Early Integration of Palliative and Supportive Care in Cellular Therapy (PALS_CT)

Early Integration of Palliative and Supportive Care for Patients and Family Caregivers Undergoing Hematopoietic Stem Cell Transplantation or Chimeric Antigen Receptor T-Cell Therapy: A Prospective Pragmatic Randomized Clinical Trial

Research has shown that early palliative care in cancer care is associated with improved symptom management, better prognostic understanding, improved quality of life for patients and family caregivers, and even improved survival. Yet, in spite of the proven benefits of integration of palliative care in oncology, it has been well established that patients with hematologic malignancies and those undergoing cellular therapy (hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy) do not routinely receive palliative care. Most of the published research on the early integration of palliative care in oncology describes studies that have involved patients with solid tumours. To date, only one randomized trial examining the impact of integrated palliative care among patients undergoing HSCT has been published and there have been no studies examining the impact of integrated palliative care for patients undergoing CAR T-cell therapy. The American Society of Clinical Oncology recommends early palliative care for patients with advanced cancers or for those with high symptom burden. Patients with blood cancers experience high symptom burden and in the last 30 days of life, compared to patients with solid tumours, patients with blood cancers are more likely to die in hospital, have more intensive care unit admissions, have prolonged hospitalizations (>14 days), and pass away in an acute care facility. There is an urgent need to proactively address suffering throughout cellular therapy trajectories, even before treatment starts, so that patients and caregivers are not inevitably waiting for symptoms to arise before they can be addressed and to optimize quality of life for patients undergoing transplant as well as their family caregivers. PALS_CT will compare early palliative care to standard care for patients and their family caregivers undergoing HSCT or CAR T-cell therapy for blood cancers.

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.

Leukemia, Lymphoma, Multiple Myeloma, Blood Cancer, Stem Cell Transplant Complications, Chimeric Antigen Receptor T-cell Therapy

It will not be possible to blind participants or researchers (PC clinicians who will be involved in delivery the intervention) to the intervention but the individual doing the data collection, the research assistant, will be blinded to the randomization allocation.

Participants randomized to the intervention arm will meet (either by phone or Zoom contingent upon participant preference) with a palliative care nurse practitioner or palliative care physician. During the first meeting, pre-transplant/CAR T-cell therapy, content will focus on the provision of information and education, including: a description of palliative and supportive care, symptom management, advance care planning, prognostic and illness understanding and treatment expectations, and coping strategies. All subsequent visits will include, at minimum, these topics. All meetings will be audio-recorded using a handheld audio-recorder; the record feature of Zoom will not be utilized. Participants in the intervention arm will meet with a member of the study team (palliative care nurse practitioner or palliative care physician) one to two times weekly, or more frequently if requested by the patient and/or family caregiver, until 3 months post-transplant/CAR T-cell therapy.

Standard care will involve the usual care that patients undergoing HSCT/CAR T-cell therapy would be expected to receive, including palliative care consultation as needed or upon request. Palliative care interventions beyond what are provided in the study will be tracked in both the intervention and the standard care arms.

The intervention itself will be predominantly the provision of education and information. It is possible that patients in the intervention arm may receive treatment recommendations to help manage symptoms.

The primary outcome of the study, QOL, will be assessed using the McGill Quality of Life Questionnaire - Expanded (MQOL-E) summary score of QOL monthly for a period of three months. The MQOL-E consists of 21 items with possible scores of 0 to 10 for each item. The higher the score, the better the QOL. The trajectories of QOL will be evaluated rather than looking at change in scores as it is anticipated that there will be significant fluctuation in QOL scores over time. The Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT) will also be used to measure QOL. The FACT-BMT is more specific to BMT and may capture issues that are unique to BMT. The FACT-BMT consists of 47 items; a 5-point Likert-type scale is used for item. The total score ranges from 0-196 and higher scores indicate better QOL.

The Edmonton Symptom Assessment System (ESAS) is a validated scale that assesses symptom burden in patients with cancer. While several iterations of the ESAS are available, this study will use the ESAS-revised (ESAS-r) which includes 10 items scored using a numeric rating scale, where 0=no symptom and 10=worst symptom. The ESAS assesses physical symptoms (pain, fatigue, nausea, drowsiness, dyspnea, loss of appetite), emotional symptoms (anxiety and depression), and well-being. Individual patient scores will be tracked over time to assess the trajectory of symptom burden.

The Perception of Treatment and Prognosis Questionnaire (PTPQ) is 10 item self-report questionnaire that assesses patients' beliefs about the likelihood of cure, the importance and helpfulness of knowing about prognosis, the primary goal of cancer treatment, the preferences for information about treatment, and the satisfaction with quality of information provided regarding prognosis and treatment. Items on the questionnaire are scored individually with statements about the degree to which the patient agrees with each item. Patients and CGs will complete the PTPQ pre-HSCT/CAR T-cell therapy and at 3 months post HSCT/CAR T-cell therapy.

The Quality of Life in Life-Threatening Illness - Family carer version 2 (QOLLTI-F v2) will be used to assess CG QOL. The QOLLTI-Fv2 is a 17-item questionnaire that includes seven subscales that assess the following domains: environment, patient condition, the CG's own state, quality of care, relationships, and financial worries. In addition, there is a single item that pertains to overall QOL. Items on the QOLLTI-Fv2 are ranked from 0-10 (total possible score ranges from 0-170), where higher scores are associated with better QOL. Caregivers in both the intervention and standard care arms will complete the QOLLTI-Fv2 pre-HSCT/CAR T-cell therapy, and at 2-weeks, 1-month, and 3-months post-HSCT/CAR T-cell therapy.

Inclusion Criteria - Patients Clinical diagnosis of hematologic malignancy with scheduled hematopoietic stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy Ability to speak, read, and understand English or, be able to complete questionnaires with minimal assistance required from an interpreter Inclusion Criteria - Family Caregivers Family caregivers of patients with a clinical diagnosis of hematologic malignancy with scheduled hematopoietic stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy A spouse, relative, or friend, identified by the patient, who either lives with the patient or has in-person contact with the patient at least twice per week. Only one family CG per patient will be asked to participate. Ability to speak, read, and understand English or willing to complete questionnaires with minimal assistance required from an interpreter Exclusion Criteria - Patients Patients undergoing HSCT for a non-malignant hematologic condition Inability to provide informed consent Exclusion Criterion - Family Caregivers * Inability to provide informed consent

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