Article Text
PDF
Abstract
Chimeric antigen receptor (CAR)-T cells targeting CD30 have demonstrated high response rates with durable remissions observed in a subset of patients with relapsed/refractory CD30+ hematologic malignancies, particularly classical Hodgkin lymphoma. This therapy has low rates of toxicity including cytokine release syndrome with no neurotoxicity observed in our phase 2 study. We collected patient-reported outcomes (PROs) on patients treated with CD30 directed CAR-T cells to evaluate the impact of this therapy on their symptom experience. We collected PROs including PROMIS (Patient-Reported Outcomes Measurement Information System) Global Health and Physical Function questionnaires and selected symptom questions from the NCI PRO-CTCAE in patients enrolled on our clinical trial of CD30-directed CAR-T cells at procurement, at time of CAR-T cell infusion, and at various time points post treatment. We compared PROMIS scores and overall symptom burden between pre-procurement, time of infusion, and at 4 weeks post infusion. At least one PRO measurement during the study period was found in 23 out of the 28 enrolled patients. Patient overall symptom burden, global health and mental health, and physical function were at or above baseline levels at 4 weeks post CAR-T cell infusion. In addition, PROMIS scores for patients who participated in the clinical trial were similar to the average healthy population. CD30 CAR-T cell therapy has a favorable toxicity profile with patient physical function and symptom burden recovering to at least their baseline pretreatment health by 1 month post infusion. Trial registration number: NCT02690545.
- Immunotherapy
- Receptors, Chimeric Antigen
- Hematologic Neoplasms
Data availability statement
Data are available upon reasonable request.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
Background
Chimeric antigen receptor (CAR)-T cells have revolutionized the care of patients with hematologic malignancies, including CD19 directed CAR-T cells for B-cell non-Hodgkin lymphomas and acute lymphoblastic leukemia and B-cell maturation antigen directed CAR-T cells for multiple myeloma.1 CD30 is also a promising target for CAR-T cells given its universal expression in classical Hodgkin lymphoma (HL).2 Although HL generally has a favorable prognosis, about 20–25% of patients are refractory to first-line therapy or relapse after an initial response.3 Novel agents such as brentuximab vedotin and programmed cell death protein 1 inhibitors have altered the treatment landscape, but alternative therapies are needed for patients who progress after these treatments.4
We recently published a manuscript that characterized the safety and efficacy of CD30.CAR T cells in 41 heavily pretreated patients with HL (median of 7 lines of prior therapy) treated at two centers. We found an overall response rate of 62% in all evaluable patients. With a median follow-up of 533 days, the 1-year progression-free survival and overall survival were 36% (95% CI, 21% to 51%) and 94% (95% CI, 79% to 99%), respectively. Some patients had more durable remissions including one patient who was in continued complete remission for over 3.5 years at time of publication.5 In addition to demonstrating promising efficacy in this patient population, we also reported low rates of toxicities, which were primarily hematologic; there were no dose limiting toxicities. Compared with other CAR-T cell trials, we saw lower rates of cytokine release syndrome (CRS) (24% for the whole patient cohort) and all instances were grade 1. We did not observe any instances of immune effector cell-associated neurotoxicity syndrome (ICANS).
CAR T-cell therapy is associated with a unique toxicity profile secondary to immune activation following infusion of engineered T cells, in addition to toxicities associated with the administration of lymphodepleting chemotherapy, which can be prolonged in a minority of patients. While we have ample data on the acute toxicities of CAR T-cell therapy, such as CRS and ICANS, we have comparably little information on the patient experience over time and the impact of lymphodepleting chemotherapy on patient’s quality of life.
Patient-reported outcomes (PROs) are defined as any report of a patient’s health status that comes directly from the patient. PROs can impact cancer treatment by improving survival and quality of life, extending the cancer treatment tolerability period, detecting adverse events, increasing physician–patient communication, and improving symptom management. PROs promote patient-centeredness in clinical trials and contribute to the delivery of effective oncology high-quality care. The prognostic value of baseline and follow-up PROs has been highlighted in randomized clinical trials and observational ‘real-world’ cohort studies. However, suboptimal reporting of PROs is common in cancer immunotherapy trials, and increased efforts are needed to maximize the value of these data in cancer immunotherapy development and approval.6–10
As there are no longitudinally validated PRO instruments in the setting of CAR-T cell therapy, universally validated measures like PROMIS (Patient-Reported Outcomes Measurement Information System) are available to capture the patient experience. Although limited studies evaluating PROs for those undergoing CAR-T cell treatments have been reported, most of these studies detail CD19-directed CAR-T cell therapies and, to date, there have been no PRO studies for patients receiving CD30-directed CAR-T cell therapy.11–14 To further characterize the impact of CD30-CAR-T treatments on the patient experience at our center, we collected PROs in subjects enrolled on this clinical trial and report on these results here.
