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Introduction Mutations in the IDH1 or IDH2 genes are detected in approximately 20% of cases of acute myeloid leukemia (AML). Few studies have examined the impact of IDH mutations in AML on allogeneic bone marrow transplant (alloBMT) outcomes. Patients and methods In this single center study, alloBMT outcomes for 61 patients with IDH-mutated (mIDH) AML were compared to those for 146 patients with IDH-wildtype (wtIDH) AML. Results Patients with mIDH AML had a 2-year overall survival (OS) of 85% (95% CI 76%-95%), 2-year relapse free survival (RFS) of 71% (95% CI 59%-85%), 1-year cumulative incidence of relapse (CIR) of 14% (95% CI 5%-23%) and a 1-year cumulative incidence of transplant related mortality (CITRM) of 3% (95% CI 0%-8%). Patients with wtIDH had a 2-year OS of 61% (95% CI 53%-70%), 2-year RFS of 58% (95% CI 50%-67%), 1-year CIR of 27% (95% CI 20%-35%), and a 1-year CITRM of 9% (95% CI 5%-14%). In a univariate analysis cox-proportional hazard model, mIDH was associated with significantly better OS (HR 0.52, 95% CI 0.29-0.96) and a trend toward better RFS (HR 0.60, 95% CI 0.35-1.01). After controlling for donor age, diagnosis, and ELN risk category, mIDH was associated with a nonsignificantly improved OS (HR 0.54, 95% CI 0.29-1.01) and RFS (HR 0.67, 95% CI 0.39-1.15). Conclusion Among patients with mIDH AML, patients who received a peritransplant IDH inhibitor had improved OS (P = .03) compared to those who did not, but there was no detectable difference for RFS (P = .29).

Background Patients with sickle cell disease (SCD) have vaso-occlusive crises (VOCs). Infusion centers (ICs) are alternatives to emergency department (ED) care and may improve patient outcomes. Objective To assess whether care in ICs or EDs leads to better outcomes for the treatment of uncomplicated VOCs. Design Prospective cohort. (ClinicalTrials.gov: NCT02411396). Setting 4 U.S. sites, with recruitment between April 2015 and December 2016. Participants Adults with SCD living within 60 miles of a study site. Measurements Participants were followed for 18 months after enrollment. Outcomes of interest were time to first dose of parenteral pain medication, whether pain reassessment was completed within 30 minutes after the first dose, and patient disposition on discharge from the acute care visit. Treatment effects for ICs versus EDs were estimated using a time-varying propensity score adjustment. Results Researchers enrolled 483 participants; the 269 who had acute care visits on weekdays are included in this report. With inverse probability of treatment-weighted adjustment, the mean time to first dose was 62 minutes in ICs and 132 minutes in EDs; the difference was 70 minutes (95% CI, 54 to 98 minutes; E-value, 2.8). The probability of pain reassessment within 30 minutes of the first dose of parenteral pain medication was 3.8 times greater (CI, 2.63 to 5.64 times greater; E-value, 4.7) in the IC than the ED. The probability that a participant's visit would end in admission to the hospital was smaller by a factor of 4 (0.25 [CI, 0.18 to 0.33]) with treatment in an IC versus an ED. Limitation The study was restricted to participants with uncomplicated VOCs. Conclusion In adults with SCD having a VOC, treatment in an IC is associated with substantially better outcomes than treatment in an ED. Primary funding source Patient-Centered Outcomes Research Institute.

