Real-world treatment outcomes for Hodgkin lymphoma in South Africa: a prospective observational study.

BACKGROUND: Prospective data from sub-Saharan Africa suggests that treatment outcomes for people living with HIV (PWH) with Hodgkin lymphoma (HL) are similar to those without HIV. However, real-world data from high-resource settings and retrospective studies from sub-Saharan Africa, suggest inferior outcomes. We set out to evaluate the real-world treatment outcomes for HL in South Africa to better understand the disparate outcomes. METHODS: We established a prospective, observational cohort of newly diagnosed, adult (≥ 18 years) HL cases recruited from Chris Hani Baragwanath Academic and Netcare Olivedale Hospitals in Johannesburg, South Africa between March 2021 and March 2023. Participants were followed for up to 18 months after enrollment with data censored on December 23rd, 2023. The primary endpoint was 1-year overall survival. RESULTS: We enrolled 47 participants with HL including 31 PWH and 16 HIV-negative. Advanced stage disease and B symptoms were common at time of diagnosis irrespective of HIV status. Bone marrow biopsy, performed during the work-up and evaluation of cytopenias, provided the initial diagnosis of HL in 16/31 (52%) PWH. HIV status and bone marrow involvement were associated with early mortality (within 3 months of diagnosis) and a poorer 1-year overall survival from diagnosis (HIV: 55% vs. 88%; p = 0.03; bone marrow involvement: 50% vs. 80%; p = 0.02). Among evaluable participants, those that received at least 6 cycles of chemotherapy and underwent response assessment, there was no difference between those with and without HIV. CONCLUSION: Traditional laboratory markers of poor prognosis including anemia, lymphopenia and hypoalbuminemia were more common among PWH and those with bone marrow involvement and suggest high risk disease. A better understanding of the drivers of these aggressive presentations is warranted to ensure more PWH are able to tolerate chemotherapy.

Activation of Cell-Intrinsic Signaling in CAR-T Cells via a Chimeric IL7R Domain.

Chimeric antigen receptor (CAR) T cells can effectively treat leukemias, but sustained antitumor responses can be hindered by a lack of CAR T-cell persistence. Cytotoxic effector T cells are short-lived, and establishment of CAR-T cells with memory to ensure immune surveillance is important. Memory T cells depend on cytokine support, with IL7 activation of the IL7 receptor (IL7R) being critical. However, IL7R surface expression is negatively regulated by exposure to IL7. We aimed to support CAR T-cell persistence by equipping CAR-T cells with a sustained IL7Rα signal. We engineered T cells to constitutively secrete IL7 or to express an anti-acute myeloid leukemia-targeted IL7Rα-chimeric cytokine receptor (CCR) and characterized the phenotype of these cell types. Canonical downstream signaling was activated in CCR-T cells with IL7R activation. When coexpressed with a cytotoxic CAR, functionality of both the CCR and CAR was maintained. We designed hybrid CAR-CCR and noted membrane proximity of the intracellular domains as vital for signaling. These data show cell-intrinsic cytokine support with canonical signaling, and functionality can be provided via expression of an IL7Rα domain whether independently expressed or incorporated into a cytotoxic CAR for use in anticancer therapy. SIGNIFICANCE: To improve the phenotype of tumor-directed T-cell therapy, we show that provision of cell-intrinsic IL7R-mediated signaling is preferable to activation of cells with exogenous IL7. We engineer this signaling via independent receptor engineering and incorporation into a CAR and validate maintained antigen-specific cytotoxic activity.

Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis.

BACKGROUND: High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. OBJECTIVE: In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. METHODS: We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). RESULTS: The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). CONCLUSION: Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.

Virtual patient analysis identifies strategies to improve the performance of predictive biomarkers for PD-1 blockade.