Methods
Study design and patients
Patients with relapsed or refractory CD30+ lymphoma who received at least two prior lines of therapy were enrolled at the University of North Carolina (UNC) between August, 2016, and June, 2020 (see online supplemental file 1 for study protocol). All patients provided written informed consent. Patients underwent procurement and CD30 CAR-T cells were manufactured at the UNC Good Manufacturing Practice-compliant facility (IND14688). Patients received lymphodepleting chemotherapy with either 3 days of bendamustine 90 mg/m2 per day or 3 days of bendamustine 70 mg/m2 per day and fludarabine 30 mg/m2 per day. Patients were treated on two different dose levels as part of dose escalation: 1×108 CAR-T cells/m2 and 2×108 CAR-T cells/m2. The safety and efficacy for the HL cohort have been published.5 Lymphodepletion and CAR-T cell infusion were all done on an outpatient basis for this study. Patients were required to stay locally during the initial 4 weeks post treatment for monitoring of adverse events.
Supplemental material
Data collection
PROs were collected for consenting adult patients on paper prior to cell procurement, at time of CAR-T cell infusion (post lymphodepletion), weekly post treatment for weeks 1 through week 4, at week 6, every 3 months for the first year, and subsequently every 6 months for the following 4 years. Patients were encouraged by study coordinators to complete the PRO assessments in person at their appointments. Measures collected included PROMIS questionnaires corresponding to Global Health (PROMIS GHS SF V.1.0–1.1) and Physical Function (PROMIS Physical Function SF20a) (www.nihpromis.org) as well as selected symptom questions from the NCI PRO-CTCAE (V.1.0). From the PROMIS questionnaires collected, we calculated a PROMIS global physical health, global mental health, and physical function score. PROMIS scores reflect the symptom burden of the respective measure being assessed. Higher scores indicate a greater symptom burden, and in turn, lower individual function. Individual PRO scores from the NCI PRO-CTCAE combine any individual frequency, severity, and/or interference scores for the PRO symptom (final scores range from 0 to 3).15 In addition, we created an overall symptom burden score based on responses to the NCI PRO-CTCAE symptom questions. From these PRO scores, we added the scores for the following nine symptoms to create an overall symptom burden score: appetite, nausea, vomiting, constipation, diarrhea, shortness of breath, pain, insomnia, and depression. This overall symptom burden score ranges from 0 to 27 with a higher score indicating increased symptom burden.
In these analyses, we focused on three time points: pre-procurement, CAR-T cell infusion (post lymphodepletion), and 4 weeks post infusion. If survey results were not available at 4 weeks post infusion, we used week 6 and if week 6 was also not available, we then used week 3 for our analyses.
Statistical analyses
PROMIS measures were standardized to a T-score metric, noting a score of 50 as representative of the general US population mean. Clinically meaningful differences in scores were defined as a 5-point difference between scores (1/2 SD).
For the three PROMIS scores (global physical health, global mental health, and physical function), we created spaghetti plots of the scores over time for each individual and we calculated longitudinal analyses over time. We fit the longitudinal models using linear regression model generalized estimating equation (GEE) analyses. In these longitudinal models, we treated time as a categorical covariate and treated the pre-procurement time point as the ‘reference’ time point. Therefore, the results compare the PROMIS scores for infusion versus pre-procurement and the post infusion versus pre-procurement.
Associations between patient characteristics and the symptom burden and PROMIS score outcomes were evaluated using linear regression models. Associations between patient characteristics and whether subjects had at least one PRO measurement during the three time points were assessed using Fisher’s exact tests and Wilcoxon rank-sum tests for categorical and continuous characteristics, respectively. Correlations between PROMIS scores were evaluated using Pearson correlations.
Notably, these were secondary analyses, utilizing GEE models for the longitudinal data.16 This study was not powered to detect changes over time, thus the results should be primarily considered hypothesis generating. The values reported here can be used to appropriately power future studies evaluating changes over time.
