Thanarajasingam, Gita

Mantle cell lymphoma (MCL) is a rare lymphoma with a median age at diagnosis of 60-70 years. Front line therapy has traditionally been bendamustine-rituximab (BR) in older patients and then Bruton Tyrosine kinase inhibitors (BTKi) for relapsed disease. Due to their efficacy, BTKi are now being combined with chemotherapy as induction treatment. The TRIANGLE trial of R-CHOP/R-DHAP +/- ibrutinib +/- transplant showed the benefit of adding a BTKi in young patients (Dreyling M, 2022). The SHINE trial, a phase III trial of BR +/- ibrutinib in patients >65 years, showed a significant improvement in median PFS (81 months vs. 53 months) (Wang M, 2022). However, this came with an increase in toxicity with more treatment related deaths in the ibrutinib arm (11% vs. 6%) and no difference in overall survival. Therefore, a better tolerated approach is still needed in older patients. A phase II study of rituximab + indefinite ibrutinib in 50 patients >65 years demonstrated efficacy of frontline BTKi with a 96% ORR and 71% CR (Jain P, 2021). However, a disadvantage of BTKi therapy is continuous treatment until disease progression or intolerance. In this study half of patients required dose reductions and almost a third of patients stopped treatment due to drug toxicity, most frequently atrial fibrillation or bleeding. If front line intermittent BTKi therapy is as effective as continuous therapy, it could minimize cumulative toxicity. A052101 (NCT05976763), an Alliance for Clinical Trials in Oncology trial, is a randomized phase 3 multicenter trial of upfront zanubrutinib that asks the question “in older patients with previously untreated MCL who obtain a CR with zanubrutinib-rituximab, is it safe and equally effective to stop treatment and restart it upon disease progression rather than continuing indefinitely?” The A052101 trial is enrolling pts with previously untreated MCL who are either >70 years old or 60-69 years old but are not transplant candidates due to cardiac ejection fraction <45%, DLCO <60% of predicted, creatinine clearance <70, Eastern Cooperative Oncology Group (ECOG) performance status of >2, or a Cumulative Illness Rating Scales score of >6. Key exclusion criteria include: history of a severe bleeding disorder or clinically significant cardiac arrhythmias. Patients will take zanubrutinib 320 mg daily and rituximab/rituximab biosimilar once monthly for 6 cycles. Patients with less than partial response after 6 cycles will go off study treatment. Patients with a complete remission will be randomized in a 1:1 manner to intermittent treatment versus continuous treatment. Randomization will be stratified by age (60-69 years vs ≥70 years) and MIPI score. Those randomized to the continuous arm will receive zanubrutinib until intolerance or disease progression. Those randomized to the intermittent arm will stop all study drugs after those initial 6 cycles and will restart zanubrutinib at first disease progression and continue it until intolerance or second disease progression. In order to make the study results generalizable to clinical practice, disease progression will be defined by clinical parameters rather than minimal residual disease testing. The primary objective of this study is to compare time from randomization to first progression or death (PFS1) in the continuous treatment arm to the time to second progression or death (PFS2) in the intermittent treatment arm. The primary evaluation will be to determine whether, for patients in a CR, active monitoring followed by retreatment with zanubrutinib therapy upon disease progression will result in non-inferior clinical outcomes compared to indefinite zanubrutinib. Serial quality of life testing and adverse event monitoring will be performed throughout the study to gain a full understanding of the impact of continuous vs intermittent zanubrutinib on patients' lives. A052101 has the potential to change management of older patients with previously untreated MCL. If our study demonstrates that the time to second progression/death when using the stop and retreat strategy is non-inferior to time to first progression/death when using continuous BTK therapy, then it might lead to a new standard of care in this patient population. This could result in decreased health care costs, decreased toxicity and improved quality of life for older patients with mantle cell lymphoma. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org

Background/Aims: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE ® ) was developed to capture symptomatic adverse events from the patient perspective. We aim to describe statistical properties of PRO-CTCAE items and summary scores and to provide evidence for recommendations regarding PRO-CTCAE administration and reporting. Methods: Using data from the PRO-CTCAE validation study (NCT02158637), prevalence, means, and standard deviations of PRO-CTCAE items, composite scores, and mean and maximum scores across attributes (frequency, severity, and/or interference) of symptomatic adverse events were calculated. For each adverse event, correlations and agreement between attributes, correlations between attributes and composite scores, and correlations between composite, mean, and maximum scores were estimated. Results: PRO-CTCAE items were completed by 899 patients with various cancer types. Most patients reported experiencing one or more adverse events, with the most prevalent being fatigue (87.7%), sad/unhappy feelings (66.0%), anxiety (63.6%), pain (63.2%), insomnia (61.8%), and dry mouth (60.0%). Attributes were moderately to strongly correlated within an adverse event ( r = 0.53 to 0.77, all p < 0.001) but not fully concordant (κ weighted = 0.26 to 0.60, all p < 0.001), with interference demonstrating lowest mean scores and prevalence among attributes of the same adverse event. Attributes were moderately to strongly correlated with composite scores ( r = 0.67 to 0.97, all p < 0.001). Composite scores were moderately to strongly correlated with mean and maximum scores for the same adverse event ( r = 0.69 to 0.94, all p < 0.001). Correlations between composite scores of different adverse events varied widely ( r = 0.04 to 0.68) but were moderate to strong for conceptually related adverse events. Conclusions: Results provide evidence for PRO-CTCAE administration and reporting recommendations that the full complement of attributes be administered for each adverse event, and that attributes as well as summary scores be reported.