BACKGROUND Sex hormone-binding globulin (SHBG) is a glycoprotein that regulates sex hormone bioavailability and increases with age in the general population. SHBG concentrations are higher in people with HIV, a population in whom accelerated aging has been hypothesized. It is unclear whether longitudinal changes in SHBG increase over time and differ by HIV serostatus. METHODS In a longitudinal study, SHBG was measured in 182 men with HIV (MWH) and 267 men without HIV (seronegative) from the Multicenter AIDS Cohort Study and matched for age, race, site, and time, with ≥2 SHBG serum samples over the 10 years after HAART initiation. Multivariable linear mixed-effects regression models were used to evaluate whether log-transformed SHBG [ln(SHBG)] and its rate of change differed by HIV serostatus. RESULTS At baseline, the mean age in MWH was similar to that in HIV-seronegative men (51 ± 5 vs 49 ± 6 years). However, SHBG mean values were higher in MWH compared with those in HIV-seronegative men (65.6 ± 48.8 vs. 45.4 ± 22 nmol/L, P < 0.001). In a fully adjusted model, SHBG increased over time and at a faster rate in MWH compared with that in HIV-seronegative men: [2.0%/year (95% CI: 1.4 to 2.7) vs 1.3%/year (95% CI: 0.8 to 1.8), respectively, P = 0.038]. Among MWH, higher SHBG concentrations were significantly associated with lower CD4+ T-cell count [β= -0.02 (95% CI: -0.03 to -0.0002), P < 0.05], fewer cumulative years on zidovudine [β = -0.027 (95% CI: -0.045 to -0.009), P < 0.001], and greater cumulative years on nonnucleoside reverse transcriptase inhibitors drugs [β = 0.022 (95% CI: 0.0006 to 0.04), P < 0.05]. CONCLUSIONS Aging-related increases in SHBG were faster in MWH compared with those in HIV-seronegative men and were related to poorer immunologic status and antiretroviral medication exposure. The mechanisms and consequences of these findings require further investigation.

PURPOSE: Hope is a modifiable entity that can be augmented. We evaluated the feasibility, acceptability, and efficacy of a short intervention to increase hopefulness in patients with advanced breast cancer and oncologists. METHODS: We enrolled eligible participants to two cohorts: one for patients with metastatic breast cancer and one for medical, radiation, or surgical oncologists. The intervention, a half-day hope enhancement workshop, included groups of 10-15 participants within each cohort. Participants in both cohorts completed preworkshop, postworkshop, and 3-month evaluations, which included the Adult Hope Scale (AHS), Herth Hope Index (HHI), and Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-GH) measures in patients, and the AHS, HHI, and a burnout self-assessment tool in physicians. RESULTS: We consented 13 patients and 26 oncologists for participation in the workshop and 76.9% (n = 10) of consented patients and 100% (n = 26) of consented physicians participated. Postworkshop, all participants planned to incorporate what they learned into their daily lives. In patients, AHS scores increased from preworkshop to postworkshop, and the mean change of 5.90 was significant (range 0-15, SD: 4.7, t = 3.99, P = .0032). HHI scores also increased, although the mean change was not significant. AHS and HHI scores did not significantly change in oncologists from preworkshop to postworkshop. At 3 months, less than half of the participants responded to the evaluation. CONCLUSION: We found that conducting a hope-enhancement workshop for patients with metastatic breast cancer and oncologists was feasible, generally acceptable to both populations, and associated with increased hopefulness in patients. Next steps should focus on confirming this effect in a randomized study and maintaining this effect in the postworkshop interval.

The traditional disease-oriented model of healthcare is inadequate to address the needs of the older population. Greater attention should be given to strategies that promote healthy aging. Recently proposed constructs of intrinsic capacity (IC) and physical resilience (PR) hold great potential to reshape geriatric medicine and aging research. These constructs accentuate the positive health attributes of older people in contrast to the popular frailty construct that is centered on functional deficits. IC was introduced by the World Health Organization (WHO) as a composite of all the physical and mental capacities. WHO has emphasized enhancement of IC throughout the life course so as to maintain functional ability in old age. PR, recently highlighted by the National Institute on Aging, is the ability to successfully cope with stressors. High levels of resilience can result in desirable clinical and functional outcomes after stressors. Therefore, it is important to understand the underlying physiology of PR and the risk factors contributing to diminished PR. The main goal of this article is to explore the potential relationship between IC and PR. Based on a classical theory of aging, we postulate that IC is a determinant of PR and is also a high-level integrative measure of physiologic reserve which is the fundamental factor underlying one's ability to withstand stressors. A major implication of our postulates is that even though IC is only one of the many determinants of PR, it could serve as an important intervenable target for enhancing resilience in older adults.

