Abstract
Background:
Chimeric antigen receptor (CAR) T-cell therapy is becoming increasingly used for the treatment of patients with advanced hematological malignancies. However, the symptoms related to the standard of care CAR T-cell therapy during the first year after treatment have not been assessed using patient-reported outcome (PRO) measurements.
Objective:
This study aimed to quantify patient’s perspectives of symptom burden and functional status using PROs during the first year following CAR-T-cell therapy for hematological malignancies, especially in patients who experienced grade 2–4 toxicities.
Study Design:
Sixty patients were enrolled any time during their first 12-month following therapy in this observational, cross-sectional study. All received CAR T-cell therapy as a standard of care at MD Anderson Cancer Center in 2019. PROs were measured by the MD Anderson Symptom Inventory (MDASI), the PROs Measurement Information System® 29 (PROMIS-29), the global health tool EQ5D-5L, and the single item health-related quality of life scale (HRQoL). Twenty-two additional symptoms related to CAR T-cell therapy, as identified by an expert panel, were also evaluated. CAR T-cell therapy-related toxicities were rated according to the ASTCT consensus grading criteria.
Results:
The majority of patients (52/60, 87%) received axicabtane cilocleucel (Yescarta). One-third of the patients developed grade 2–4 cytokine release syndrome or neurotoxicity. The first 90 days following infusion represented the most symptomatic period, in which more than 10% of patients rated 18 symptoms as severe (MDASI symptom score of 7–10 on a 0–10 scale) that indicated needs for effective symptom management. PROs reported with MDASI and PROMIS-29 indicated that significantly more severe symptom burden and impaired physical functioning compared to the first 90 days following infusion (all p<0.05 with Hochberg step up procedure), while the EQ5D-5L and single item HRQoL did not detect such differences. Compared to patients who had mild cytokine release syndrome or neurotoxicity (grade 0–1), patients who developed grade 2–4 toxicities persistently reported multiple severe symptoms after 30 days following therapy (all p<0.05). Furthermore, although utilizing a different recall period, patient-reported scores on several PROMIS-29 domains were significantly correlated with the scores of corresponding MDASI symptom items.
Conclusion:
This real-world quantitative PRO symptoms study provides evidence of unique profiles of physical, psychological, and cognitive symptoms burden in patients undergoing CAR T-cell therapy that vary within the first year following infusion and demonstrates differences between PRO measurement scales. These results support the need for validation of fit-for-purpose PRO measurements for routinely monitoring symptom and toxicity burdens in CAR T-cell therapy patient care settings.
Introduction
Effective care for cancer patients receiving standard of care therapy includes a comprehensive assessment and management of symptom burden. The proper evaluation of symptoms is particularly important when using therapies that have unique toxicities. Chimeric antigen receptor (CAR) T-cell therapy has become a standard-of-care option for increasing cohorts of patients with advanced B-cell lymphoid malignancies who have failed multiple lines of therapy1–3 and it is anticipated that the FDA will approve CAR T-cell therapy products for other diseases in the near future. Despite promising response rates and durable remission, CAR T-cell therapy is associated with potentially serious toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS)1, 2. These toxicities arise following CAR T-cell activation, which has downstream effects leading to an overproduction of cytokines by multiple immune cell types and results in a severe systemic inflammatory response3. ICANS and CRS typically manifest within 30 days following infusion and can progress rapidly. Earlier onset of CRS is correlated with increased severity of neurotoxicity and lower grade toxicities (grades 0–2) frequently progress to higher grades (grades 3–4)4–7. While there is growing evidence regarding the optimal management of CAR T-cell toxicities, the prospective evaluation of risk-adapted strategies to predict and reduce toxicities while maintaining treatment efficacy is a research priority1, 8, 9.
While all clinical trials report clinician-rated adverse events, such as CRS and ICANS, the symptoms related to CAR T-cell therapy and the impact of those symptoms on physical, mental, and cognitive functioning, as well as health-related quality of life (HRQoL), have not been well defined10. Furthermore, no prospective clinical studies have examined the patient perspective of symptom burden relevant to acute and late toxicities after CAR-T cell infusion and current clinical guidelines do not include methods for patient-reported symptom measurement. Efforts to detect symptom development and prevent and reduce symptom burden will have important practical implications for patients receiving CAR T-cells as a standard of care therapy11. We postulated that describing patient-reported outcomes (PROs) would be useful in establishing the symptom experience of patients over time following CAR T-cell therapy. Such quantitative study would address a clear gap in our understanding of symptom burden related to this treatment and would allow for enhanced management of potentially serious toxicities, resulting in overall improvement of patient-centered care for this practice-changing therapy.
It is important to use validated PRO tools with established measures for the interpretation of PROs. However, the use of universal PRO measures may not provide clinically meaningful information in special clinical settings, such as in CAR T-cell therapy in which patients may experience a unique set of symptoms and toxicities following therapy. Our previous clinical research established the MD Anderson Symptom Inventory (MDASI)12, a measure of the symptom burden of patients with cancer. This tool has been extensively validated for reporting PROs among patients with hematological malignancies during chemotherapy or hematopoietic stem cell transplant, making it a valuable tool for the patient population we examined12–15.
In this cross-sectional observational study, we aimed to define real-world profile of the clinically meaningful symptom burdens up to 12 months following infusion among patients receiving CAR T-cell therapy to support the further development of fit-for-purpose PRO measurement tools. We administrated different PRO tools in this one-time survey, including MDASI, Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29), the global health tool EQ5D, as well as the single item HRQoL scale. At the same time, we also administered a set of unique CAR T-cell therapy-related-symptom items that were identified from the MDASI-item library by an expert panel of clinicians who manage CAR T-cell therapy patients. We expected that PROs would describe symptom burden and functional impairments after CAR T-cell therapy infusion.
Methods
Sample
Patients who received CAR T-cell therapy in 2019 as standard care for a hematological malignancy diagnosis have participated in this cross-sectional observational study at The University of Texas MD Anderson Cancer Center (MDACC). Eligibility criteria included receipt of CAR T-cell therapy within 12 months of entering the study, 18 years of age or older, fluency in English, and having a diagnosis of a hematological malignancy. Screening eligible patients occurred post CAR T-cell therapy infusion. The study was approved by the MDACC Institutional Review Board and all participants provided written informed consent. Demographic, disease, and treatment data were collected for all participants from their medical records. CRS and ICANS were rated by the patients’ treating clinicians based on the ASTCT consensus grading criteria16.
PRO measurements and data collection
Patients were approached at any time within the first 12 months following CAR T-cell therapy, either in person or via phone. Upon signing the electronic informed consent, patients completed the PROs, either receiving the REDCap link online or in-person using a study iPad, to rate their symptoms, functioning, and health status.