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable, but is hindered by the limited performance of existing biomarkers. Here, we leveraged in-silico patient cohorts generated using a quantitative systems pharmacology model of metastatic TNBC, informed by transcriptomic and clinical data, to explore potential ways to improve patient selection. We tested 90 biomarker candidates, including various cellular and molecular species, by a cutoff-based biomarker testing algorithm combined with machine learning-based feature selection. Combinations of pre-treatment biomarkers improved the specificity compared to single biomarkers at the cost of reduced sensitivity. On the other hand, early on-treatment biomarkers, such as the relative change in tumor diameter from baseline measured at two weeks after treatment initiation, achieved remarkably higher sensitivity and specificity. Further, blood-based biomarkers had a comparable ability to tumor- or lymph node-based biomarkers in identifying a subset of responders, potentially suggesting a less invasive way for patient selection.

Nonlinear modeling of oral glucose tolerance test response to evaluate associations with aging outcomes.

As people age, their ability to maintain homeostasis in response to stressors diminishes. Physical frailty, a syndrome characterized by loss of resilience to stressors, is thought to emerge due to dysregulation of and breakdowns in communication among key physiological systems. Dynamical systems modeling of these physiological systems aims to model the underlying processes that govern response to stressors. We hypothesize that dynamical systems model summaries are predictive of age-related declines in health and function. In this study, we analyze data obtained during 75-gram oral-glucose tolerance tests (OGTT) on 1,120 adults older than 50 years of age from the Baltimore Longitudinal Study on Aging. We adopt a two-stage modeling approach. First, we fit OGTT curves with the Ackerman model-a nonlinear, parametric model of the glucose-insulin system-and with functional principal components analysis. We then fit linear and Cox proportional hazards models to evaluate whether usual gait speed and survival are associated with the stage-one model summaries. We also develop recommendations for identifying inadequately-fitting nonlinear model fits in a cohort setting with numerous heterogeneous response curves. These recommendations include: (1) defining a constrained parameter space that ensures biologically plausible model fits, (2) evaluating the relative discrepancy between predicted and observed responses of biological interest, and (3) identifying model fits that have notably poor model fit summary measures, such as [Formula: see text], relative to other fits in the cohort. The Ackerman model was unable to adequately fit 36% of the OGTT curves. The stage-two regression analyses found no associations between Ackerman model summaries and usual gait speed, nor with survival. The second functional principal component score was associated with faster gait speed (p<0.01) and improved survival (p<0.01).

Recipient clonal hematopoiesis in allogeneic bone marrow transplantation for lymphoid malignancies.

ABSTRACT: Allogeneic blood and marrow transplantation (alloBMT) is increasingly being used in older patients with blood cancer. Aging is associated with an increasing incidence of clonal hematopoiesis (CH). Although the effects of donor CH on alloBMT has been reported, the impact of recipient CH on alloBMT outcomes is unknown. In this retrospective study, alloBMT recipients age 60 and older with lymphoid malignancies were included. Among 97 consecutive patients who received alloBMT between 2017 and 2022, CH was detected in 60 (62%; 95% confidence interval [CI], 51-72). CH was found in 45% (95% CI, 28-64) of patients aged 60 to 64, 64% (95% CI, 44-81) of patients aged 65% to 69%, and 73% (95% CI, 59-87) in those above 70. Pretransplant CH was associated with worse survival after alloBMT: 3-year overall survival (OS) was 78% (95% CI, 65-94) for patients without CH vs 47% (95% CI, 35-63) for those with CH, (unadjusted HR, 3.1; [95% CI, 1.4-6.8; P < .001]). Nonrelapse mortality (NRM) was higher in patients with CH; cumulative incidence of NRM at 1-year was 11% (95% CI, 1-22) vs 35% (95% CI, 23-48), (HR, 3.4; [95% CI, 1.4-8.5], P = .009]). Among CH patients, worse OS and NRM was associated with CH burden and number of mutations. Recipient CH had no effect on relapse. In conclusion, older patients with CH experience worse outcomes after alloBMT, almost exclusively attributable to increased NRM. CH is a strong, independent predictor of outcomes. Novel strategies to ameliorate the adverse impacts of patient CH on transplant outcomes are being evaluated.