Allogeneic blood or marrow transplantation (BMT) physicians seek to optimize all possible variables to improve outcomes. Selectable factors include conditioning, graft-versus-host disease (GVHD) prophylaxis, graft source, and donor. Many patients, especially those with eligible haploidentical (haplo) donors, will have multiple donor options. We seek to identify factors to optimize the choice of haplo donors when using posttransplantation cyclophosphamide (PTCy) GVHD prophylaxis. We evaluated the effect of modifiable donor characteristics (donor age and relationship) on outcomes following haplo BMT with a uniform nonmyeloablative conditioning and PTCy. From 2002 to 2017, 889 consecutive adult patients underwent nonmyeloablative haplo BMT with PTCy. Median follow-up among survivors was 2.5 years after BMT. Median recipient age was 59 (range: 18 to 76) years and median donor age was 40 (range: 13 to 79) years. Multivariable analyses demonstrated that increasing donor age by decade was associated with poorer overall survival (hazard ratio [HR], 1.13 [1.05, 1.22; P = .0015]), worse progression-free survival (HR, 1.09 [1.02, 1.16; P = .015]), and a higher risk for grade 2 to 4 and grade 3 to 4 GVHD (1.3 [1.06, 1.61; P = .013]), but not for chronic GVHD (HR, 1.06 [0.94, 1.2]; P = .37). These less-favorable results with older donors were attributable to worse nonrelapse mortality (HR, 1.19 [1.05, 1.34]; P = .006), not relapse. Parents were associated with inferior outcomes compared with sibling donors, whereas no significant differences were observed between parental donors. These data suggest that the youngest, adult-sized donors should be preferred when multiple haplo donors are available.

Frailty in aging marks a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. This Perspective synthesizes the evidence on the aging-related pathophysiology underpinning the clinical presentation of physical frailty as a phenotype of a clinical syndrome that is distinct from the cumulative-deficit-based frailty index. We focus on integrating the converging evidence on the conceptualization of physical frailty as a state, largely independent of chronic diseases, that emerges when the dysregulation of multiple interconnected physiological and biological systems crosses a threshold to critical dysfunction, severely compromising homeostasis. Our exegesis posits that the physiology underlying frailty is a critically dysregulated complex dynamical system. This conceptual framework implies that interventions such as physical activity that have multisystem effects are more promising to remedy frailty than interventions targeted at replenishing single systems. We then consider how this framework can drive future research to further understanding, prevention and treatment of frailty, which will likely preserve health and resilience in aging populations. Linda Fried and colleagues argue that physical frailty reflects the dysregulation of a complex dynamical system underpinning health and resilience, and discuss the implications for new prevention and treatment approaches.

Transplant-associated thrombotic microangiopathy (taTMA) is a systemic vascular illness associated with significant morbidity and mortality, resulting from a convergence of risk factors after allogeneic blood or marrow transplantation (alloBMT). The diagnosis of taTMA has been a challenge, but most criteria include an elevated lactate dehydrogenase (LDH), low haptoglobin, and schistocytes on peripheral blood smear. We performed a retrospective review of the 678 consecutive adults who received high-dose post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis between January 1, 2015, and August 31, 2018. In April 2016, we initiated a monitoring program of weekly LDH and haptoglobin measurements and blood smears when those 2 parameters were both abnormal on all of our adult patients undergoing alloBMT for hematologic malignancies. During the entire period, the 1-year cumulative incidence of taTMA was 1.4% (95% confidence interval, 0.5% to 2.3%). Eight patients were taking tacrolimus at the time of diagnosis, and 1 was not on any immunosuppression. Eight of 9 patients (89%) were hypertensive. Four patients had invasive infections at the time of diagnosis, 4 patients required renal replacement therapy, and 5 of 9 patients were neurologically impaired. Eculizumab was given to 6 patients (0.9%), of whom 2 died and 4 recovered with resolution of end-organ dysfunction. The paucity of events made the determination of risk factors difficult; however, the low incidence of taTMA in this cohort may be related to the limited use of myeloablative conditioning regimens, low incidence of severe GVHD, and use of PTCy. PTCy-based GVHD prophylaxis appears to be associated with a low incidence of severe taTMA.

The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.