MDASI:
The core MDASI items12 have been validated for use in multiple cancer diagnoses and include physical symptoms (fatigue, pain, nausea, vomiting, lack of appetite, numbness/tingling, dry mouth, shortness of breath), psychological symptoms (distress, sadness) and a cognitive symptom (difficulty remembering). The MDASI also measures 6 symptom-related interference items for physical functioning (work, general activity walking), and psychological functioning (relations, enjoyment of life, mood). The recall of all items is over the past 24 hours. The MDASI is sensitive to capture symptomatic changes after aggressive cancer therapies, including the symptom burden before, during, and after treatment. All items are measured on a 0–10 scale. The MDASI is structured to allow for additional patient-generated symptom items that could be added to create MDASI modules for specific cancers and treatments. This study was an initial step in development of a CAR T-cell therapy specific module.
PROMIS-29:
The PROMIS-29 presents 7 common domains of symptoms and functioning, including 2 subdomains related to pain, in a computer-adaptive framework for increased precision17. The PROMIS-29 has been used to measure HRQoL and health outcomes in the acute setting and in clinical trials18–21, with a recall time of 7 days for all items.
EQ5D-5L:
This test was used to assess health status22 and consists of the descriptive EQ-5D system, as well as the EQ visual analog scale (EQ-VAS), which measures the patient’s self-rated health on a vertical visual analog scale. The 5-level EQ-5D version (EQ-5D-5L) contains five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems.
Single item HRQoL:
The use of a single item “How would you describe your overall quality of life in the past 7 days?” was used to measure HRQoL in a simple, valid, and reliable measure23. The measure asks patients to describe their overall QoL and various aspects of well-being during the past week on a 0–10 scale with 0 being “as bad as it can be” and 10 being “as good as it can be.”
CAR T-cell therapy-specific symptoms:
Additional 22 symptom items were selected from the validated items of the MDASI-item library, which are cognitively debriefed items that were developed for other disease and treatment-specific MDASI modules24. The selection of the CAR T-cell-related items was based on clinician expertise and the published literature related to CAR T-cell therapy8, 9, 25–31. We added these items to the core MDASI symptoms, to form the provisional MDASI CAR T-cell therapy module for the purpose of this study. These additional symptom items included lack of energy, feeling of malaise (not feeling well), bone aches, coughing, changes in sexual function, inability to eat, irritability, muscle soreness or cramping, problems with paying attention (concentrating), headache, balance or falling, fever or chills, dizziness, problems with racing heartbeat or palpitation, swelling of the hands, legs, feet, abdomen, or around the eyes, tremors, difficulty swallowing, mouth/throat sores, and rash. Our qualitative work from a subset of this study sample of patients undergoing CAR T-cell therapy (n=21/60) confirmed the content validity of these 22 items32.
Statistical analysis
Descriptive statistics were used to describe symptoms burden of 3 patient subgroups who were surveyed one time at distinct time points following CAR T-cell therapy infusion. T-tests and Cohen’s effect sizes were used to determine differences between groups and to estimate the magnitude of the therapy-related toxicities. Wilcoxon Rank Sum tests were used if the normal distribution assumption was not met. The 95% confidence intervals were calculated around effect sizes. To account for multiplicity, the Hochberg step up procedures were used33 The Spearman correlation coefficient was also used to assess the association between core PRO items on MDASI and domains of PROMIS-29.
Results
Sample
Table 1 presents the total sample patients’ characteristics (N=60). The majority of patients (N=52, 86.7%) received axicabtagene ciloleucel (Yescarta) and the others (N=8, 13.3%) received Kymriah. Except for 2 cases with acute leukemia who received Kymriah, all were diagnosed with B-cell lymphoid malignancies. All patients were either in the refractory (36.7%) or relapsed status (63.3%) of disease, while 30% of all patients had poor ECOG performance status (grade 2–4) at the time of completing the PROs. Acute toxicities of CRS and ICANS were observed in 90% of patients in the first two weeks following CAR T-cell therapy infusion. The distribution of maximum toxicity scores per patient was: no toxicities (10% on CRS, 51.7% on ICANS), grade 1 (56.7% on CRS; 16.7% on ICANS), grade 2 (30% on CRS; 11.7% on ICANS), and grade 3–4 (3.3% on CRS; 20% on ICANS).
Table 1.
Demographic and clinical characteristics of study cohort (N=60)
| Cohort description | ALL (N=60) | |
|---|---|---|
| Mean (sd) | Median (min, max) | |
| Age, years | 56.4 (14.9) | 58.9 (18.7, 78.6) |
| Cohort description | ALL (N=60) | |
| N | % | |
| Sex | ||
| Female | 14 | 23.33 |
| Male | 46 | 76.67 |
| Ethnicity | ||
| Hispanic or Latino | 15 | 25 |
| Not Hispanic or Latino | 45 | 75 |
| Race | ||
| White or Caucasian | 49 | 81.67 |
| Other | 11 | 18.33 |
| Select only the highest grade completed: | ||
| High school and under | 37 | 61.67 |
| some college and higher | 23 | 38.33 |
| *CCI Total scored: | ||
| 0 | 10 | 16.67 |
| 1+ | 50 | 83.33 |
| *Patient’s ECOG Performance Status (Grade 0–5) | ||
| Missing | 1 | 1.67 |
| 0–1 (Good) | 41 | 68.33 |
| 2–4 (Poor) | 18 | 30 |
| Diagnosis | ||
| Leukemia (acute) | 3 | 5 |
| Large B cell Lymphoma | 57 | 95 |
| Reason for CAR-T | ||
| Refractory disease | 22 | 36.67 |
| Relapse | 38 | 63.33 |
| Radiotherapy (within 3m before CAR-T) | ||
| Yes | 11 | 18.33 |
| Chemotherapy (within 3m before CAR-T) | ||
| Yes | 37 | 61.67 |
| Immunotherapy (within 3m before CAR-T) | ||
| Yes | 17 | 28.33 |
| Transplants (within 3m before CAR-T) | ||
| Yes (once) | 2 | 3.33 |
| CAR-T therapy product | ||
| Axicabtagene ciloleucel (Yescarta) | 52 | 86.67 |
| Tisagenlecleucel (Kymriah) | 8 | 13.33 |
| Acute toxicities in the first two weeks after the CAR-T infusion | ||
| No | 6 | 10 |
| Yes | 54 | 90 |
| CRS Grade Max | ||
| No CRS | 6 | 10 |
| CRS Grade 1 | 34 | 56.67 |
| CRS Grade 2 | 18 | 30 |
| CRS Grade 3 | 1 | 1.67 |
| CRS Grade 4 | 1 | 1.67 |
| ICANS Grade Max | ||
| No Neurotoxicity | 31 | 51.67 |
| Grade 1 (7–9 ICE Scored) | 10 | 16.67 |
| Grade 2 (3–6 ICE Scored) | 7 | 11.67 |
| Grade 3 (0–2 ICE Scored) | 9 | 15 |
| Grade 4 (0 ICE scored due to patient being unable to perform ICE assessment) | 3 | 5 |
Profiles of symptom burden and functioning status after CAR T-cell therapy
Table 2 presents the mean severity scores of the symptom and interference items on the MDASI+, along with the mean scores of the 7 domains on PROMIS-29, EQ5D-5L, and single item HRQoL for patients who completed PROs within 30 days after therapy (N=28, 46.7%), patients who completed PROs 30 to 90 days post-infusion (N=13, 21.7%), and those who completed PROSs after 90 days and up to one year post-therapy (N=19, 31.7%). For patients who were surveyed within 30 days of cell infusion, the mean and median days from CAR T-cell infusion to the survey administration were 14.8 and 15 days, respectively. While mean and median days from CAR T-cell infusion to the survey administration were 48.1 and 45 days for patients who were surveyed within 30–90 days; and 213 and 198 days for those who were surveyed within 3–12 months of cell infusion.
