patient, if multiple scores were reported within 1 of these intervals, scores were averaged, excluding baseline. To visualize longitudinal trends, individual PROMIS score trajectories were plotted using cubic smoothing splines (ie, nonlinear smooth functions; k = 3 degrees of freedom), to determine whether the trajectories exhibited approximately linear relationships over time and were suitable for advanced analysis using linearized mixed-effect models. Linear mixed-effects models with a random intercept for each individual patient were used to evaluate changes in PROMIS scores over time. We fit separate models to evaluate the difference in trends over time to compare age (<65 vs ≥65 years), sex, and day +90 disease response status. This was achieved by including an interaction term between time and each covariate. Separate models were fit for time windows extending to days +15, +30, and +720 after CAR-T infusion. Because CRS and ICANS were not significantly associated with treatment response, they were not included as covariates in the models. Patients missing all PROMIS assessments or with <2 time points were excluded. For descriptive plots, missing data categories (eg, previous lines of therapy, responder status) were labeled as “not applicable (NA).” Regression analyses used complete-case analysis, excluding patients with missing covariates. Type I error was controlled by adjusting the P values using the Benjamini-Hochberg (BH) method. BH-adjusted P values correspond to the respective interaction terms for each pair of variables, and a full set of linear mixed-effect model parameters are included in supplemental Table 1 . Statistical tests were 2-sided with a significance level of .05. All analyses were conducted using R version 4.5.1.

Results

Patient characteristics

There were 83 patients treated between January 2021 and January 2025 who met study inclusion criteria from The University of Chicago Cellular Therapy Biobank. Patients had a mean of 5.2 distinct PRO time points included in the study (range, 2-9). Table 1 summarizes the characteristics of the patients included in this study. The median age was 66 years (range, 20-82), 51/83 (61%) were male, 63/83 (76%) were White, 11/83 (13%) were Black, and all patients spoke English as a primary language. Hematologic malignancy diagnoses included 44/83 (53%) lymphoma (mostly aggressive B-cell lymphomas), 36/83 (43%) multiple myeloma, and 3/83 (4%) B-cell acute lymphoblastic leukemia (B-ALL). Nearly the entire cohort (79/83, 95%) received ≥2 previous lines of therapy before CAR-T treatment. Among 44 patients with lymphoma, 18/44 (41%) received axicabtagene ciloleucel (axi-cel), 9/44 (21%) lisocabtagene maraleucel, 7/44 (14%) tisagenlecleucel, 8/44 (18%) brexucabtagene autoleucel, and 5/44 (7%) investigational anti-CD19 autologous CAR-T products. For patients with multiple myeloma, 19/36 (53%) received ciltacabtagene autoleucel, 4/36 (11%) idecabtagene vicleucel, and the remaining 13/36 (36%) received investigational anti–B-cell maturation antigen autologous CAR-T products.

Clinical outcomes

Patients had a median follow-up of 15.1 months (range, 1-48). At day +90, overall response rate was 78% (34/44 patients; CR 24/44, 54%) for lymphoma, 92% (33/36 patients; CR 13/36, 37%) for myeloma, and 67% (2/3 patients; CR 2/3, 67%) for B-ALL. For best response to CAR-Ts, 54/83 (65%) of patients achieved a CR or stringent CR, 14/83 (17%) a PR or very good PR, 3/83 (3%) stable disease, and 12/83 (14%) had progressive disease. The median time from CAR-T therapy to death and/or censoring was 578 days (IQR, 282-925), and the median time from CAR-T therapy to progression was 439 days (IQR, 110-735). Of patients who were responders by day +90 (including those with day +30 early responses), 15/67 (23%) of patients died, compared with 7/16 (42%) of nonresponders by the end of the study period. CRS occurred in 67/83 (81%) of patients, with no patient experiencing grade ≥3 CRS. ICANS was observed in 17/83 (20%) of patients, with 5/83 (6%) experiencing grade 3 ICANS but no grade 4 or 5 events. CRS occurrence was not significantly associated with treatment response status at the day +90 assessment ( P = .52).