BackgroundThe prognosis of patients with recurrent/refractory acute myelogenous leukemia (AML) remains poor and cell-based immunotherapies hold promise to improve outcomes. NK cells can elicit an anti-leukemic response via a repertoire of activating receptors that bind AML surface ligands. NK cell adoptive transfer is safe but thus far has shown limited anti-AML efficacy. Here, we aimed to overcome this limitation by engineering NK cells to express chimeric antigen receptors (CARs) to boost their anti-AML activity, and interleukin-15 (IL15) to enhance their persistence.MethodsWe characterized in detail NK cell populations expressing a panel of AML (CD123)-specific CARs and/or IL15 in vitro and in AML xenograft models.ResultsCARs with 2B4.ζ or 4-1BB.ζ signaling domains demonstrated greater cell surface expression and endowed NK cells with improved anti-AML activity in vitro. Initial in vivo testing revealed that only 2B4.ζ CAR-NK cells had improved anti-AML activity in comparison to untransduced (UTD) and 4-1BB.ζ CAR-NK cells. However, the benefit was transient due to limited CAR-NK cell persistence. Transgenic expression of secretory (s)IL15 in 2B4.ζ CAR and UTD NK cells improved their effector function in the setting of chronic antigen simulation in vitro. Multiparameter flow analysis after chronic antigen exposure identified the expansion of unique NK cell subsets. 2B4.ζ/sIL15 CAR and sIL15 NK cells maintained an overall activated NK cell phenotype. This was confirmed by transcriptomic analysis, which revealed a highly proliferative and activated signature in these NK cell groups. In vivo, 2B4.ζ/sIL15 CAR-NK cells had potent anti-AML activity in one model, while 2B4.ζ/sIL15 CAR and sIL15 NK cells induced lethal toxicity in a second model.ConclusionTransgenic expression of CD123-CARs and sIL15 enabled NK cells to function in the setting of chronic antigen exposure but was associated with systemic toxicities. Thus, our study provides the impetus to explore inducible and controllable expression systems to provide cytokine signals to AML-specific CAR-NK cells before embarking on early phase clinical testing.Abstract FigureIn BriefSecretion of IL15 from anti-CD123.2B4.CD3ζ CAR-NK cells enhances their activation and killing potential against Acute Myelogenous Leukemia, but carries the risk of severe systemic toxicity.

Background Long-term prognostication is important to inform preventive care in older adults. Existing prediction indices incorporate age and comorbidities. Frailty is another important factor in prognostication. In this project, we aimed at developing life expectancy estimates that incorporate both comorbidities and frailty. Methods In this retrospective cohort study, we used data from a 5% sample of Medicare beneficiaries with and without history of cancer from Surveillance, Epidemiology, and End Results (SEER) cancer registry areas. We included adults aged 66-95 years who were continuously enrolled in fee-for-service Medicare for ≥1 year from 1998 to 2014. Participants were followed for survival until 12/31/2015, death, or disenrollment. Comorbidity (none, low/medium, high) and frailty categories (low, high) were defined using established methods for claims. We estimated 5- and 10-year survival probabilities and median life expectancies by age, sex, comorbidities, and frailty. Results The study included 479,646 individuals (4,128,316 person-years), of whom most were women (58.7%). Frailty scores varied widely among participants in the same comorbidity category. In Cox models, both comorbidities and frailty were independent predictors of mortality. Individuals with high comorbidities (HR, 3.24; 95% CI, 3.20-3.28) and low/medium comorbidities (HR, 1.36; 95% CI, 1.34-1.39) had higher risks of death than those with no comorbidities. Compared to low frailty, high frailty was associated with higher risk of death (HR, 1.55; 95% CI, 1.52-1.58). Frailty affected life expectancy estimates in ways relevant to preventive care (i.e., distinguishing 10-year life expectancy) in multiple subgroups. Conclusion Incorporating both comorbidities and frailty may be important in estimating long-term life expectancies of older adults. Our life expectancy tables can aid clinicians' prognostication and inform simulation models and population health management.