Table 2.
Symptom profiles by period post CAR T-cell therapy within the first year
| <=30 days | 30–90 days | >90 days | P-value <30 vs. >90 | P -value 30–90 vs. >90 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | Mean (SD) | Median (min, max) | % Severe (≥7)# | N | Mean (SD) | Median (min, max) | % Severe (≥7)# | N | Mean (SD) | Median (min, max) | % Severe (≥7)# | |||
| MDASI-Core (0–10 scale) | ||||||||||||||
| Pain | 28 | 2.89 (3.13) | 2 (0, 10) | 21.4 | 13 | 2.54 (3.38) | 0 (0, 9) | 15.4 | 19 | 0.95 (2.04) | 0 (0, 7) | 5.3 | 0.0114 ǂ | 0.1888 |
| Fatigue | 28 | 4.79 (2.73) | 5 (0, 10) | 32.1 | 13 | 5.31 (2.5) | 6 (0, 8) | 38.5 | 19 | 2.21 (2.25) | 2 (0, 7) | 5.3 | 0.0021 ǂ | 0.0025 ǂ |
| Nausea | 28 | 1.21 (2.27) | 0 (0, 8) | 7.1 | 13 | 1.46 (1.94) | 0 (0, 5) | 0.0 | 19 | 0.58 (1.61) | 0 (0, 6) | 0.0 | 0.1565 | 0.0858 |
| Sleep | 28 | 2.29 (2.97) | 1 (0, 10) | 14.3 | 13 | 3.31 (3.07) | 3 (0, 8) | 15.4 | 19 | 2.11 (2.73) | 1 (0, 8) | 10.5 | 0.9728 | 0.2857 |
| Distress | 28 | 1.57 (2.43) | 0 (0, 8) | 3.6 | 13 | 2.46 (2.73) | 1 (0, 7) | 7.7 | 19 | 0.95 (1.54) | 0 (0, 5) | 0.0 | 0.4418 | 0.0921 |
| Shortness of breath | 28 | 0.93 (1.94) | 0 (0, 8) | 3.6 | 13 | 1.15 (2.03) | 0 (0, 7) | 7.7 | 19 | 1.63 (2.09) | 0 (0, 7) | 5.3 | 0.1884 | 0.4704 |
| Remember | 28 | 1.46 (2.3) | 0 (0, 8) | 3.6 | 13 | 1.54 (1.9) | 1 (0, 5) | 0.0 | 19 | 1.11 (1.56) | 0 (0, 5) | 0.0 | 0.9519 | 0.5778 |
| Appetite | 28 | 3.29 (2.92) | 3.5 (0, 10) | 14.3 | 13 | 4.54 (3.07) | 4 (0, 10) | 30.8 | 19 | 0.53 (1.35) | 0 (0, 5) | 0.0 | 0.0002 ǂ | <0.0001 ǂ |
| Drowsy | 28 | 3.86 (2.86) | 4 (0, 10) | 17.9 | 13 | 4.31 (3.52) | 5 (0, 8) | 38.5 | 19 | 2.05 (2.59) | 1 (0, 8) | 10.5 | 0.0234 | 0.0597 |
| Dry mouth | 28 | 2.89 (3.27) | 1 (0, 8) | 21.4 | 13 | 2.85 (3.51) | 1 (0, 9) | 23.1 | 19 | 0.84 (1.46) | 0 (0, 5) | 0.0 | 0.0418 | 0.0717 |
| Sad | 28 | 1 (2.16) | 0 (0, 8) | 3.6 | 13 | 2.08 (2.81) | 1 (0, 8) | 7.7 | 19 | 0.42 (0.9) | 0 (0, 3) | 0.0 | 0.7619 | 0.0436 |
| Vomiting | 28 | 0.43 (1.32) | 0 (0, 5) | 0.0 | 13 | 1.08 (2.25) | 0 (0, 7) | 7.7 | 19 | 0.21 (0.71) | 0 (0, 3) | 0.0 | 0.6945 | 0.1505 |
| Numbness | 28 | 0.89 (1.52) | 0 (0, 5) | 0.0 | 13 | 1.92 (2.99) | 0 (0, 10) | 7.7 | 19 | 1.11 (1.45) | 0 (0, 4) | 0.0 | 0.5445 | 0.6256 |
| MDASI-Interference (0–10 scale) | ||||||||||||||
| Activity | 27 | 3.67 (3.26) | 4 (0, 10) | 25.0 | 12 | 3.42 (2.91) | 3.5 (0, 8) | 15.4 | 19 | 1.53 (2.48) | 0 (0, 8) | 10.5 | 0.0220 ǂ | 0.0496 |
| Mood | 27 | 1.78 (2.47) | 0 (0, 7) | 7.1 | 12 | 2.75 (2.45) | 3 (0, 8) | 7.7 | 19 | 1.26 (2.42) | 0 (0, 8) | 10.5 | 0.4622 | 0.0271 ǂ |
| Work | 27 | 2.04 (2.9) | 0 (0, 10) | 10.7 | 11 | 3 (3) | 3 (0, 8) | 15.4 | 19 | 1.74 (2.49) | 0 (0, 8) | 10.5 | 0.9320 | 0.1766 |
| Relations | 27 | 1.26 (2.51) | 0 (0, 9) | 7.1 | 12 | 1.67 (2.02) | 0.5 (0, 5) | 0.0 | 19 | 0.95 (2.37) | 0 (0, 8) | 10.5 | 0.5536 | 0.1297 |
| Walking | 27 | 2.56 (2.82) | 2 (0, 9) | 14.3 | 11 | 2.91 (2.55) | 3 (0, 7) | 7.7 | 19 | 2.05 (2.82) | 0 (0, 8) | 10.5 | 0.4137 | 0.2651 |
| Enjoyment of life | 27 | 2.15 (3.07) | 0 (0, 10) | 14.3 | 12 | 3.42 (3.2) | 3 (0, 9) | 15.4 | 19 | 1.68 (2.54) | 0 (0, 8) | 10.5 | 0.7299 | 0.0765 |
| CAR T-cell Therapy related Symptoms (0–10 scale) | ||||||||||||||
| Diarrhea | 28 | 0.89 (2.39) | 0 (0, 9) | 7.1 | 13 | 2.46 (3.99) | 0 (0, 10) | 23.1 | 19 | 0.32 (0.75) | 0 (0, 2) | 0.0 | 0.6133 | 0.2028 |
| Inability to eat | 28 | 2.39 (3.11) | 1 (0, 10) | 14.3 | 13 | 2.23 (2.8) | 2 (0, 8) | 15.4 | 19 | 0.11 (0.46) | 0 (0, 2) | 0.0 | 0.0007 ǂ | 0.0019 ǂ |
| Rash | 27 | 0.11 (0.58) | 0 (0, 3) | 0.0 | 13 | 0.31 (1.11) | 0 (0, 4) | 0.0 | 19 | 0.16 (0.69) | 0 (0, 3) | 0.0 | 0.8251 | 0.7839 |
| Malaise | 28 | 2.93 (3.37) | 2 (0, 10) | 17.9 | 13 | 3 (3.03) | 2 (0, 8) | 15.4 | 19 | 1.11 (1.63) | 0 (0, 5) | 0.0 | 0.0524 | 0.0662 |