Allogeneic Hematopoietic Cell Transplantation with Non-Myeloablative Conditioning and Post-Transplant Cyclophosphamide Prophylaxis in Patients with Reduced Systolic Function.

Post-transplantation cyclophosphamide (PTCy) has become standard of care for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (alloHCT), allowing for expanded donor options. However, there is scant literature examining outcomes of patients with reduced systolic function receiving PTCy. The present study aimed to describe our experience in performing alloHCT in patients with reduced systolic function, including their nonrelapse mortality (NRM), overall survival (OS), and cumulative incidence of early cardiac events (ECEs). We performed a retrospective descriptive analysis using the Johns Hopkins Hematologic Malignancy database. From 2017 through 2021, 1118 consecutive patients underwent alloHCT with nonmyeloablative (NMA) conditioning and PTCy. Forty-three of those patients had a pretransplantation left ventricular ejection fraction (LVEF) ≤45% measured by transthoracic echocardiography. Patients whose LVEF improved on treatment prior to transplantation were also included. These 2 cohorts were stratified into 2 groups-heart failure with reduced ejection fraction (HFrEF) and heart failure with recovered ejection fraction (HFrecEF)-and subgroup analyses compared NRM, OS, and cumulative incidence of ECEs, including arrhythmia, coronary artery disease, reduction in LVEF, and pericardial effusion, within 100 days post-transplantation. The median LVEF was 40% to 45% (range, 30% to 45%) for the 31 patients undergoing transplantation with HFrEF and 35% to 40% (range, 20% to 45%) for the 12 patients with HFrecEF. The NRM for all 43 patients was 16% (95% confidence interval [CI], 5% to 27%) at 100 days and 23% (95% CI, 11% to 36%) at 2 years. The NRM was 23% (95% CI, 8% to 38%) at 100 days and 26% (95% CI, 10% to 42%) at 2 years for the HFrEF cohort and 0 at 100 days and 18% (95% CI, 0 to 41%) at 2 years for the HFrecEf cohort. The OS at 3 years was 41% (95% CI, 26% to 62%), 40% (95% CI, 25% to 65%) and 38% (95% CI, 14% to 100%) in the combined, HFrEF, and HFrecEF cohorts, respectively. The cumulative incidence of any ECE was 37.2% (95% CI, 22% to 51.9%), including 39% of HFrEF subjects and 33% of HFrecEF subjects. Grade ≥3 toxicities were seen in 56% of patients. Reduced ejection fraction was the most common ECE. One death was attributable to a cardiac etiology. Cardiac toxicities seemed to be more frequent and severe in patients with a history of systolic dysfunction, but this did not lead to worse survival outcomes. This study adds to and extends the existing literature supporting the use of NMA conditioning and PTCy in patients with systolic dysfunction.

Soluble TNFR1 has greater reproducibility than IL-6 for the assessment of chronic inflammation in older adults: the case for a new inflammatory marker in aging.

Chronic inflammatory pathway activation, commonly referred to as "Inflammaging" or chronic inflammation (CI), is associated with frailty, cognitive and functional decline, and other causes of health span decline in older adults. We investigated the variability of candidate serum measures of CI among community-dwelling older adults selected for mild low-grade inflammation. We focused on serum cytokines known to be highly predictive of adverse health outcomes in older adults (sTNFR1, IL-6) during a short-term (weeks) and medium-term (months) follow-up, as well as immune markers that are less studied in aging but reflect other potentially relevant domains such as adaptive immune activation (sCD25), innate immune activation (sCD14 and sCD163), and the inflammation-metabolism interface (adiponectin/Acrp30) during short-term (weeks) follow up. We found that sTNFR1 was more reproducible than IL-6 over a period of weeks and months short-term and medium-term. The intra-class correlation coefficient (ICC) for sTNFR1 was 0.95 on repeated measures over 6 weeks, and 0.79 on repeated measures with mean interval of 14 weeks, while the ICC for IL-6 was 0.52 over corresponding short-term and 0.67 over corresponding medium-term follow-up. This suggests that sTNFR1 is a more reliable marker of CI than IL-6. This study provides new insights into the reproducibility of serum markers of CI in older adults. The findings suggest that sTNFR1 may be a better marker of CI than IL-6 in this population. Further studies are needed to confirm these findings and to investigate the clinical utility of sTNFR1 in older adults.

Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors.

Background: Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens. Methods: We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens. Results: Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least 1 line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Conclusions: Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.

Association of Cardiovascular Disease in Patients with Mycosis Fungoides and Sézary Syndrome Compared to a Matched Control Cohort.

Mycosis fungoides/Sézary syndrome (MF/SS) produces a low-grade chronic inflammatory state that may be associated with an increased risk of cardiovascular (CV) events, as seen in other chronic, systemic dermatologic diseases. To assess this association, a retrospective, cross-sectional study was designed in which 421 patients with a biopsy-proven diagnosis of MF/SS were compared with a control cohort of 4,210 age-, gender-, and race-matched patients randomly selected from the National Health and Nutritional Evaluation Survey database. The MF/SS cohort had a 14% prevalence of CV events, which was not statistically different from the control population's prevalence of 13%. In the MF/SS cohort, a multivariable logistic regression model showed that older patients (OR = 1.05 for each year of age, 95% confidence interval = 1.02-1.07) and those diagnosed with hypertension (OR = 3.40, 95% confidence interval = 1.71-6.75) had a higher risk of a CV event (P < 0.001). Risk factors such as gender, race, smoking, diabetes, and obesity were not significantly associated with CV events. Findings suggest that in the MF/SS population, advancing age and hypertension are risk factors for CV events, requiring clinical recognition and management. In addition, further research is needed to understand the complex interplay of how chronic inflammation in MF/SS impacts the immune development of CV disease.

Identifying predictors of resilience to stressors in single-arm studies of pre-post change.

Many older adults experience a major stressor at some point in their lives. The ability to recover well after a major stressor is known as resilience. An important goal of geriatric research is to identify factors that influence resilience to stressors. Studies of resilience in older adults are typically conducted with a single-arm where everyone experiences the stressor. The simplistic approach of regressing change versus baseline yields biased estimates due to mathematical coupling and regression to the mean (RTM). We develop a method to correct the bias. We extend the method to include covariates. Our approach considers a counterfactual control group and involves sensitivity analyses to evaluate different settings of control group parameters. Only minimal distributional assumptions are required. Simulation studies demonstrate the validity of the method. We illustrate the method using a large, registry of older adults (N  =7239) who underwent total knee replacement (TKR). We demonstrate how external data can be utilized to constrain the sensitivity analysis. Naive analyses implicated several treatment effect modifiers including baseline function, age, body-mass index (BMI), gender, number of comorbidities, income, and race. Corrected analysis revealed that baseline (pre-stressor) function was not strongly linked to recovery after TKR and among the covariates, only age and number of comorbidities were consistently and negatively associated with post-stressor recovery in all functional domains. Correction of mathematical coupling and RTM is necessary for drawing valid inferences regarding the effect of covariates and baseline status on pre-post change. Our method provides a simple estimator to this end.

Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

A Study of Physical Resilience and Aging (SPRING): Conceptual framework, rationale, and study design.

Understanding the physiological basis of physical resilience to clinical stressors is crucial for the well-being of older adults. This article presents a novel framework to discover the biological underpinnings of physical resilience in older adults as part of the "Characterizing Resiliencies to Physical Stressors in Older Adults: A Dynamical Physiological Systems Approach" study, also known as The Study of Physical Resilience and Aging (SPRING). Physical resilience, defined as the capacity of a person to withstand clinical stressors and quickly recover or improve upon a baseline functional level, is examined in adults aged 55 years and older by studying the dynamics of stress response systems. The hypothesis is that well-regulated stress response systems promote physical resilience. The study employs dynamic stimulation tests to assess energy metabolism, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the innate immune system. Baseline characteristics influencing resilience outcomes are identified through deep phenotyping of physical and cognitive function, as well as of biological, environmental, and psychosocial characteristics. SPRING aims to study participants undergoing knee replacement surgery (n = 100), bone and marrow transplantation (n = 100), or anticipating dialysis initiation (n = 60). Phenotypic and functional measures are collected pre-stressor and at multiple times after stressor for up to 12 months to examine resilience trajectories. By improving our understanding of physical resilience in older adults, SPRING has the potential to enhance resilient outcomes to major clinical stressors. The article provides an overview of the study's background, rationale, design, pilot phase, implementation, and implications for improving the health and well-being of older adults.