The identification of new molecular pathways supporting the growth of myelodysplastic syndrome (MDS) stem and progenitor cells is needed to understand clinical variation and develop targeted therapies. Within myeloid malignancies, men have worse outcomes compared to women, suggesting male sex hormone driven effects in malignant hematopoiesis. The androgen receptor promotes the expression of five granulocyte-colony factor receptor regulated genes. Among them, CCRL2 encodes an atypical chemokine receptor that regulates cytokine signaling in differentiated granulocytes but its role in myeloid malignancies is unknown. Our study revealed that CCRL2 is upregulated in stem and progenitor cells from patients with MDS and secondary acute leukemia. CCRL2 knockdown suppressed the growth and clonogenicity of MDS92 and MDS-L cells in vitro and in vivo. Moreover, CCRL2 knockdown significantly suppressed the phosphorylation of JAK2, STAT3, and STAT5 in MDS cells. CCRL2 co-precipitated with JAK2 and its suppression decreased the interaction of JAK2 with STAT proteins. Cell lines expressing JAK2V617F showed less effect of CCRL2 knockdown on growth and clonogenicity compared to those expressing wild type. However, the selective JAK2 inhibitor fedratinib potentiated the effects of CCRL2 knockdown in MDS and leukemia cells expressing both wild type JAK2 and JAK2V617F. In conclusion, our results implicate CCRL2 as a mediator of MDS and secondary acute leukemia cell growth, in part through JAK2/STAT signaling.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

Introduction “Frailty” has attracted attention for its promise of identifying vulnerable older adults, hence its potential use to better tailor geriatric health care. There remains substantial controversy, however, regarding its nature and ascertainment. Recent years have seen a proliferation of frailty assessment methods. We argue that the development of frailty assessments should be grounded in “validation”—the process of substantiating that a measurement accurately and precisely measures what it intends, identify unresolved measurement issues, and highlight measurement-related considerations for clinical practice. Methods Principles for validating frailty measures are elucidated. We follow principles—articulated, for example, by Borsboom—in which a construct must be clearly defined and then analyses undertaken to substantiate that a measurement accurately and precisely measures what it intends. Key elements are content validity, criterion validity, and construct validity, with an emphasis on the latter. Results We illustrate the principles for a physical frailty phenotype construct. Conclusions Unresolved conceptual issues include the roles of intersecting concepts such as cognition, disease severity, and disability in frailty measurement, conceptualization of frailty as a state versus a continuum, and the potential need for dynamic measures and systems concepts in furthering understanding of frailty. Clinical considerations include needs to distinguish interventions designed to address frailty “symptoms” versus underlying physiology, improve “prefrailty” measures intended to screen individuals early in their frailty progression, address feasibility demands, and further visioning followed by rigorous efficacy research to address the landscape of potential uses of frailty assessment in clinical practice.

Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes show a male predominance and men with MDS/MPN have worse outcomes, but it is unknown if the mutational burden differs between genders. We reviewed 167 patients with MDS/MPN and found that men had worse overall survival [hazard ratio (HR) 2·09, 95% confidence interval (CI) 1·16-3·75; P = 0·013] independent of subtype, Revised International Prognostic Scoring System score and age at diagnosis. We analysed the genomic data of a subset of 100 patients. Men had 0·88 more somatic mutations on average (95% CI 0·20-1·56, P = 0·011) independent of subtype, sample source and blast percentage. More somatic mutations was associated with a higher incidence of transformation to acute myeloid leukaemia (subdistribution HR 1·30, 95% CI 1·01-1·70; P = 0·046). Men had 0·70 more mutations in high-risk genes [additional sex combs like-1 (ASXL1), enhancer of zeste homolog 2 (EZH2), Runt-related transcription factor 1 (RUNX1), SET binding protein 1 (SETBP1), NRAS proto-oncogene, GTPase (NRAS), stromal antigen 2 (STAG2)] on average (95% CI 0·11-1·29, P = 0·021), and 13-times higher odds of harbouring an EZH2 mutation (95% CI 1·64-102·94, P = 0·015). The presence of an EZH2 mutation was associated with worse survival among men (HR 2·98, 95% CI 1·1-8·0; P = 0·031). Our present findings suggest that the worse outcomes in men with MDS/MPN are associated with a higher number of somatic mutations, especially in high-risk genes. These results warrant validation in larger cohorts and investigation of the underlying mechanisms.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.