| Lack of energy | 28 | 4.04 (3.32) | 3.5 (0, 10) | 25.0 | 13 | 4.23 (3) | 4 (0, 10) | 23.1 | 19 | 2.05 (2.44) | 1 (0, 9) | 5.3 | 0.0477 | 0.0354 |
| Tremors | 28 | 0.93 (2.26) | 0 (0, 10) | 3.6 | 13 | 1.15 (2.12) | 0 (0, 6) | 0.0 | 19 | 0.05 (0.23) | 0 (0, 1) | 0.0 | 0.1152 | 0.0485 |
| Muscle | 28 | 1.25 (2.15) | 0 (0, 7) | 3.6 | 13 | 2.46 (3.18) | 1 (0, 8) | 15.4 | 19 | 1.47 (1.84) | 0 (0, 6) | 0.0 | 0.4642 | 0.5242 |
| Weakness | 28 | 2.75 (2.78) | 2 (0, 10) | 10.7 | 13 | 4.23 (3.44) | 4 (0, 10) | 30.8 | 19 | 1 (1.49) | 0 (0, 5) | 0.0 | 0.0228 | 0.0030 ǂ |
| Fever | 28 | 1.46 (2.6) | 0 (0, 9) | 7.1 | 13 | 1 (1.29) | 0 (0, 3) | 0.0 | 19 | 0.47 (1.22) | 0 (0, 5) | 0.0 | 0.2220 | 0.1344 |
| Headache | 28 | 1.64 (3.07) | 0 (0, 10) | 10.7 | 13 | 1.92 (3.17) | 0 (0, 9) | 15.4 | 19 | 0.42 (0.69) | 0 (0, 2) | 0.0 | 0.4031 | 0.3403 |
| Irritability | 28 | 1.68 (2.2) | 0.5 (0, 7) | 3.6 | 13 | 2.54 (2.93) | 2 (0, 9) | 7.7 | 19 | 0.89 (1.45) | 0 (0, 5) | 0.0 | 0.2627 | 0.1221 |
| Balance | 28 | 1.46 (2.3) | 0 (0, 8) | 7.1 | 13 | 2 (2.97) | 0 (0, 10) | 7.7 | 19 | 0.37 (0.83) | 0 (0, 3) | 0.0 | 0.0827 | 0.0684 |
| Mouth | 28 | 0.46 (1.35) | 0 (0, 6) | 0.0 | 13 | 0 (0) | 0 (0, 0) | 0.0 | 19 | 0.32 (1.16) | 0 (0, 5) | 0.0 | 0.7085 | 0.2531 |
| Dizziness | 28 | 0.82 (1.85) | 0 (0, 8) | 3.6 | 13 | 2.38 (3.23) | 0 (0, 8) | 23.1 | 19 | 0.32 (0.75) | 0 (0, 3) | 0.0 | 0.6088 | 0.0583 |
| Swallowing | 28 | 0.64 (2.06) | 0 (0, 10) | 3.6 | 13 | 0.15 (0.55) | 0 (0, 2) | 0.0 | 19 | 0.53 (2.06) | 0 (0, 9) | 5.3 | 0.7085 | 0.8200 |
| Attention | 28 | 1.29 (2.11) | 0 (0, 7) | 3.6 | 13 | 2.77 (3.17) | 1 (0, 9) | 23.1 | 19 | 1.05 (1.18) | 1 (0, 3) | 0.0 | 0.6504 | 0.1871 |
| Bone | 28 | 1.86 (2.88) | 0 (0, 9) | 10.7 | 13 | 2.77 (3.37) | 0 (0, 8) | 23.1 | 19 | 1 (1.29) | 0 (0, 4) | 0.0 | 0.8850 | 0.3379 |
| Heartbeat | 28 | 0.89 (2.35) | 0 (0, 9) | 7.1 | 13 | 1.92 (2.78) | 0 (0, 7) | 7.7 | 19 | 0.21 (0.63) | 0 (0, 2) | 0.0 | 0.4622 | 0.0437 |
| Swelling | 28 | 0.96 (2.19) | 0 (0, 7) | 7.1 | 13 | 0.85 (1.91) | 0 (0, 6) | 0.0 | 19 | 0.84 (2.12) | 0 (0, 9) | 5.3 | 0.6604 | 0.8996 |
| Speaking | 28 | 0.86 (2.05) | 0 (0, 9) | 3.6 | 13 | 1.23 (2.62) | 0 (0, 8) | 7.7 | 19 | 0.74 (2.13) | 0 (0, 9) | 5.3 | 0.7477 | 0.5612 |
| Coughing | 28 | 1.14 (2.19) | 0 (0, 9) | 3.6 | 13 | 2.54 (3.18) | 1 (0, 10) | 15.4 | 19 | 2.05 (2.78) | 1 (0, 10) | 5.3 | 0.1845 | 0.6585 |
| Sexual | 27 | 1.74 (3.48) | 0 (0, 10) | 14.3 | 12 | 2.75 (4.16) | 0 (0, 10) | 23.1 | 19 | 1.05 (2.27) | 0 (0, 8) | 5.3 | 0.8510 | 0.4329 |
| Health Status on EQ5D-5L (0–100 scale) and Single Item HRQoL (0–10 scale) | ||||||||||||||
| EQ5D-5L VAS scale * | 28 | 78.7 (18.7) | 80 (20, 100) | . | 13 | 74.5 (20.5) | 80 (20, 100) | . | 17 | 75.1 (23.8) | 80 (20, 100) | . | 0.6040 | 0.8501 |
| HRQoL * | 28 | 7.71 (2.12) | 8 (3, 10) | . | 13 | 7.54 (1.9) | 8 (4, 10) | . | 19 | 8.16 (1.61) | 8 (5, 10) | . | 0.6001 | 0.3527 |
| PROMIS-29 Domains (50 for T-score) & Pain average rating (0–10 scale) | ||||||||||||||
| Physical function * | 28 | 38.7 (9.65) | 37.3 (22.9, 56.9) | . | 13 | 36.7 (12.2) | 39.1 (22.9, 56.9) | . | 19 | 46 (8.57) | 45.3 (35.6, 56.9) | . | 0.0152 ǂ | 0.0506 |
| Anxiety | 28 | 48.7 (9.51) | 48 (40.3, 71.2) | . | 13 | 49.5 (9.36) | 48 (40.3, 67.3) | . | 19 | 45 (7.38) | 40.3 (40.3, 61.4) | . | 0.2259 | 0.1540 |
| Depression | 28 | 52 (3.44) | 51 (49, 63.9) | . | 13 | 51.8 (2.22) | 51 (49, 57.3) | . | 19 | 51.5 (1.93) | 51 (49, 57.3) | . | 0.8245 | 0.7988 |
| Fatigue | 28 | 52.9 (11.9) | 52.05 (33.7, 75.8) | . | 13 | 57 (12.1) | 58.8 (33.7, 75.8) | . | 19 | 46.8 (9.72) | 46 (33.7, 64.6) | . | 0.0679 | 0.0126 ǂ |
| Sleep disturbance | 28 | 47.9 (9.97) | 47.3 (32, 73.3) | . | 13 | 52.2 (8.83) | 50.5 (37.5, 63.8) | . | 19 | 49.4 (7.15) | 50.5 (37.5, 66) | . | 0.5643 | 0.3262 |