Longitudinal HRQoL global trajectories in the entire cohort

In the entire study cohort, physical function, sleep disturbance, and social role functioning trended toward improvement in the 2 years after CAR-T therapy. Longitudinal trajectories for all PROMIS HRQoL domains are displayed in Figure 1 .

Linear mixed-effect models of HRQoL trajectories by age and sex

When stratifying patients by age (age ≤65 vs >65 years), there were no differences in fatigue, physical function, global physical health, or social role function at day +15 after infusion ( supplemental Figure 1 ). By day +30, physical function significantly worsened in patients aged ≥65 years compared with patients aged <65 years (BH-adjusted P = .0496; Figure 2 ; model coefficients in supplemental Table 1 ). At day +720, there were no statistically significant differences in fatigue, global physical health, physical function, and social role function between age cohorts, with improvements in these HRQoL domains seen in patients aged ≤65 years and aged >65 years ( supplemental Figure 1 ).

When comparing men vs women, there were no statistically significant differences in trends of fatigue, global physical health, physical function, or social role function at the day +15 ( Figure 3 ) or day +30 ( supplemental Figure 2 ) time points. Male patients had, at baseline, less fatigue, better global physical health and physical function, and better social role function than women ( Figure 3 ).

However, women had significantly more improvement in fatigue (BH-adjusted P = .0155) and global physical health (BH-adjusted P = .0414; model coefficients in supplemental Table 1 ) at day +720 after CAR-T infusion compared with men ( Figure 4 ). Physical function and social role function scores improved over time for both men and women but were not significantly different ( Figure 4 ).

Differences in patient-reported fatigue and other HRQoL domains across disease and CAR-T subgroups

Over the 2-year post–CAR-T infusion period, patients with aggressive lymphomas had improvements in fatigue scores, whereas patients with myeloma had stable fatigue scores; patients with indolent lymphomas and B-ALL reported improved fatigue scores over the first 200 days, but follow-up was limited within these subgroups ( supplemental Figure 3 A). Similarly, over the 2-year period, global physical health, physical function, and social role function generally improved for patients with aggressive lymphomas beyond the minimally important difference (MID), and were approximately stable for patients with myeloma, with similar short-term improvements for indolent lymphoma and B-ALL over a 200-day period ( supplemental Figure 3 B-D).

Comparison of fatigue between recipients of different CAR-T products over the 2-year period demonstrated unique trajectories for each group at day +720 ( supplemental Figure 4 ). Recipients of lisocabtagene maraleucel and tisagenlecleucel had sustained trends of fatigue improvement over this period, whereas recipients of axi-cel had improved fatigue over the first year with a subsequent increase in fatigue toward the end of the 2-year period.

Differences in HRQoL and fatigue between CAR-T responders and nonresponders

Patients who responded to CAR-T therapy by day +90 had significantly better social role functioning over the 2-year period than nonresponders (BH-adjusted P = .041; model coefficients in supplemental Table 1 ). Responders trended toward improved fatigue over the 2 years, which did not reach statistical significance (BH-adjusted P = .0577). There were no statistically significant differences between trends for global physical health or physical function measured over the 2-year period ( Figure 5 ).

In the early post–CAR-T period, responders had significantly worse fatigue at day +15 as compared with nonresponders (BH-adjusted P = .043; model coefficients in supplemental Table 1 ), without significant differences in global physical health, physical functioning, or social role functioning and with no significant differences in baseline fatigue ( Figure 6 ). By day +30, there were no differences in fatigue between responders vs nonresponders ( P = .954; supplemental Figure 5 ).

Discussion

In this study, the largest cohort of long-term PROMIS PRO data in real-world patients who received CAR-T therapy, we demonstrated clinically meaningful improvements in physical and social role functioning as well as sleep in the 2 years after CAR-T infusion. In addition, we observed that patients had longitudinal improvements in multiple HRQoL domains regardless of age over the 2-year period, and women had greater improvements in fatigue and global physical health than men. Our study suggests that CAR-T therapy confers long-term HRQoL benefit in patients with hematologic malignancies and further identifies patient-reported fatigue as a potential prognostic marker of subsequent CAR-T response at day +90.