Background The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old adults and may provide insight into the physiologic response to stress. Method We performed a standard 250 µg ACTH stimulation test in a home-based substudy of 51 women aged 85–96 years enrolled in the Women’s Health and Aging Study II who were not taking corticosteroids. We examined the cortisol and dehydroepiandrosterone (DHEA) responses at 0, 30, 60, and 120 minutes, overall and by frailty status. Results The peak cortisol response to ACTH could not be determined, with the highest levels at the 120-minute time point. Pre- and post-ACTH stimulated cortisol levels did not differ by frailty status over this time frame, with no difference in the characteristics of the dose-response curves. Pre- and post-ACTH stimulated DHEA levels also did not differ by frailty status, though the dose-response curves suggested divergence after stimulation, with a more rapid DHEA response with increasing frailty. Conclusions Our data demonstrate a robust cortisol response to ACTH challenge testing, but inadequate negative feedback in old-old women, resulting in prolonged exposure to cortisol. Future studies should examine dynamic cortisol and DHEA responses in this age group, using a less potent ACTH stimulus and longer collection period.

Introduction Multifactorial biological processes underpin dysregulation over several individual physiological systems. However, it is challenging to characterize and model this multisystemic dysregulation and its relationship with individual physiologic systems. We operationalized a theory-driven measure of multisystem dysregulation and empirically tested for measurement differences by key characteristics. Methods We used the Women's Health and Aging Studies (WHAS) I and II (N = 649), and the Health ABC study (N = 1515). Twelve biomarkers representing multiple systems including stress response (e.g., inflammation), endocrine system, and energy regulation were identified. A series of confirmatory factor analyses (CFA) were conducted to evaluate the interplay between physiological systems and underlying multisystem dysregulation. We evaluated convergent criterion validity of a score for multisystem dysregulation against the physical frailty phenotype, and predictive criterion validity with incidence of walking difficulty and mortality. Results A bifactor CFA, a model in which dysregulation of individual systems proceeds independently of generalized dysregulation, fit data well in WHAS (RMSEA: 0.019; CFI: 0.977; TLI: 0.961) and Health ABC (RMSEA: 0.047; CFI: 0.874; TLI: 0.787). The general dysregulation factor was associated with frailty (OR: 2.2, 95 % CI: 1.4, 3.5), and elevated risk of incident walking difficulty and mortality. Findings were replicated in Health ABC. Discussion Biomarker data from two epidemiologic studies support the construct of multisystem physiological dysregulation. Results further suggest system-specific and system-wide processes have unique and non-overlapping contributions to dysregulation in biological markers.

Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P = .17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P = .05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD. ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneous treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made based only on an overall average treatment effect. We distinguished two categories of predictive HTE approaches (a “risk modeling” and an “effect modeling” approach) and developed four sets of guidance statements: 1) criteria to determine when risk modeling approaches are likely to identify clinically meaningful HTE; 2) methodological aspects of risk modeling methods; 3) considerations for translation to clinical practice; and 4) considerations and caveats in the use of effect modeling approaches. We also discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation; and discusses related analytic considerations, caveats, and reservations.

Subgroup analysis is a frequently used tool for evaluating heterogeneity of treatment effect and heterogeneity in treatment harm across observed baseline patient characteristics. While treatment efficacy and adverse event measures are often reported separately for each subgroup, analyzing their within-subgroup joint distribution is critical for better informed patient decision-making. In this paper, we describe Bayesian models for performing a subgroup analysis to compare the joint occurrence of a primary endpoint and an adverse event between two treatment arms. Our approach emphasizes estimation of heterogeneity in this joint distribution across subgroups, and our approach directly accommodates subgroups with small numbers of observed primary and adverse event combinations. In addition, we describe several ways in which our models may be used to generate interpretable summary measures of benefit-risk tradeoffs for each subgroup. The methods described here are illustrated throughout using a large cardiovascular trial ( $$N = 9361$$ ) investigating the efficacy of an intervention for reducing systolic blood pressure to a lower-than-usual target.