| Social roles * | 28 | 48 (11.3) | 48.1 (27.5, 64.2) | . | 13 | 46.2 (9.65) | 44.2 (27.5, 64.2) | . | 19 | 52.4 (8.45) | 51.9 (37.3, 64.2) | . | 0.1563 | 0.0636 |
| Pain interference | 28 | 50.3 (7.93) | 52 (41.6, 66.6) | . | 13 | 54.8 (11.8) | 55.6 (41.6, 75.6) | . | 19 | 46.5 (7.81) | 41.6 (41.6, 61.2) | . | 0.1307 | 0.0381 |
| Pain average | 28 | 2.79 (2.38) | 3 (0, 8) | . | 13 | 4 (3.16) | 3 (0, 8) | . | 19 | 1.68 (2.06) | 1 (0, 6) | . | 0.1220 | 0.0369 |
Score the higher the better.
indicated the >10% of patients reported the severe symptom.
Statistically significant level using Hochberg step up procedure at 0.05 by Wilcoxon rank sum test on medians.
All patients completed the single item HRQoL, MDASI, and PROMIS-29 modules, while 96.7% of the patients completed the EQ5D-5L.
For all participants at any time during the first year following receipt of CAR T-cell therapy, fatigue-related symptoms (fatigue, lack of energy, weakness in the arm and legs, and feeling malaise) were the most severe symptoms reported on the MDASI+. Other severe symptoms (mean score at least 2 or greater on a 0–10 scale) reported on the MDASI-core assessment, included drowsiness, lack of appetite, disturbed sleep, dry mouth, and pain. The most severe symptom interference was with general activity.
The first 90 days after CAR T-cell infusion therapy represented the most symptomatic period, in which more than 10% of patients reported severe level (7–10/10) of fatigue, pain, sleeping disturbance, poor appetite, drowsiness, dry mouth from core MDASI items, and inability to eat, lack of energy, weakness, tremors, heartbeats from MDASI CAR T-cell therapy-related additional items. Multiple symptoms from both the core MDASI and CAR T-cell therapy-related additional items (fatigue, lack of appetite, and inability to eat) were significantly different among the three different patient subgroups. Pain is significantly higher in the patients who completed PROs within 30 days post-therapy compared to those who completed PROs after 90 days of therapy. Weakness is significantly higher in patients who completed PROs within 30–90 days post-therapy compared to those completed PROs after 90 days of therapy (all p<0.05 with Hochberg step-up procedure), as shown in Table 2.
Physical function, as reported on the MDASI-General Activity interference item and the “Physical Function” domain on PROMIS-29, is significantly lower in the patient who completed PROs within 30 days of therapy compared to those who completed PROs after 90 days and up to a year after therapy (all p<0.05 with Hochberg step-up procedure), as shown in Table 2. Mood interference on MDASI-Interference module is significantly higher in the patients who completed PROs 30–90 days post-therapy compared to those who completed PROs after 90 days post-therapy (p<0.05 with Hochberg step-up procedure). Of the 7 domains on PROMIS-29, the lowest reported mean score during the first 30 days of the therapy was for the physical function, which indicates that it was the most impacted PRO domains after the therapy.
CAR T-cell therapy-relevant symptom burden is associated with health utility and HRQoL score
Multiple symptoms on MDASI+ (9 of 35 items) and physical functioning items on MDASI-Interference reached a moderate level of association with the Utility-VAS score on the EQ5D-5L (r > =.3). The more severe symptoms of fatigue, nausea, drowsiness, malaise, lack of energy, weakness and dizziness, and all the MDASI-Interference items correlated with a lower rating on the single item HRQoL measure (all r > 0.3). However, there were no observed differences within the EQ5D-5L or single item HRQoL scores between the time periods, see Table 2.