Results
Baseline patient characteristics and missingness
Baseline patient characteristics are summarized in table 1. Of the 28 adult patients enrolled on the CD30-directed CAR-T cell clinical trial at UNC, 82% (n=23) had at least one PRO measurement during the three time points (23/23 pre-procurement, 19/23 at infusion, 16/23 at post infusion) and 75% (n=21) had at least one PROMIS measurement during the three time points (17/21 at pre-procurement, 19/21 at infusion, 18/21 at post infusion). We examined absence of data patterns and associations between absence of data and several baseline characteristics, as shown in table 1. There were no associations between data absence and any of the variables examined in the analyses.
Patient characteristics
Quality of life
Baseline quality of life scores for this cohort were 49.7 (IQR 37.4–54.10) for PROMIS global physical health, 53.0 (IQR 38.8–56.0) for PROMIS global mental health, and 50.0 (IQR 37.7–54.4) for PROMIS physical function.
Subjects with Karnofsky Performance Score (KPS) of 100 had higher baseline quality of life scores compared with those with KPS ≤90, as determined by higher physical health (56.2vs 46.1, p=0.001), higher physical function (55.4 vs 46.8, p=0.009), and a non-significant higher mental health (57.6 vs 51.1, p=0.07).
Compared with white patients, black patients had higher mental health (60.4 vs 52.4, p=0.05) and a non-significant higher physical health (57.0 vs 49.7, p=0.07). Mental health was higher in those who had not been treated with prior checkpoint inhibitor (60.5 vs 50.2, p<0.001) and non-significantly in those diagnosed with limited stage disease at diagnosis compared with advanced stage disease (58.1 v 51.9, p=0.09).
Scores on the three PROMIS measures were all positively correlated with one another.
Over time, physical health scores decreased slightly from pre-procurement to time of CAR-T cell infusion (−2.2, p=0.06), but returned to baseline levels when measured post infusion (figure 1A). Mental health scores were similar from pre-procurement to time of infusion measurements and increased an average of 3.22 points post infusion (p=0.03) (figure 1B). Similarly, physical function scores were similar from pre-procurement to time of infusion measurements and increased an average of 2.61 points post infusion (p=0.004) (figure 1C).
Longitudinal assessment of patient-reported outcomes pre-procurement, on the day of CD30 CAR-T cell infusion, and the post-infusion follow-up visit assessed by (A) PROMIS Global Physician Health Scores, (B) PROMIS Global Mental Health Scores, and (C) PROMIS Physical Function Scores. CAR, Chimeric antigen receptor; PROMIS, Patient-Reported Outcomes Measurement Information System.
Symptom burden
Individual symptoms as well as overall symptom burden were inventoried across pre-procurement, at time of cell infusion (after receipt of lymphodepletion chemotherapy), and at 4-week post-CAR infusion follow-up (figure 2). Individual symptom reports were low at baseline, but there were some higher-grade reports of diarrhea, shortness of breath, pain, insomnia, and sadness (figure 3). The overall symptom burden score was also low at baseline (3.0). Patients who had received prior checkpoint inhibitors had higher overall symptom burden scores at baseline (3.82 vs 1.88, p=0.07).
PRO overall symptom burden, by NCI PRO-CTCAE, of patients who received CD30-directed CAR-T cell product collected at pre-procurement, at time of cell infusion, and at post infusion follow-up. The gray lines are individual patients, and the black line is the median for each time point. CAR, Chimeric antigen receptor; PRO, patient-reported outcome.
Bar charts Indicating individual symptoms at pre-infusion, time of CAR-T cell infusion and post-infusion time points as measured by NCI PRO-CTCAE. CAR, Chimeric antigen receptor.
The overall symptom burden score increased on average from preprocurement to infusion (3.34, p<0.0001) (which was the time point post lymphodepleting chemotherapy but prior to CAR-T cell infusion), and it was significantly lower than baseline reports at post-infusion (1.35, p=0.0002). This general pattern was seen in most of the individual PRO scores collected as well, with appetite, nausea and constipation being the most common symptoms post lymphodepletion at time of CAR-T cell infusion (figure 3).
While there were increases in patient-reported symptoms at the time of cell infusion, these were collected prior to cell infusion and likely represent the sequelae of the conditioning regimen. Patients’ individual symptoms as well as their reported overall symptom burden returned to pre-procurement baseline by the time of their post-CAR infusion follow-up.