Abstract Background The US Food and Drug Administration (FDA) released a draft guidance document detailing core patient-reported outcomes in cancer clinical trials, including physical function (PF). This study aimed to develop analytic methods and visualizations of patient-reported PF in patients with cancer. Methods We applied an estimand framework to a patient-reported tolerability endpoint to develop data summaries cross-sectionally and over time, along with visualizations. We accomplished this through iterative feedback with clinicians, statisticians, and FDA stakeholders using three clinical trial datasets in hematologic malignancies. Graphical approaches were applied to three datasets in hematologic malignancies: (1) patients with myeloproliferative neoplasms enrolled in MPN-RC 111/112 trials completed EORTC QLQ-C30 over 12 months; (2) patients with hematologic malignancies undergoing CAR-T cell therapy or autologous transplant who completed FACT questionnaires over 6 months; and (3) patients with multiple myeloma or amyloidosis who completed the PROMIS-29 questionnaire over 6 months. Zoom polls were administered to two stakeholder groups (clinicians/clinical investigators and patient advocates) to elicit feedback. Results Visualizations included stacked bar charts, line plots of arithmetic mean changes from baseline, pie charts, waffle plots, and waterfall plots of PF data. Graphics considered scaled scores and individual items and included delineation of PRO completion rate at each time point. Confidence intervals and reference lines were included as applicable, and colorblind accessible colors were implemented to ensure inclusivity of all visualizations. Data summaries over time reporting “worst” change were difficult to interpret. In terms of stakeholders’ preference, patients preferred stacked bar charts while clinicians equally favored stacked bar charts and line plots; both patients and clinicians preferred waterfall plots to pie charts. Patient feedback highlighted the need for various graphics to convey group level trends and granular individual-patient level information. Conclusion Patient-reported PF informs the evaluation of treatment tolerability in cancer trials. Data summaries and visualizations of physical function developed through an iterative process were reviewed favorably by patients, clinicians and FDA stakeholders in this study. Future work to systematically assess accuracy of interpretation of the various analytic and visualization methods is a necessary next step across clinical, regulatory, payer and patient stakeholders. Trial registration NCT01259817, NCT01259856

1564 Background: Physical function (PF) is a core outcome in cancer trials that can inform treatment tolerability. PF can be assessed across modalities including by patient (pt) report, clinician (clin) report, performance tests and digital sensors. The optimal approach for PF measurement has not been defined. Methods: In4M is a prospective observational study evaluating PF in pts initiating chemotherapy for breast cancer or lymphoma followed over 9 months. We used an electronic platform (Hugo) to aggregate serially assessed pt-reported PF, clin- and pt-reported ECOG performance status (PS), 6-minute walk test (6MWT) and wearable (Fitbit) data. We evaluated feasibility in all pts; associations among PF measures and the ability of PF measures to detect change were evaluated in pts with both baseline (BL) and 3-month (3M) data. We used Pearson correlations to assess the relationship of average daily steps with measures of PF. To assess change, we compared each PF measure from BL to 3M using a 2-sided α=.05 paired t-test. Results: Of the208 pts enrolled, 193 (93%) and 159 (76%) completed surveys, and 121 (58%) and 124 (60%) provided wearable data (evaluable: ≥1 day data) at BL and 3M, respectively. When requiring a stringent BL with 4+ days of data with ≥1 weekend day to be evaluable, 88 (42%) and 120 (58%) provided wearable data at BL and 3M. At both BL and 3M, pt-reported PF was generally more highly correlated with wearable-derived daily steps than clin-reported PF and 6MWT were (Table). Significant declines in PF were observed for pt- and clin-reported PF (all p<0.05), but not other modalities. Conclusions: Longitudinalassessment of multi-modal PF data including pragmatic wearable data collection was feasible in pts receiving chemotherapy. Pt-reported PF was the only modality that was both correlated with step count and able to detect change. Additional wearable metrics, correlations among PF measurements and outcomes, and clinically meaningful change scores will be reported. Optimal PF measurement may improve future reporting of treatment tolerability. Clinical trial information: NCT05214144 . [Table: see text]