PROs related to the toxicities of CAR T-cell therapy
Table 3 presents the symptoms burden of the core MDASI and additional CAR T items 30 days after CAR T-cell therapy infusion in patients who had maximum CRS or ICANS toxicities grade of 2–4 versus 0–1. Compared to patients who experienced grade 0–1 CRS, after the first 30 days post-therapy, patients with grade 2–4 CRS consistently rated more severe symptoms of fatigue, appetite, drowsiness, dry mouth, sadness, vomiting, interference with walking, interference with enjoyment of life, lack of energy, weakness, irritability, balance problems, mouth sores, dizziness, swallowing difficulties, speaking difficulties, coughing and sexual function, all with an effect size of >.30. Besides those symptoms, after 30 days of therapy, patients who had grade 2–4 ICANS neurotoxicity also reported more severe scores of inability to eat and swelling, all with an effect size >.30.
Table 3.
Toxicity relevant symptom burden 30 days after CAR T-cell infusion
| Acute CRS | Acute ICANS | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Grade 0–1 (N=17) | Grade 2–4 (N=15) | 95% CI | Grade 0–1 (N=20) | Grade 2–4 (N=12) | 95% CI | |||||||||
| Mean | SD | Mean | SD | Effect size | Lower | Upper | Mean | SD | Mean | SD | Effect size | Lower | Upper | |
| MDASI-Core items | ||||||||||||||
| Pain | 1.59 | 2.85 | 1.6 | 2.69 | 0.00 | −0.70 | 0.69 | 1.65 | 2.96 | 1.5 | 2.43 | 0.05 | −0.66 | 0.77 |
| Fatigue | 2.94 | 2.79 | 4.07 | 2.74 | −0.41 | −1.10 | 0.30 | 2.8 | 2.86 | 4.58 | 2.35 | −0.66 | −1.38 | 0.09 |
| Nausea | 0.71 | 1.61 | 1.2 | 1.97 | −0.27 | −0.96 | 0.43 | 0.6 | 1.5 | 1.5 | 2.11 | −0.51 | −1.23 | 0.22 |
| Sleep | 2.76 | 3.03 | 2.4 | 2.8 | 0.12 | −0.57 | 0.81 | 2.9 | 3.09 | 2.08 | 2.54 | 0.28 | −0.44 | 0.99 |
| Distress | 1.82 | 2.51 | 1.27 | 1.83 | 0.25 | −0.46 | 0.94 | 1.6 | 2.41 | 1.5 | 1.88 | 0.04 | −0.67 | 0.76 |
| Short breath | 1.24 | 1.89 | 1.67 | 2.26 | −0.21 | −0.90 | 0.49 | 1.35 | 2.03 | 1.58 | 2.15 | −0.11 | −0.82 | 0.61 |
| Remember | 1.06 | 1.52 | 1.53 | 1.88 | −0.28 | −0.97 | 0.43 | 1.05 | 1.54 | 1.67 | 1.92 | −0.37 | −1.08 | 0.36 |
| Appetite | 1.41 | 2.43 | 3 | 3.34 | −0.55 | −1.24 | 0.17 | 1.4 | 2.6 | 3.42 | 3.18 | −0.71 | −1.43 | 0.04 |
| Drowsy | 2.18 | 2.83 | 3.87 | 3.36 | −0.55 | −1.24 | 0.17 | 2.35 | 3.01 | 4 | 3.25 | −0.53 | −1.25 | 0.21 |
| Dry mouth | 1.24 | 2.44 | 2.13 | 2.88 | −0.34 | −1.03 | 0.37 | 1.65 | 2.81 | 1.67 | 2.46 | −0.01 | −0.72 | 0.71 |
| Sadness | 0.71 | 1.53 | 1.53 | 2.5 | −0.40 | −1.09 | 0.31 | 1 | 1.86 | 1.25 | 2.42 | −0.12 | −0.83 | 0.60 |
| Vomiting | 0.29 | 0.77 | 0.87 | 2.13 | −0.37 | −1.06 | 0.34 | 0.25 | 0.72 | 1.08 | 2.35 | −0.54 | −1.25 | 0.20 |
| Numbness | 1.82 | 2.7 | 1 | 1.41 | 0.37 | −0.34 | 1.06 | 1.3 | 2.41 | 1.67 | 1.87 | −0.17 | −0.88 | 0.55 |
| MDASI-Interference Items | ||||||||||||||
| Activity | 1.94 | 2.93 | 2.64 | 2.62 | −0.25 | −0.95 | 0.47 | 2.2 | 2.86 | 2.36 | 2.73 | −0.06 | −0.79 | 0.68 |
| Mood | 1.71 | 3.02 | 2 | 1.8 | −0.11 | −0.82 | 0.60 | 1.9 | 2.88 | 1.73 | 1.74 | 0.07 | −0.67 | 0.80 |
| Work | 2 | 3.02 | 2.46 | 2.33 | −0.17 | −0.89 | 0.56 | 2 | 2.89 | 2.55 | 2.46 | −0.20 | −0.93 | 0.54 |
| Relations | 1.53 | 2.65 | 0.86 | 1.61 | 0.30 | −0.42 | 1.00 | 1.4 | 2.5 | 0.91 | 1.7 | 0.22 | −0.53 | 0.95 |
| Walking | 1.94 | 2.7 | 2.92 | 2.72 | −0.36 | −1.08 | 0.38 | 1.85 | 2.6 | 3.4 | 2.76 | −0.58 | −1.34 | 0.20 |
| Enjoyment of life | 1.76 | 2.95 | 3.07 | 2.76 | −0.46 | −1.16 | 0.27 | 1.75 | 2.77 | 3.45 | 2.91 | −0.60 | −1.34 | 0.16 |
| CAR-T related Symptoms | ||||||||||||||
| Diarrhea | 0.82 | 2.01 | 1.6 | 3.46 | −0.28 | −0.97 | 0.42 | 0.7 | 1.87 | 2 | 3.79 | −0.48 | −1.19 | 0.26 |
| Inability to eat | 0.76 | 2.05 | 1.2 | 2.14 | −0.21 | −0.90 | 0.49 | 0.6 | 1.85 | 1.58 | 2.35 | −0.48 | −1.19 | 0.26 |
| Rash | 0.41 | 1.18 | 0 | 0 | 0.48 | −0.24 | 1.17 | 0.35 | 1.09 | 0 | 0 | 0.40 | −0.33 | 1.12 |
| Malaise | 5 | 4.6 | 2.13 | 2.67 | 0.95 | −0.33 | 2.15 | 1.4 | 2.19 | 2.67 | 2.74 | −0.53 | −1.24 | 0.21 |