Trajectories in the entire study cohort reflect an initial decrease in HRQoL, with increased fatigue, worsened social role functioning, and worsened physical functioning in the early posttreatment phase, consistent with previous observations. 13 Comparison of trajectories for CAR-T responders vs nonresponders by day +90 identified important differences in HRQoL trajectories. Over the 2-year post–CAR-T period, responders had statistically significant improvements in social role functioning compared with nonresponders, most likely due to improved disease control enabling better participation in daily routines with fewer negative HRQoL impacts. There was also a trend toward improved fatigue in responders during the 2-year period ( P = .0577). As noted earlier, at day +15, responders had significantly worsened fatigue scores compared with nonresponders, with no difference in other HRQoL trajectories. By day +30, this difference in fatigue between responders and nonresponders was no longer present. Other HRQoL domains at days 15 and 30 after CAR-T infusion were not affected by the worsened fatigue, which is helpful for counseling patients on expected symptom burden in the post–CAR-T period.

Fatigue temporarily worsens in the acute post–CAR-T phase, particularly among patients who subsequently respond to CAR-Ts by day +90. This suggests that patient-reported fatigue as measured by PROMIS instruments may be a “PRO marker,” a prognostic indicator of disease response similar to some biomarkers in hematologic malignancies. 35 , 36 The potential underlying physiologic mechanism for this finding may be related to inflammatory cytokines and systemic metabolic demand, which are known to increase after CAR-T infusion more in responders compared with nonresponders. 37 , 38 , 39 Our data indicate that fatigue may be the PRO most sensitive to these physiological changes associated with better responses to CAR-T therapies.

In the long term, we observed a trend toward improved fatigue over 2 years in responders compared with nonresponders ( P = .057). This is consistent with previous data from a study of patients with relapsed/refractory lymphoma treated with CAR-T therapy that showed responders had significantly lower fatigue at 1 year after treatment than nonresponders. 40 Previously, a longitudinal cohort study exploring long-term patient-reported fatigue in patients with lymphoma treated in both the first-line and relapsed/refractory setting found that, in the pre–CAR-T era, there was a large proportion of patients who had worsened fatigue even years after completion of treatment. 20 More recently, a European cohort study of patients receiving CAR-T therapy for hematologic malignancies demonstrated that HRQoL including fatigue generally improved over time, including at >1 year after CAR-T treatment. 41 Our study’s findings support the conclusion that CAR-T therapies lead to long-term improvements in HRQoL and fatigue compared with chemoimmunotherapy and/or autologous stem cell transplantation.

Lower baseline patient-reported fatigue may be predictive of OS, underscoring the importance of monitoring PRO trajectories while measuring treatment response and other biomarker-based outcomes. 16 , 17 , 18 Further study of fatigue and other PRO measures as PRO markers is warranted in the relapsed/refractory setting. Previous examination of PROs in the first-line treatment setting found that, for patients with diffuse large B-cell lymphoma treated with chemoimmunotherapy in the GOYA trial, longitudinal PROs were predictive of disease PFS and OS. 22 A separate analysis of longitudinal PROs found that fatigue, specifically, was predictive of OS, and that other PROs were prognostic for progression. 23 The findings of our study suggest that PROs may have similar prognostic utility in the relapsed/refractory disease setting for patients with hematologic malignancies undergoing CAR-T treatment.

Because PRO administration can be performed rapidly and at low cost compared with other testing, PROs may also serve as a useful tool to assist with risk stratification of patients who may warrant shorter-interval or more frequent response assessments after CAR-T infusion. 42 Future prospective studies of early post−CAR-T infusion PROs as prognostic markers could further explore the need for earlier interval imaging or other response assessments. Preliminary work in lung cancer has demonstrated that longitudinal PRO trajectories are accurate predictors of radiographic changes in tumor volume, 43 providing important foundational work for future studies of PRO-markers in hematologic malignancies.