Among community-dwelling older adults, frailty is associated with heightened markers of inflammation and subsequent mortality. Although frailty is common among end-stage renal disease (ESRD) patients, the role of frailty and markers of inflammation in this population remains unclear. We quantified these associations in patients on the kidney transplant waitlist and tested whether frailty and/or markers of inflammation improve waitlist mortality risk prediction.We studied 1975 ESRD patients on the kidney transplant waitlist (November 1, 2009, to February 28, 2017) in a multi-center cohort study of frailty. Serum inflammatory markers (interleukin-6 [IL-6], soluble tumor necrosis factor-α receptor-1 [sTNFR1], and C-reactive protein [CRP]) were analyzed in 605 of these participants; we calculated the inflammatory index score using IL-6 and sTNFR1. We compared the C-statistic of an established registry-based prediction model for waitlist mortality adding frailty and/or inflammatory markers (1 SD change in log IL-6, sTNFR1, CRP, or inflammatory index).The registry-based model had moderate predictive ability (c-statistic = 0.655). Frailty was associated with increased mortality (2.19; 95% confidence interval [CI], 1.26-3.79) but did not improve risk prediction (c-statistic = 0.646; P = 0.65). Like frailty, IL-6 (2.13; 95% CI, 1.41-3.22), sTNFR1 (1.70; 95% CI, 1.12-2.59), CRP (1.68; 95% CI, 1.06-2.67), and the inflammatory index (2.09; 95% CI, 1.38-3.16) were associated with increased mortality risk; unlike frailty, adding IL-6 (c-statistic = 0.777; P = 0.02), CRP (c-statistic = 0.728; P = 0.02), or inflammatory index (c-statistic = 0.777; P = 0.02) substantially improved mortality risk prediction.Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy-to-measure markers of increased waitlist mortality risk.

Background Chronically elevated interleukin-6 (IL-6) levels contribute to fatigue and functional decline via multiple pathways that often lead to frailty. Lesser known is the contribution of IL-6 to fatigue in relation to a standardized workload (fatigability), a precursor to functional decline. Therefore, the purpose of this study was to examine the longitudinal relationship between IL-6 and fatigability. Methods About 985 participants from the Baltimore Longitudinal Study of Aging (mean age: 70 ± 10 years) were evaluated every 1–4 years. IL-6 was measured in fasting serum samples at each visit and log-transformed for analyses. Perceived fatigability (PF) was defined as self-reported exertion (rate of perceived exertion; RPE) after a 5-min, 0.67 m/s, 0% grade treadmill walk. Continuous and categorical associations between IL-6 (baseline and repeated measures) and PF were assessed using generalized estimating equations, adjusting for demographics, behavioral factors, and comorbid conditions. Results In fully adjusted continuous models, twofold higher baseline IL-6 was associated with a 0.28 higher RPE (p = .03). This relationship tended to remain constant annually (baseline log IL-6 by time interaction p = .29). To provide clinical relevance, the sample median (3.7 pg/mL) was used to examine high versus low IL-6 levels. Over time, the high group reported an average 0.25 higher RPE (p = .03) than the low group. Annual change in logged IL-6 was not associated with annual change in PF (p = .48). Conclusion Findings suggest that elevated IL-6 is a biomarker of physiological dysregulation associated with greater fatigability, but there is no longitudinal association between IL-6 and fatigability. Future studies should evaluate whether interventions that aim to reduce inflammation also attenuate fatigability.

