Patient-Reported Outcomes at Time of CAR-T Cell Therapy
Authors: Mullane Erin , Jones Taylor , Voutsinas Jenna , Wu Qian Vicky , Loggers Elizabeth , Fann Jesse , Maloney David G. , Bar Merav 
Published: February 2021

Chimeric antigen receptor (CAR)-T cell therapy is a novel treatment with promising results for patients with hematological malignancies. Currently three FDA approved products are available for treatment of relapsed/refractory lymphoid malignancies, and several products are in different stages of clinical investigations for treatment of multiple myeloma and other hematological malignancies. CAR-T cell therapy has known early toxicities of cytokine release syndrome (CRS) and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We previously reported neuropsychiatric patient-reported outcomes (PROs) of long-term survivors after CAR-T cell therapy (Ruark at al. BBMT 2020; 26: 34-43), but without baseline PROs before treatment for comparison.
In this study we have utilized PROs, including PROMIS® measures, to assess symptoms and quality of life (QOL) of patients with relapse/refractory non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM) at time of arrival to our cellular immunotherapy clinic for CAR-T cell therapy.
Between February 2019 and March 2020, patients received a PRO questionnaire at time of their arrival to our immunotherapy clinic. The questionnaire included the PROMIS Scale v1.2-Global Health, PROMIS-29 Profile v2.1, PROMIS Cognitive Function Short-Form v2.0, as well as 30 additional questions, including questions pertaining to cognitive function. As of March 30, 2020, 58 questionnaires were returned (59% response rate for online questionnaire versus 80% for paper questionnaire) and included in the analysis. Patients' characteristics are summarized in Table 1.
PROMISmeasures are standardized to a T-score metric, with a score of 50 representing the general US population mean. Clinically meaningful differences were defined as a 5-point difference in scores (1/2 standard deviation). Cognitive function was assessed for all patients by asking if patients had experienced difficulties with concentration, finding words, memory, or solving problems; answering "yes" to each of the questions received "1" point to determine the total cognitive difficulty score (0-4). The PROMIS Cognitive Function Short-Form was added later to the PRO questionnaire and data are available for 28 patients.
The cohort's self-reported cognitive difficulties and PROMIS mean T scores are shown in Table 2. Mean T score of PROMIS Global Physical Health was clinically meaningfully different from the mean in the general US population (43.7), while the mean T scores of all the other domains, including Global Mental Health, Social Function, Anxiety, Depression, Fatigue, Pain Interference, Sleep Disturbance and Cognitive Function were not clinically meaningfully different from the mean in the general US population. 23 of the 56 participants for whom complete data were available (41%) reported at least one cognitive difficulty and/or clinically meaningful depression and/or anxiety (Figure 1).
On univariate risk factor analysis, older age was found to be associated with worse Global Physical Health (p=0.04) but with a trend for less depression (p=0.07). Diagnosis of ALL was found to be a risk factor for depression (p&lt;0.01). Time from diagnosis or number of prior lines of treatment were not found to be risk factors for neuropsychiatric status at time of CAR-T cell therapy.
Our study demonstrates overall worse physical function in our cohort of 58 patients with hematological malignancies at time of CAR-T cell therapy, compared to the general population, but no clinically meaningful difference was found in neuropsychiatric status. 41% of the participants reported depression, anxiety or cognitive difficulties at time of CAR-T cell therapy, compared to 47.5% of participants 1-5 years after CAR-T cell therapy in our prior published work (Ruark at al. BBMT 2020; 26: 34-43). Ten participants (17.2%) reported 1-4 cognitive difficulties at time of CAR-T cell therapy compared to 37.5% of participants 1-5 years after CAR-T cell therapy. However, conclusions cannot be drawn from these two independent cohorts, and longitudinal data are needed to compare patients' neuropsychiatric status before and after CAR-T cell therapy in order to determine the treatment effect. Such study is currently ongoing in our institution.

Disclosures
Maloney: Celgene: Consultancy, Honoraria, Research Funding; Gilead Sciences: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Amgen: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Bioline Rx: Consultancy, Honoraria.