Patient age appeared to play a role in physical function after CAR-T infusion, with patients aged >65 years reporting worsening physical function by day +30. The acute HRQoL burdens of CAR-T treatment are high and affect patients of all ages, often involving significant interruption to work and social routines in addition to physical symptom burden. With longer follow-up, these differences in HRQoL trajectories by age dissipate, which suggests that older patients do eventually recover physical function, albeit with a slower trajectory. In our cohort, 29% of patients aged >65 years died by the end of the study compared with 34% in those aged ≤65 years, suggesting that this recovery is not solely due to large differences in survivorship. The long-term improvements in HRQoL likely reflect the overall net clinical benefit of CAR-T treatment and further demonstrate that these PRO benefits are not limited to younger, healthier patients, with previous data demonstrating curative potential and meaningful benefit of CAR-T therapies in older patients despite comorbidities and potential toxcities. 13 , 44 , 45 , 46 , 47 Our study further supports these previous data indicating that HRQoL and clinical outcomes can improve with CAR-T treatment for older patients.

Stratification of PRO trajectories by sex demonstrated 2 distinct findings. Initially, men and women had no significant differences in PRO trajectories at the day +15 and day +30 time points, suggesting similar changes in HRQoL in the acute post–CAR-T period. However, at baseline, men reported less fatigue, better physical function, and better global physical health than women. These differences may be due to differences in self-reporting, with previous comparative data suggesting women are more likely to report HRQoL changes in PRO questionnaires. 48 At the 2-year time point, women had statistically improved trajectories in fatigue and global physical health compared with men, which appears to overcome the initial differences. Recent publication of 5-year axi-cel follow-up data from the US Lymphoma CAR-T Consortium suggested there may be superior PFS and OS for women after CAR-T, 49 which could mean that improved outcomes lead to improved HRQoL; however, most other clinical trials and real-world studies have not observed any meaningful differences in sex-specific post−CAR-T outcomes. 50 Further study will be needed to examine whether these intergroup sex-specific differences in PROs persist in larger cohorts.

This study has several limitations that warrant further discussion. First, the patient cohort included in the study is derived from a single academic CAR-T biobank, which affects the generalizability of the findings. Furthermore, our sample size prevented further evaluation of subgroup analyses and comparisons, including comparisons between CAR-T products and disease-specific differences for less common diagnoses such as indolent lymphomas and ALL. Given that 95% of patients had received at least 2 previous lines of therapy, we did not capture patients and HRQoL trajectories in patients treated with CAR-T therapy in the second-line setting. In addition, at long-term time points after CAR-T, there may not be significant differences in fatigue trajectories due to underrepresented fatigue scoring from patients in the nonresponder group, because their disease progression may lead to attrition from PRO participation due to severity of illness or death (42% for nonresponders vs 23% for responders). Although the 17 patients who were excluded due to completing <2 PRO assessments had similar baseline characteristics to those of the study population, we cannot fully account for the impact these individuals may have on final responder and survival analyses. Finally, lower PRO completion rates at the final day +720 time point limited statistical power at this specific time point, although remaining follow-up data were not affected.

Conclusions

In summary, we compared longitudinal HRQoL trajectories as measured by PROMIS PROs over a 2-year period after CAR-T therapy. We identified worsened fatigue scores in the short-term after CAR-T infusion as an important predictor of response to therapy, with potential implications for incorporating PROs into standardized post–CAR-T assessments to screen for patients who may warrant shorter-interval response assessment. We also observed better social role functioning for responders to therapy in the long term, faster recovery of physical function for younger patients aged <65 years, and a higher burden of fatigue with poorer physical health and function for female patients. Our findings add to the growing body of evidence supporting the continued expanded study of PROs in CAR-T recipients and support further exploration of fatigue in the acute posttreatment phase as a prognostic marker of disease response in larger cohorts.

Conflict-of-interest disclosure: P.A.R has served as a consultant and/or advisory board member for AbbVie, Bristol Myers Squibb (BMS), CVS Caremark, Genentech/Roche, Genmab, Johnson & Johnson, Kite/Gilead, Lilly, Miltenyi, Novartis, and Pfizer; has received travel support from Adaptive Biotechnologies; and has received institutional research support from AbbVie, AstraZeneca, BMS, Cellectis, Genentech, Kite Pharma, Lilly, and Novartis. P.F.C. has served as a statistical consultant to Academic Impressions Inc. A.M. has served as a consultant and/or advisory board member for BMS, Kite, Genentech, and AbbVie; and has received research funding (paid to the institution) from Incyte and GSK. The remaining authors declare no competing financial interests.