Discussion
This analysis of patient-reported experience during receipt of CD30-directed CAR-T cell treatment represents the first PRO evaluation in this treatment population. We confirm the favorable toxicity profile reported in our clinical trial with patients’ overall symptom burden, global health, global mental health, and physical function at or above baseline levels at approximately 4 weeks post lymphodepletion and CAR-T cell infusion. These results support the tolerability of this treatment with patients reporting that their functional status 1 month post therapy being similar to the status prior to treatment. The scores worsened at the time of CAR-T cell infusion, which we speculate is likely secondary to the acute toxicities of lymphodepleting chemotherapy, which patients had received several days prior to CAR-T cell infusion. In addition, other factors that may contribute include possible increase in disease burden or receipt of bridging therapy while CAR-T cells were manufactured as the median time from procurement to infusion was 87 days (range 46–337 days). Changes in PRO measurements over time were compared graphically based on responder status and no differences were noted (online supplemental figures).
Supplemental material
Supplemental material
Interestingly, the PROMIS scores also suggest that this multiply refractory patient population has similar global physical health, mental health, and physical function scores to the population average of 50 despite patients being heavily pretreated. This may be attributed to the, at times, indolent nature of HL, the overall young patient population, as well as some selection bias secondary to a patient population that is robust enough to travel and participate in a clinical trial.
Limitations to this study include small sample size and a relatively high proportion of missing data which precluded the ability to evaluate long-term PROs post treatment. This study was a secondary analysis of a series of under-reported measures and was not powered in anticipation of this specific longitudinal analysis. We did perform missingness analyses and did not find a statistically significant difference in key characteristics between patients who filled out and did not fill out the surveys. However, the sum of the data collected does provide the basis on which to more accurately power future studies with longitudinal assessments. The lack of quality PRO assessments in immunotherapy trials in general, and the absence of regular assessments in cellular immunotherapy trials is a prominent knowledge gap in the field and performing post hoc analysis provide perspective for the field as well as a foundation for our group to more regularly incorporate and plan for PRO measures in future trials.
Taken together, PRO measures highlight the tolerability of CD30-CAR infusion and the return to pre-procurement baseline by the time of post-infusion follow-up, suggesting that receipt of CD30-CAR T cells might not impact the tolerability of subsequent lines of treatment. This is of utmost importance as we identify when patients should consider adoptive cell therapy with CD30-CAR T cells in their treatment course, contrasted against consideration of additional cytotoxic therapy or hematopoietic stem cell transplant. Further research is needed to validate these PROs and to dissect out the impact of pre-CAR T-cell conditioning therapy against the receipt of the CAR T-cells themselves on treatment-related symptoms.
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by UNC Institutional Review Board - 16-0046. Participants gave informed consent to participate in the study before taking part.
Acknowledgments
We thank the clinical research and nursing staff of the University of North Carolina – Chapel Hill as well as the fellows and advance practice providers of the Hematology/Oncology Divisions at the University of North Carolina – Chapel Hill for their care of our patients. Most importantly, we appreciate the patients with cancer who enroll into investigational trials to advance knowledge in this disease.
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @SeroBMT1, @NatalieGroverMD
Contributors NG conceptualized the work. NPT and NG researched data for the article. NPT and NG contributed to writing early drafts of the paper. HH and AMD performed the statistical analysis. NPT, HH, ADM, CC, CB, CD, JKM, GD, AWB, JSS, WAW, BS, and NG made substantial contributions to the discussion of the content of the article and edited the manuscript before submission. All authors revised and approved the final version.
Funding This work was supported by National Heart, Lung, and Blood Institute grant RO1HL114564 (to BS), the University Cancer Research Fund at the Lineberger Comprehensive Cancer Center (to BS and GD), and Lymphoma Research Foundation Career Development Award (to NG) and Stand up to Cancer (7000000853) (to GD).
Competing interests The University of North Carolina (UNC) has a research collaboration with Tessa Therapeutics. Competing interests of authors from UNC (GD, JSS, BS) are managed in accordance with institutional policies. NG has received research funding from Tessa Therapeutics. WAW has received research funding from Genentech and Pfizer, has consulted with Teladoc, has been an advisor for Quantum Health and has advisor equity with Koneska. The remaining authors declare no competing financial interests.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.