PURPOSE Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated remarkable response rates in relapsed or refractory Hodgkin lymphoma (HL). Still, most patients eventually progress. Patterns of progression after ICIs are not well described and are essential to defining the role of local therapies in combination with ICIs. We identified patients who received ICIs for HL between 2013 and 2022. Fludeoxyglucose-18 positron emission tomography (FDG-PET) before initiating ICI and at progression on/after ICI were reviewed, and areas of active HL were recorded. An exploratory analysis of treatable progression included patients with ≤5 sites of disease on pre-ICI FDG-PET and progression only at pre-ICI sites. Ninety patients were identified; 69 had complete records, and of these, 32 (52%) had relapsed at ICI initiation, 17 (25%) were refractory, and 16 (23%) received ICI as first-line therapy. Forty-five of 69 patients had ≤5 sites of disease (limited) on pre-ICI FDG-PET. Patients with &gt;5 sites of disease had a higher risk of progression, and every site of disease &gt;5 sites conferred an additional 1.2x higher chance of progression. At a median follow-up of 4.0 years, 41 of 69 patients had progressed on/after ICIs (cumulative incidence 66.4%), and of these, 22 of 41 patients progressed only at pre-ICI sites (cumulative incidence 39.4%). In an exploratory analysis, the cumulative incidence of a treatable progression among 45 patients with limited disease was 34%. The cumulative incidence of any progression among this cohort was 58.9%. More than one-third of patients with limited disease before ICIs experienced progression only at pre-ICI sites of disease. These patients could be candidates for radiation during or after ICIs.

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb &lt;12g/dL for women or &lt;13g/dL for men) in 58%, LDH &gt;UNL in 46%, lymphocytosis (&gt;5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.

Background: Understanding the symptoms and quality of life (QOL) over time of adults with follicular lymphoma (FL) is important for treatment decision-making and clinical management. However, there are limited population-level data on the long-term QOL of adults with FL. We aim to describe the real-world, long-term QOL of adults with newly diagnosed FL up to 5/6 years after diagnosis. Methods: We used the Mayo Clinic/Iowa Molecular Epidemiology Resource (MER) and the multi-institutional Lymphoma Epidemiology of Outcomes (LEO) to identify adults with grade 1-3A FL who completed QOL surveys at baseline and follow-up. Participants with lymphoma were prospectively enrolled within 9 months of diagnosis in the MER cohort from 2002-2015 and within 6 months of diagnosis in the multi-institutional LEO cohort study across 8 cancer centers from 2015-2020. The LEO/MER cohort studies systematically collected information on disease status, QOL, health behaviors, and functional assessment. Treatments, disease relapses, and deaths were verified by medical record review. Treating physicians determined clinical management. QOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G) at years 1, 2, 3, and 5/6 post-diagnosis. A higher FACT-G total score (range 0-108) indicated better QOL across 4 subscales (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being. We categorized participants based on their frontline management at time of diagnosis: “observation” (surveillance), “treatment” (systemic treatment with immunotherapy +/- chemotherapy), and “local” (radiation) groups. We employed a generalized linear mixed model to evaluate and compare the changes in QOL scores (as a continuous variable) from baseline for the observation, treatment, and local groups, adjusting for sex, race/ethnicity, age, FLIPI risk, and cohort (i.e., LEO or MER). We also evaluated QOL changes by FLIPI risk. Results: Our study included 1,544 participants with FL and QOL data. At the time of enrollment, median age was 61 years (range 19-91), 88% were non-Hispanic White, and 49% were female. Based on initial management, 529 (34%) were in the observation group, 880 (57%) were in the treatment group, and 135 (9%) were in the local group. FLIPI risk was high for 17% in the observation group, 29.3% in the treatment group, and 3% in the local group. The mean (standard deviation) baseline FACT-G total score was lowest in the treatment group with the following baseline scores: 86 (13) for the observation group, 83 (14) for the treatment group, and 88 (12) for the local group (Table 1). The observation and local groups reported a greater worsening of their baseline FACT-G total score vs the treatment group at both the 2-year (-1.2, -0.8 vs +1.8, respectively) and 5/6 year (-5.4, -6 vs. -1.6, respectively) timepoints (Figure 1). This appeared to be driven by worsened physical and functional well-being in the observation (-1.3, -2.2, respectively) and local (-0.9, -2.4, respectively) groups vs the treatment group (0, -0.3, respectively). These differences were statistically significant between the observation vs treatment groups. There were no statistically significant differences in the other subscales, i.e., social/family and emotional well-being, by frontline management. Social/family well-being decreased across all groups by 5/6 years (-2.3 in observation, -2.2 in treatment, and -3 in local, p&lt;0.05). Regardless of FLIPI risk, the total FACT-G scores decreased within each FLIPI risk group at 5/6 years (-4.4 for low, -3.8 for intermediate, and -4.9 for high, p&lt;0.05). This was primarily due to worsened social/family well-being (-2.4 for low, -2.2 for intermediate, and -3 for high, p&lt;0.05) at 5/6 years. There was no statistically significant difference in QOL between FLIPI risk groups. Conclusion: This is one of the first and largest studies with real-world longitudinal QOL data for FL. Our study suggests that frontline systemic treatment initially improved QOL and resulted in a lower degree of QOL decline over time. Social/family well-being decreased over time regardless of frontline management or FLIPI risk. Further research is warranted to explore the impact of timing and specific systemic treatments on QOL, incorporate the patient/caregiver experience to address social/family well-being, and identify the clinical significance of our findings.