Acknowledgments

Authorship

Contribution: V.J.P., P.A.R., J.K., M.R.B., A.D., K.C., and A.M. contributed to the conception and design of the analysis; M.S., S.H., T.A., J.K., M.R.B., P.A.R., and A.M. provided study materials, enrolled patients in the study, and contributed to the collection and assembly of data; V.J.P., A.D., K.C., and A.M. contributed to the data analysis and interpretation; and all authors contributed to the writing and/or critical revision of the manuscript, approved the final manuscript for publication, and were accountable for all aspects of the work.

Footnotes

P.A.R. and A.M. are joint senior authors.

Data are available from the corresponding author, Ajay Major ( ajay.major@cuanschutz.edu ), on request.

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Figures and Table

References

1. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839–852. doi: 10.1016/S0140-6736(20)31366-0.

2. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531–2544. doi: 10.1056/NEJMoa1707447.

3. Brudno JN, Maus MV, Hinrichs CS. CAR T cells and T-cell therapies for cancer: a translational science review. JAMA. 2024;332(22):1924–1935. doi: 10.1001/jama.2024.19462.

4. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care for second-line relapsed/refractory large B-cell lymphoma: 3-year follow-up from the randomized, phase III TRANSFORM study. J Clin Oncol. 2025;43(24):2671–2678. doi: 10.1200/JCO-25-00399.

5. Neelapu SS, Chavez JC, Sehgal AR, et al. Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5) Blood. 2024;143(6):496–506. doi: 10.1182/blood.2023021243.

6. Landsburg DJ, Frigault MJ, Heim M, et al. Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry. J Immunother Cancer. 2025;13(2) doi: 10.1136/jitc-2024-009890.

7. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335–347. doi: 10.1056/NEJMoa2303379.

8. Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800–1808. doi: 10.1182/blood-2017-03-769620.

9. Neelapu SS, Jacobson CA, Ghobadi A, et al. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023;141(19):2307–2315. doi: 10.1182/blood.2022018893.

10. Westin JR, Oluwole OO, Kersten MJ, et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148–157. doi: 10.1056/NEJMoa2301665.

11. Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(10):1403–1415. doi: 10.1016/S1470-2045(21)00375-2.

12. Elsawy M, Chavez JC, Avivi I, et al. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022;140(21):2248–2260. doi: 10.1182/blood.2022015478.

13. Johnson PC, Dhawale T, Newcomb RA, et al. Longitudinal patient-reported outcomes in patients receiving chimeric antigen receptor T-cell therapy. Blood Adv. 2023;7(14):3541–3550. doi: 10.1182/bloodadvances.2022009117.

14. Puckrin R, Jamani K, Jimenez-Zepeda VH. Long-term survivorship care after CAR-T cell therapy. Eur J Haematol. 2024;112(1):41–50. doi: 10.1111/ejh.14100.

15. Barata A, Dhawale T, Newcomb RA, et al. Quality of life and prognostic awareness in caregivers of patients receiving chimeric antigen receptor T cell therapy. Transplant Cell Ther. 2024;30(4):452.e1–452.e11. doi: 10.1016/j.jtct.2024.01.063.

16. Wang XS, Srour SA, Whisenant M, et al. Patient-reported symptom and functioning status during the first 12 months after chimeric antigen receptor T cell therapy for hematologic malignancies. Transplant Cell Ther. 2021;27(11):930.e1–930.e10. doi: 10.1016/j.jtct.2021.07.007.

17. Efficace F, Bonifazi F, Zinzani PL, et al. Health-related quality of life trajectories of patients with aggressive B-cell lymphomas treated with CAR T-cell therapy: results from a prospective observational study. Blood. 2025;146(suppl 1):6279.