Cell-free DNA measurable residual disease as a predictor of postallogeneic hematopoietic cell transplant outcomes.

The measurable residual disease (MRD) assessment provides an attractive predictor of allogeneic hematopoietic cell transplnat (alloHCT) outcomes. Cell-free DNA (cfDNA) has been applied to diagnosis, early detection, and disease burden monitoring in various tumors, but its utility as an MRD test in myeloid malignancies has not been systematically evaluated. We sought to determine the differential sensitivity between bone marrow (BM) and cfDNA MRD and to assess the effect of cfDNA MRD on alloHCT outcomes. The technical and clinical validation cohorts, including 82 patients participating in clinical trials (Bone Marrow Transplant Clinical Trials Network-0201 and 0402), were used. Ultradeep error-corrected targeted sequencing was performed on plasma and BM-derived DNA. We demonstrated that 94.6% (range, 93.9-95.3) of cfDNA was derived from hematopoietic tissue. The mutant allele fraction was congruent between BM and cfDNA (rho = 0.8; P < .0001); however, cfDNA seemed to be more sensitive in detecting clones with a variant allele frequency (VAF) of <0.26%. cfDNA-MRD clearance by day 90 after alloHCT (D90) was associated with improved relapse-free survival (RFS, median survival not reached vs 5.5 months; P < .0001) and overall survival (OS, median survival not reached vs 7.3 months; P < .0001) when compared with patients with persistent MRD. Irrespective of pre-alloHCT MRD, D90 cfDNA MRD was associated with inferior 2-year OS (16.7% vs 84.8%; P < .0001) and RFS (16.7% vs 80.7%; P < .0001). cfDNA seems to be an accurate, minimally invasive alternative to BM aspirates in MRD assessment and confers important prognostic implications in patients with myeloid malignancies undergoing alloHCT.

An overview of the resilience world: Proceedings of the American Geriatrics Society and National Institute on Aging State of Resilience Science Conference.

Resilience, which relates to one's ability to respond to stressors, typically declines with age and the development of comorbid conditions in older organisms. Although progress has been made to improve our understanding of resilience in older adults, disciplines have employed different frameworks and definitions to study various aspects of older adults' response to acute or chronic stressors. "Overview of the Resilience World: State of the Science," a bench-to-bedside conference on October 12-13, 2022, was sponsored by the American Geriatrics Society and National Institute on Aging. This conference, summarized in this report, explored commonalities and differences among the frameworks of resilience most commonly used in aging research in the three domains of resilience: physical, cognitive, and psychosocial. These three main domains are intertwined, and stressors in one domain can lead to effects in other domains. The themes of the conference sessions included underlying contributors to resilience, the dynamic nature of resilience throughout the life span, and the role of resilience in health equity. Although participants did not agree on a single definition of "resilience(s)," they identified common core elements of a definition that can be applied to all domains and noted unique features that are domain specific. The presentations and discussions led to recommendations for new longitudinal studies of the impact of exposures to stressors on resilience in older adults, the use of new and existing cohort study data, natural experiments (including the COVID-19 pandemic), and preclinical models for resilience research, as well as translational research to bring findings on resilience to patient care.

Clinical trial participation predicts improved survival in older adults receiving allogeneic blood and marrow transplant.

