Early Integration of Palliative and Supportive Care in Cellular Therapy

Problem: patients undergoing HSCT and CAR T-cell therapy experience high symptom burden (physical, psychological, spiritual), lack illness and prognostic understanding (which can adversely impact medical decision making). Research has found that patients with blood cancers experience poor end-of-life (EOL) quality indicators such as disease-directed therapy in the weeks before death, emergency room visits in the weeks before death, intensive care unit (ICU) admissions near the EOL, low rates of hospice use, and dying in hospital. Family caregivers (CGs) of patients undergoing HSCT and CAR T-cell therapy experience impaired QOL, physical and psychosocial concerns, and have expressed that their needs have not been adequately addressed by care teams. Palliative care, with its multidisciplinary approach and focus on improving QOL from a holistic perspective, can help reduce symptom burden and improve QOL, improve illness and prognostic understanding, and improve EOL care for patients undergoing HSCT and CAR T-cell therapy and their family CGs. This trial will assess the effectiveness of early PC in improving QOL for patients and their family CGs undergoing HSCT or CAR T-cell therapy for hematological malignancies.

Objectives The objectives for this study were developed after extensive review of the literature as well as were informed by preliminary data derived from an ongoing qualitative study that sought the perspectives of patients, family CGs, and clinicians regarding the integration of PC in HSCT.

Objective 1: To examine the impact of an outpatient PC intervention on patient-reported QOL for patients undergoing HSCT or CAR T-cell therapy Hypothesis: patients randomized to the PC intervention will report greater improvement in QOL at 1-month post-HSCT/CAR T-cell therapy and at 3 months post-HSCT/CAR T-cell therapy compared to patients receiving standard care.

Objective 2: To examine the impact of an outpatient PC intervention on symptoms at 2 weeks, 1 month, and 3 months post-HSCT/CAR T-cell therapy for patients undergoing HSCT/CAR T-cell therapy Hypothesis: patients randomized to the PC intervention will report a greater reduction in physical symptoms at 2 weeks, 1 month, and 3 months post-HSCT/CAR T-cell therapy compared to patients receiving standard care

Objective 3: To examine the impact of an outpatient PC intervention on family CG QOL at 1 month and 3 months post-HSCT/CAR T-cell therapy for CGs of patients undergoing HSCT/CAR T-cell therapy Hypothesis: family CGs of patients randomized to the PC intervention will report greater improvement in QOL compared to family CGs of patients receiving standard care

Objective 4: To examine the impact of an outpatient PC intervention on patient and family CG understanding of prognosis.

Hypothesis: patients and family CGs randomized to the PC intervention will report more accurate prognostic understanding compared to those receiving standard care

Exploratory objective 1: To evaluate whether an outpatient PC intervention is associated with overall survival at 1 and 5 years post-study enrolment.

Methods This is a prospective pragmatic randomized clinical trial to evaluate the effectiveness of an outpatient PC intervention integrated with standard care compared to standard care alone in 152 patients undergoing HSCT or CAR T-cell therapy. Randomization will be stratified by type of treatment: autologous transplant, allogeneic transplant, or CAR T-cell therapy. A pragmatic approach was selected given the desire to assess the effectiveness of integrating early PC in HSCT/CAR T-cell therapy. Previous studies have examined the efficacy of PC in oncology in patients with advanced cancer. This study will build the work of El-Jawahri et al. who studied the impact of inpatient PC on patients undergoing HSCT with the main difference being that participants will be recruited in the outpatient setting and the intervention will be delivered in the outpatient setting. Selected outcomes have been chosen as they are congruent with patient, family CG and clinician perspectives, based upon the qualitative study that was undertaken by the PI (R Booker) in 2020-2021.

Data Collection Participants will be emailed a secure link for the questionnaires. Data from questionnaires will be collected electronically using Research Electronic Data Capture (REDCap). Email reminders will be sent to participants to remind them to complete the surveys and if necessary, a research assistant will contact patients and family CGs to provide reminders to complete the surveys.

Following randomization, participants (patients and family CGs) will be asked to complete baseline questionnaires and demographic information (such as age, gender, diagnosis, urban/rural residence, religious affiliation, highest level of education, main CG (for patients), main source of support (for family CGs) will be collected via REDCap. The next evaluation will occur during the second week following HSCT or CAR T-cell therapy. For participants undergoing autologous HSCT or CAR T-cell therapy (and their family CGs), the second evaluation will occur on day +5 (with a 48-hour window). For participants undergoing allogeneic HSCT (and their family CGs), the second evaluation will occur on day +8 (with a 72-hour window). These time points were chosen based upon the study conducted by El-Jawahri et al. who indicated they selected the time points to coincide with the peak of severity in symptoms based upon the type of transplant being performed. All patients and family CGs will also complete questionnaires at 1 and 3 months post HSCT/CAR T-cell therapy. Data collection will be done remotely, with links to questionnaires sent via email completed via REDCap. As part of the consent process, participants will be asked if they would consider completing questionnaires at 6-12 months post-HSCT/CAR T-cell therapy. Patient participants will also be asked if they consent to the researchers accessing their medical charts until 5 years post-HSCT/CAR T-cell therapy in order to collect disease and treatment information.

Data Analysis Exclusive intention-to-treat (ITT) analysis may not be aligned with patient-centered outcomes and as such, this study will use both ITT and per protocol analyses. For any imbalances between the intervention and control groups, sensitivity analyses while be conducted and g-methods will be used to adjust for confounders that may vary over time. As per the revised CONSORT guidelines for reporting parallel-group randomized trials, the investigators will collect and report the reasons for participants lost to follow-up as well as the reasons why any participants' data were excluded from analysis.

Analysis Plan Primary Outcome To assess the primary outcome of the study, difference in QOL, as measured by the MQOL-E, between the intervention group and the standard care group will be compared. Because QOL will be assessed at multiple time points, area under the curve (AUC) will be used to calculate a summary score for each patient. Assessing multiple domains over time increases the possibility of Type I error. In particular, because it is expected that patient trajectories of QOL will be non-linear, AUC seems more appropriate than using specific time points as the latter may underestimate or overestimate treatment differences. Summary scores will be averaged across all patients in both the intervention and standard care arms and differences between the groups will be assessed using t-tests. The summary profiles for patients will be presented in graphical form for the MQOL and FACT-BMT.

Analysis Plan - Secondary Outcomes Family CG QOL will be analyzed using AUC and comparing the two groups using t-tests. For patient symptom burden, as measured by the ESAS, symptom scores will be tracked over time for each patient. An overall summary score for the ESAS will not be used given the diversity of symptoms assessed by the ESAS as well as the possibility that patients can add another symptom or concern to the tool. The latter would mean that there could be different symptoms being reported amongst participants, thereby making it difficult to compare groups. Patient and family CG prognostic understanding will be assessed using t-tests to compare the intervention group and standard care group at two time points, pre-HSCT/CAR T-cell therapy and at 3 months post-HSCT/CAR T-cell therapy.