| Lack of energy | 2.18 | 2.38 | 3.8 | 3.17 | −0.58 | −1.28 | 0.14 | 2 | 2.18 | 4.5 | 3.23 | −0.96 | −1.68 | −0.18 |
| Tremors | 0.59 | 1.58 | 0.4 | 1.3 | 0.13 | −0.57 | 0.82 | 0.5 | 1.47 | 0.5 | 1.45 | 0.00 | −0.72 | 0.72 |
| Muscle weakness | 2.06 | 2.38 | 1.67 | 2.64 | 0.16 | −0.54 | 0.85 | 1.7 | 2.27 | 2.17 | 2.86 | −0.19 | −0.90 | 0.53 |
| Weakness | 1.12 | 1.93 | 3.67 | 3.29 | −0.96 | −1.67 | −0.21 | 1.5 | 2.69 | 3.67 | 2.87 | −0.79 | −1.51 | −0.03 |
| Fever | 0.53 | 1.01 | 0.87 | 1.51 | −0.27 | −0.96 | 0.44 | 0.7 | 1.13 | 0.67 | 1.5 | 0.02 | −0.69 | 0.74 |
| Headache | 1 | 2 | 1.07 | 2.43 | −0.03 | −0.73 | 0.66 | 0.8 | 1.85 | 1.42 | 2.68 | −0.28 | −0.99 | 0.44 |
| Irritability | 1.18 | 1.81 | 2 | 2.73 | −0.36 | −1.05 | 0.35 | 1.2 | 1.7 | 2.17 | 3.01 | −0.43 | −1.14 | 0.31 |
| Balance | 0.35 | 1 | 1.8 | 2.76 | −0.72 | −1.41 | 0.02 | 0.8 | 2.35 | 1.42 | 1.68 | −0.29 | −1.00 | 0.44 |
| Mouth sore | 0.35 | 1.22 | 0 | 0 | 0.39 | −0.32 | 1.08 | 0.3 | 1.13 | 0 | 0 | 0.33 | −0.39 | 1.05 |
| Dizziness | 0.59 | 1.7 | 1.8 | 2.81 | −0.53 | −1.22 | 0.19 | 0.45 | 1.57 | 2.33 | 2.93 | −0.87 | −1.59 | −0.10 |
| Difficulty Swallowing | 0.06 | 0.24 | 0.73 | 2.34 | −0.42 | −1.11 | 0.30 | 0.05 | 0.22 | 0.92 | 2.61 | −0.55 | −1.26 | 0.19 |
| Attention | 1.82 | 2.38 | 1.67 | 2.35 | 0.06 | −0.63 | 0.76 | 1.5 | 2.28 | 2.17 | 2.44 | −0.29 | −1.00 | 0.44 |
| Bone aches | 1.53 | 2.24 | 1.93 | 2.79 | −0.16 | −0.85 | 0.54 | 1.65 | 2.54 | 1.83 | 2.48 | −0.07 | −0.79 | 0.65 |
| Heart bead | 0.88 | 2.18 | 0.93 | 1.83 | −0.02 | −0.72 | 0.67 | 0.85 | 2.03 | 1 | 2 | −0.07 | −0.79 | 0.64 |
| Swelling | 0.65 | 1.17 | 1.07 | 2.69 | −0.21 | −0.90 | 0.49 | 0.3 | 0.73 | 1.75 | 2.99 | −0.76 | −1.48 | 0.00 |
| Difficulty Speaking | 0.12 | 0.33 | 1.87 | 3.16 | −0.81 | −1.51 | −0.06 | 0.55 | 1.47 | 1.58 | 3.26 | −0.45 | −1.16 | 0.29 |
| Coughing | 1.65 | 2.37 | 2.93 | 3.37 | −0.44 | −1.14 | 0.27 | 1.8 | 2.33 | 3 | 3.67 | −0.41 | −1.13 | 0.32 |
| Sexual function | 1.24 | 2.56 | 2.29 | 3.83 | −0.33 | −1.03 | 0.39 | 1.2 | 2.61 | 2.64 | 4.01 | −0.46 | −1.19 | 0.30 |
| Health Status and HRQoL | ||||||||||||||
| EQ5D-5L VAS scale* | 81.6 | 18.9 | 68.1 | 23.6 | 0.63 | −0.12 | 1.35 | 81.6 | 18.8 | 64.8 | 23.6 | 0.81 | 0.03 | 1.54 |
| HRQoL* | 8.35 | 1.69 | 7.4 | 1.68 | 0.56 | −0.16 | 1.26 | 8.5 | 1.5 | 6.92 | 1.68 | 1.01 | 0.23 | 1.74 |
| PROMIS-29 Domains and Pain rating | ||||||||||||||
| Physical function* | 45.7 | 8.76 | 38.3 | 12.3 | 0.70 | −0.03 | 1.40 | 46.5 | 10 | 35.1 | 8.99 | 1.18 | 0.38 | 1.92 |
| Anxiety | 45.6 | 8.73 | 48.3 | 8.07 | −0.32 | −1.01 | 0.39 | 45.5 | 8.4 | 49.1 | 8.24 | −0.43 | −1.14 | 0.30 |
| Depression | 51.9 | 2.18 | 51.3 | 1.85 | 0.30 | −0.41 | 0.99 | 51.3 | 1.64 | 52 | 2.56 | −0.35 | −1.06 | 0.38 |
| Fatigue | 48.1 | 11.9 | 54.2 | 11 | −0.53 | −1.22 | 0.19 | 47.8 | 10.8 | 56.2 | 11.6 | −0.76 | −1.48 | 0.00 |
| Sleep disturbance | 49.5 | 8.1 | 51.8 | 7.68 | −0.29 | −0.98 | 0.41 | 50 | 8.72 | 51.4 | 6.47 | −0.18 | −0.89 | 0.55 |
| Social roles* | 53.2 | 8.46 | 46.1 | 9.08 | 0.81 | 0.07 | 1.51 | 51.3 | 10.1 | 47.5 | 7.72 | 0.41 | −0.32 | 1.12 |
| Pain interference | 50.2 | 8.97 | 49.5 | 12 | 0.07 | −0.63 | 0.76 | 49.7 | 10.4 | 50.2 | 10.7 | −0.05 | −0.76 | 0.67 |
| Pain average | 2.53 | 2.72 | 2.73 | 2.91 | −0.07 | −0.76 | 0.63 | 2.35 | 2.83 | 3.08 | 2.71 | −0.26 | −0.97 | 0.46 |
indicates ES>=0.5
Effect of recall differences between PRO tools
The scores of MDASI items of the “worst” symptoms or symptom-related interference with a recall period of the last 24 hours, found to be highly correlated with the scores of the domains of the PROMIS-29, with a recall time of 7 days. For example, fatigue at its worst and sleep disturbance at its worst on MDASI were highly correlated with the same domains on the PROMIS-29, r=.72 and r=.84, respectively. The MDASI-Pain worst item was correlated with the PROMIS-29-Pain Interference (r=.62).