BACKGROUND: Older adults represent a large oncologic demographic and are under-represented within oncology research despite constituting nearly two-thirds of the oncologic population in the United States. Because many social factors influence research participation, those who enroll in research do not reflect the oncology population at large, introducing bias and creating issue with external validity of studies. The same factors that influence study enrollment may also impact cancer outcomes, meaning that those who enroll in studies may already have an improved chance of cancer survival, further skewing results of these studies. This study evaluates characteristics that influence study enrollment in older adults and explore to what degree these factors may influence survival after allogeneic blood or marrow transplantation. METHODS: This retrospective comparison study evaluates 63 adults aged 60 and above undergoing allogenic transplantation at one institution. Patients who elected and declined enrollment in a non-therapeutic observational study were evaluated. Demographic and clinical characteristics between groups were compared and assessed as predictors of transplant survival, including decision to enroll in the study. RESULTS: Participants who chose to enroll in the parent study were not different with regard to gender, race/ethnicity, age, insurance type, donor age, and neighborhood income/poverty level compared to patients who were invited to participate but declined enrollment. The research participant group had higher proportion assessed as being fully active (23.8% vs. 12.7%, p = 0.034) and lower mean comorbidity scores (1.0 vs 2.47, p = 0.008). Enrollment in an observational study independently predicted transplant survival (HR = 0.316, 95% CI 0.12-0.82, p = 0.017). When controlling for relevant confounders of disease severity, comorbidities, and transplant age, enrolling in the parent study was associated with a lower hazards of death following transplant (HR = 0.302, 95% CI 0.10-0.87, p = 0.027). CONCLUSIONS: Despite being demographically comparable, persons who enrolled in one non-therapeutic transplant study had significantly improved survivorship than those who did not participate in observational research. These findings suggest that there are unidentified factors that influence study involvement that may also impact disease survivorship, over-estimating outcomes from these studies. Results from prospective observational studies should be interpreted with the consideration that study participants have an improved chance of survival at baseline.

Haploidentical Donor Blood or Marrow Transplantation for Myelodysplastic/Myeloproliferative Overlap Neoplasms: Results from a North American Collaboration.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for blood or marrow transplantation (BMT). In this collaboration across North America, we retrospectively analyzed outcomes of first BMT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN), an otherwise incurable hematological neoplasm. We included 120 patients, 38% of non-White/Caucasian ethnicity, across 15 centers with median age at BMT 62.5 years. The median follow-up is 2.4 years. Graft failure was reported in 6% patients. At 3-years, nonrelapse mortality (NRM) was 25%, relapse 27%, grade 3-4 acute graft versus host disease (GVHD) 12%, chronic GVHD requiring systemic immunosuppression 14%, progression-free survival (PFS) 48% and overall survival (OS) 56%. On multivariable analysis, statistically significant associations included older age at BMT (per decade increment) with NRM (sdHR 3.28, 95%CI 1.30-8.25), PFS (HR 1.98, 95% 1.13-3.45) and OS (HR 2.01, 95% CI 1.11-3.63), presence of mutation in EZH2/RUNX1/SETBP1 with relapse (sdHR 2.61, 95%CI 1.06-6.44), and splenomegaly at BMT/prior splenectomy with OS (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for BMT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Disease-related factors including splenomegaly and high-risk mutations dominate outcomes following BMT.

Assessing Heterogeneity of Treatment Effect in Real-World Data.

Increasing availability of real-world data (RWD) generated from patient care enables the generation of evidence to inform clinical decisions for subpopulations of patients and perhaps even individuals. There is growing opportunity to identify important heterogeneity of treatment effects (HTE) in these subgroups. Thus, HTE is relevant to all with interest in patients' responses to interventions, including regulators who must make decisions about products when signals of harms arise postapproval and payers who make coverage decisions based on expected net benefit to their beneficiaries. Prior work discussed HTE in randomized studies. Here, we address methodological considerations when investigating HTE in observational studies. We propose 4 primary goals of HTE analyses and the corresponding approaches in the context of RWD: to confirm subgroup effects, to describe the magnitude of HTE, to discover clinically important subgroups, and to predict individual effects. We discuss other possible goals including exploring prognostic score- and propensity score-based treatment effects, and testing the transportability of trial results to populations different from trial participants. Finally, we outline methodological needs for enhancing real-world HTE analysis.