18. Efficace F, Zinzani PL, Bonifazi F, et al. The prognostic value of patient-reported fatigue for survival in patients with aggressive B-cell lymphomas treated with CAR T-cell therapy. Blood. 2025;146(suppl 1):6278.

19. Patel K, Ivanov A, Jocelyn T, Hantel A, Garcia JS, Abel GA. Patient-reported outcomes in phase 3 clinical trials for blood cancers: a systematic review. JAMA Netw Open. 2024;7(6) doi: 10.1001/jamanetworkopen.2024.14425.

20. Oerlemans S, Issa DE, van den Broek EC, et al. Health-related quality of life and persistent symptoms in relation to (R-)CHOP14, (R-)CHOP21, and other therapies among patients with diffuse large B-cell lymphoma: results of the population-based PHAROS-registry. Ann Hematol. 2014;93(10):1705–1715. doi: 10.1007/s00277-014-2099-8.

21. Johnson PC, Bailey A, Ma Q, et al. Real-world evaluation of health-related quality of life in patients with diffuse large B-cell lymphoma based on a multinational survey. Front Oncol. 2024;14 doi: 10.3389/fonc.2024.1402992.

22. Yan JT, Bel C, Trask PC, Lo E. Are changes in patient-reported outcomes prognostic for diffuse large B-Cell lymphoma survival? Results from the GOYA trial. J Patient Rep Outcomes. 2024;8(1):31. doi: 10.1186/s41687-024-00708-w.

23. Huang H, Datye A, Fan M, et al. Patient-reported outcomes provide prognostic information for survival in patients with diffuse large B-cell lymphoma: analysis of 1239 patients from the GOYA study. Cancer Med. 2022;11(17):3312–3322. doi: 10.1002/cam4.4692.

24. Chakraborty R, Sidana S, Shah GL, Scordo M, Hamilton BK, Majhail NS. Patient-reported outcomes with chimeric antigen receptor T cell therapy: challenges and opportunities. Biol Blood Marrow Transplant. 2019;25(5):e155–e162. doi: 10.1016/j.bbmt.2018.11.025.

25. Major A, Dueck AC, Thanarajasingam G. SOHO state of the art updates and next questions | measuring patient-reported outcomes (PROs) and treatment tolerability in patients with hematologic malignancies. Clin Lymphoma Myeloma Leuk. 2025;25(3):142–155. doi: 10.1016/j.clml.2024.07.018.

26. Ghisoni E, Morotti M, Colomer-Lahiguera S, et al. Patient-reported outcomes in adoptive cell-therapy trials: mind the gap. J Immunother Cancer. 2022;10(12) doi: 10.1136/jitc-2022-006082.

27. Banerjee R, Amonoo HL, Barata A, et al. Assessing quality of life and symptoms in transplantation and CAR-T recipients: expert panel recommendations from the Survivorship Special Interest Group of ASTCT. Transplant Cell Ther. 2025;31(10):774–788. doi: 10.1016/j.jtct.2025.06.030.

28. Shaw BE, Flynn KE, He N, et al. Incorporating patient-reported outcome data into a predictive calculator for allogeneic hematopoietic cell transplantation recipients. Cancer. 2024;130(10):1826–1835. doi: 10.1002/cncr.35189.

29. Cook KF, Jensen SE, Schalet BD, et al. PROMIS measures of pain, fatigue, negative affect, physical function, and social function demonstrated clinical validity across a range of chronic conditions. J Clin Epidemiol. 2016;73:89–102. doi: 10.1016/j.jclinepi.2015.08.038.

30. Hays RD, Herman PM, Rodriguez A, Edelen MO. Comparison of patient-reported outcomes measurement information system (PROMIS®)-29 and PROMIS global physical and mental health scores. Qual Life Res. 2024;33(3):735–744. doi: 10.1007/s11136-023-03559-y.

31. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol. 2010;63(11):1179–1194. doi: 10.1016/j.jclinepi.2010.04.011.

32. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–3068. doi: 10.1200/JCO.2013.54.8800.

33. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328–e346. doi: 10.1016/S1470-2045(16)30206-6.

34. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625–638. doi: 10.1016/j.bbmt.2018.12.758.

35. Lossos IS, Morgensztern D. Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(6):995–1007. doi: 10.1200/JCO.2005.02.4786.

36. Papageorgiou SG, Thomopoulos TP, Katagas I, Bouchla A, Pappa V. Prognostic molecular biomarkers in diffuse large B-cell lymphoma in the rituximab era and their therapeutic implications. Ther Adv Hematol. 2021;12 doi: 10.1177/20406207211013987.

37. Fischer JW, Bhattarai N. CAR-T cell therapy: mechanism, management, and mitigation of inflammatory toxicities. Front Immunol. 2021;12 doi: 10.3389/fimmu.2021.693016.

38. Silveira CRF, Corveloni AC, Caruso SR, et al. Cytokines as an important player in the context of CAR-T cell therapy for cancer: their role in tumor immunomodulation, manufacture, and clinical implications. Front Immunol. 2022;13 doi: 10.3389/fimmu.2022.947648.

39. Raj SS, Fei T, Fried S, et al. An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma. Nat Med. 2025;31(4):1183–1194. doi: 10.1038/s41591-025-03532-x.

40. Hoogland AI, Barata A, Li X, et al. Prospective assessment of quality of life and patient-reported toxicities over the first year after chimeric antigen receptor T-cell therapy. Transplant Cell Ther. 2024;30(12):1219.e1–1219.e11. doi: 10.1016/j.jtct.2024.09.013.

41. Pennings ERA, Spanjaart AM, Thielen FW, et al. Patient-reported outcomes in patients with hematologic malignancies treated with CAR T-cell therapy in Europe. Blood Adv. 2025;9(24):6380–6393. doi: 10.1182/bloodadvances.2025017081.

42. Kaufmann TL, Rocque GB. Pathway to precision patient-reported outcomes. J Clin Oncol. 2021;39(34):3770–3772. doi: 10.1200/JCO.21.02163.

43. Bhatt AS, Schabath MB, Hoogland AI, Jim HSL, Brady-Nicholls R. Patient-reported outcomes as interradiographic predictors of response in non–small cell lung cancer. Clin Cancer Res. 2023;29(16):3142–3150. doi: 10.1158/1078-0432.CCR-23-0396.

44. Chihara D, Liao L, Tkacz J, et al. Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma. Blood. 2023;142(12):1047–1055. doi: 10.1182/blood.2023020197.

45. Johnson PC, Neckermann I, Sadrzadeh H, Newcomb R, El-Jawahri AR, Frigault MJ. Clinical outcomes and toxicity in older adults receiving chimeric antigen receptor T cell therapy. Transplant Cell Ther. 2024;30(5):490–499. doi: 10.1016/j.jtct.2024.02.019.

46. Bailén R, Iacoboni G, Delgado J, et al. Anti-CD19 CAR-T cell therapy in elderly patients: multicentric real-world experience from GETH-TC/GELTAMO. Transplant Cell Ther. 2024;30(10):988.e1–988.e11. doi: 10.1016/j.jtct.2024.06.022.

47. Shune L, Frigault MJ, Riedell PA. CAR-T cell therapy in older adults with relapsed/refractory LBCL: benefits and challenges. J Immunother Cancer. 2025;13(6) doi: 10.1136/jitc-2024-009793.

48. Schwarz R, Hinz A. Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population. Eur J Cancer. 2001;37(11):1345–1351. doi: 10.1016/s0959-8049(00)00447-0.

49. Jain MD, Spiegel JY, Nastoupil LJ, et al. Five-year follow-up of standard-of-care axicabtagene ciloleucel for large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J Clin Oncol. 2024;42(30):3581–3592. doi: 10.1200/JCO.23.02786.

50. Bock TJ, Colonne CK, Fiorenza S, Turtle CJ. Outcome correlates of approved CD19-targeted CAR T cells for large B cell lymphoma. Nat Rev Clin Oncol. 2025;22(4):241–261. doi: 10.1038/s41571-025-00992-5.

Associated Data

Supplementary Materials

Supplemental Figures and Table