Discussion
The recent Centers for Medicare & Medicaid Services (CMS) panel recommended four relevant PRO assessment tools for CAR T-cell therapy patients34, including both the MDASI and PROMIS-29 as candidates, as well as the EORTC QLQ C-30 and the PRO CTCAE. Using two of the CMS recommended PRO measures (MDASI and PROMIS-29), this prospective study is the first to quantitatively document patient-reported symptoms burden in patients with hematologic malignancies who received standard of care CAR T-cell therapy, rather than using PRO data from clinical trials. Additionally, we used newly generated CAR T-cell therapy relevant symptom items from the MDASI-item library to describe the unique symptom profiles (prevalence and severity) during the first 12 months following therapy, as well as patients who had grades 2–4 vs. 0–1 CRS or ICANS. Importantly, this study lays the groundwork for integrating workable and clinically meaningful PRO measures into the clinical care of patients immediately and during the first year following CAR T-cell infusion.
Designing an individualized, fit-for-purpose of treatment-specific PRO assessment instrument35 is the best to be done in the context of real-world prospective monitoring of patient-reported experiences of the disease and therapy of interest, which might differ from those clinicians reported symptomatic toxicities in clinical trials. Currently, there are no PRO assessment tools that were developed and validated specifically for CAR T-cell therapy. Most clinical trials that have been conducted in patients on CAR T-cell therapy report PROs that have been collected using non-disease- or therapy-specific measures35. We observed the most severe symptoms during the acute and chronic phases within the first year after treatment. More than 10% of participants rated 18 MDASI+ symptoms as severe (7 or greater on 0–10 scale) during the first 90 days following infusion. Given the breadth of items reported on the MDASI core and provisional items, we were able to comprehensively describe the symptoms burden experienced by these patients, especially compared to the assessment provided through the 7 domains on the PROMIS-29 measure and the outputs of the EQ5D-5L and single-item HRQoL. Yet, the value of the PROMIS-29 for quantifying health status during survivorship should be fully evaluated in future studies, especially as a measure of the functioning recovery. Our results provide a solution for the problematic approach of “one size fits all” measure by avoiding a generic HRQoL instrument, particularly during the symptomatic period within the first year following CAR T-cell infusion36.
This quantitative study provides an evidence-based selection of PRO items that are potentially clinically-relevant during the acute phase after CAR T-cell therapy, as well as during survivorship. The results from our nested qualitative study, which interviewed 21 of 60 patients, support the content validity of the 22 provisional CAR T-cell therapy-related symptom items that were selected by our expert clinicians and were added to the MDASI-core32. Using the MDASI+, we not only defined the prevalence and profile of severe symptoms (MDASI and provisional CAR T items with a score of 7 or greater on a 0–10 scale) during the first 30 days, but also highlighted the needs for close monitoring patients who had grade 2–4 toxicities after 30 days following infusion. The percentage of patients with severe symptoms could be potentially used to set values that trigger a triage or immediate consultation and intervention based on the severity of the reported symptoms. Thus, our work demonstrates the feasibility of further study for validating the new MDASI module for PROs assessment tool in patients on CAR T-cell therapy. Such tool is important for implementing PROs into the clinical workflow for routine evaluation of toxicity-driven symptoms burden, which will enable early and personalized interventions as needed37.
The use of PROs in routine care following CAR T-cell therapy has practical implications. For example, monitoring PROs that significantly impact the patient’s functioning and quality of life may improve symptoms and functional recovery, result in lower consumption of medical resources (e.g., emergency department visits, hospitalizations, or length of stay), and facilitate the implementation of proactive, personalized interventions for symptom control during survivorship. Fatigue-related symptoms were consistently the most significant driver of poor quality of life in this study, which may suggest the need for more effective fatigue management in patients undergoing CAR T-cell therapy38. By learning and quantifying the symptoms burden and tolerability of CAR T-cell therapy in the acute phase, we can further understand the unique toxicity challenges that are inherent to the use of PROs measures in the routine patient care setting. This is especially important for patients at higher risk of severe symptom burden at the time of discharge from the hospital following infusion. Well-defined PRO profiles that were collected from targeting both inpatients and outpatients receiving CAR T-cell therapy may assist in identifying real-time early signs of CRS and ICANS via electronic PRO tracking after discharge from the hospital.
Major limitations of this study include lack of pre-infusion baseline PRO data and limited sample size. However, a consistent trend was observed in the form of certain symptom reduction after the acute phase of therapy in this cross-sectional study. Thus a longitudinal study would be ideal for defining the trajectory of time-sensitive symptom burdens. This could be used during the relevant post-CAR T-cell therapy monitoring period, given that these symptoms could be directly correlated with the timing and severity of CRS and ICANS. Secondly, because this study was not designed as a tool validation study, the 22 additional CAR T-cell therapy-specific symptoms require further evaluation of their psychometric properties. Items reduction of the additional 22 items is needed in another tool validation study, as some of these symptom items either lack of independence, or had very low reported prevalence and clinical significance in this observational study and therefore may not be relevant for this patient population. Third, given the important impact of hematologic toxicities on symptom burden39, the current study did not collect laboratory blood count results nor clinician-rated hematologic adverse effects, which should be reviewed besides CRS and neurotoxicity in further studies. Finally, we enrolled patients in this study only when patients were able to communicate based on their cognitive function clearly. The challenge of collecting PRO data from patients with acute impaired cognitive functioning following T-cell therapy infusion needs further study.
In conclusion, during the first year following standard of care CAR T-cell therapy for hematological malignancies, the toxicity-driven symptoms burden varies at different time points and by the maximum observed grades of CRS and ICANS. Future studies are warranted to demonstrate the effectiveness of closely assessing and triaging clinically-meaningful PROs to reduce symptom burden, improve functional recovery, and potentially lead to early interventions that could reduce the severity of anticipated toxicities after CAR T-cell therapy.
Highlights.
MDASI can effectively detects symptom profiles post CAR T-cell therapy
CAR-T cell therapy has unique physical, psychological, and cognitive symptoms burden
We identified 18 severe symptoms during the first 90 days after CAR T-cell infusion
Grade 2–4 CRS or ICANs are associated with persistent symptoms 30 days post-therapy
Abbreviations
- ASTCT
American Society for Transplantation and Cellular Therapy
- CAR
Chimeric Antigen Receptor
- CRS
Cytokine Release Syndrome
- ICANS
Immune Effector Cell-Associated Neurotoxicity Syndrome
- HRQoL
Health-Related Quality of Life
- MDACC
MD Anderson Cancer Center
- MDASI
MD Anderson Symptom Inventory
- PRO
Patient-Reported Outcome
- PROMIS
Patient-Reported Outcomes Measurement Information System
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