Practitioners of Geriatric Medicine often help older patients decide whether proposed medical treatments or procedures are worth the risk of potentially devastating adverse outcomes. Although many studies have helped to identify risk factors that predispose to adverse health outcomes in older adults following medical treatments or procedures, few have allowed investigators to more deeply understand the complex biology that makes up a resilient response to medical treatments or procedures and their incumbent physical stress on the older adult. Indeed, why some older adults rebound when they experience such stressors—or are robust against insults in the first place, whereas others decline precipitously upon exposure to even mild challenges, remains largely unknown. Defining the basis of physical resilience remains one of the most complex challenges facing clinical investigators working to improve the health and safety of older adults. It is also potentially one of the most rewarding as it holds great promise for improving the health and well-being of older adults. Building on this need, and on our long-standing work to understand the biological basis of physical frailty, we have developed a conceptual framework for resiliency that hypothesizes a specific physiological underpinning, rooted in the dynamical interplay of stress-response systems. While we entertain that resiliency and frailty may entail dimensions that do not overlap, we have long hypothesized that physical or syndromic frailty is a disordered state of the same dynamical systems that produce resiliency when these same physiological systems are functioning in good order. Indeed, in our construct, frailty emerges as individual stress response systems or their networked connections erode past a functional threshold, while resiliency remains intact when the stress response systems remain functionally robust. Hence, in our view, robustness, resilience, and frailty are distinct but related and possibly overlapping concepts that tie back to homeostasis. Resiliency is a dynamic construct that can be best ascertained through “dynamic stimulation tests”. Indeed, this approach is also likely useful for identifying non-resilient persons before they encounter a major stressor as framed within a classical dynamical systems approach(1), as evidenced by a series of hallmark studies of physiological stimulation tests that were deployed in participants in the Women’s Health and Aging Studies (WHAS)(2–4). Building on this approach, we maintain that the capture of stimulated (dynamic) and unstimulated baseline measures from multiple physiological systems can be highly informative for ascertaining resiliency (5–8). Systems we have in mind include those that regulate glucose tolerance, hypothalamic pituitary adrenal (HPA) axis, autonomic nervous system, inflammatory response, and catecholamine production. This choice reflects our hypothesis that the stress response systems, represented on a measurable physiological level, lie at the center of physiological systems that either promote resilience when functioning optimally or drive frailty when functioning poorly. The dynamical systems framework by which we conceptualize the etiology of resiliency is in part informed by Csete and Doyle, who wrote that it “is in the nature of their robustness and complexity that biology and advanced engineering are most alike (9).” In engineering, robustness and resiliency are tied to a machine’s complexity, which confers flexibility by which to maintain functioning when faced with stressors. Hallmarks, and their analogy to human physiology, include: Modules - “sub-machines” or components which implement a part of the machine’s functioning. In humans, these could be cells, or organelles, or organs, or individual physiological systems. Robust health of each subcomponent tends to confer robust health of the machine as a whole. Protocols - rules by which processes governing functioning of modules and relationships between modules are managed. Even if all modules are intact, impaired protocols can lead to system failure. In the present context, protocols are the mechanisms by which physiological systems are internally regulated and co-regulated. Redundancy - well-designed complex systems have backup modules and protocols which can take over if primary modules or protocols become impaired. To implement a dynamical systems framework, we have designed research to collect measurements of physiological “modules” we hypothesize as central to resiliency and will use dynamic paradigms to assess the protocols by which they function and interact. Such a framework has clinical implications, as it might be able to distinguish whether resilience relies on the protection of key “modules” or instead on key “protocols” connecting systems to one other, or rather whether there are a multitude of ways to get to the endgame where resiliency is lost. Analysis will follow the approach proposed in Varadhan et al. (2008), where a stimulus-response modeling paradigm was detailed for deriving summary “parameters” of system functioning (1).

Background Disability in activities of daily living (ADLs) is a dynamic process and transitions among different disability states are common. However, little is known about factors affecting recovery from disability. We examined the association between frailty and recovery from disability among nondisabled community-dwelling elders. Methods We studied 1,023 adults from the Cardiovascular Health Study (CHS) and 685 adults from the Health and Retirement Study (HRS), who were ≥65 years and had incident disability, defined as having difficulty in ≥1 ADL (dressing, eating, toileting, bathing, transferring, walking across a room). Disability recovery was defined as having no difficulty in any ADLs. Frailty was assessed by slowness, weakness, exhaustion, inactivity, and shrinking. Persons were classified as “nonfrail” (0 criteria), “prefrail” (1–2 criteria), or “frail” (3–5 criteria). Results In total, 539 (52.7%) CHS participants recovered from disability within 1 year. Almost two-thirds of nonfrail persons recovered, while less than two-fifths of the frail recovered. In the HRS, 234 (34.2%) participants recovered from disability within 2 years. Approximately half of the nonfrail recovered, while less than one-fifth of the frail recovered. After adjustment, prefrail and frail CHS participants were 16% and 36% less likely to recover than the nonfrail, respectively. In the HRS, frail persons had a 41% lower likelihood of recovery than the nonfrail. Conclusions Frailty is an independent predictor of poor recovery from disability among nondisabled older adults. These findings validate frailty as a marker of decreased resilience and may offer opportunities for individualized interventions and geriatric care based on frailty assessment.

Introduction: Frailty affects 15% of non-institutionalized older adults in the United States, yet confusion remains in defining and, in turn, assessing frailty. Figurative language, such as metaphor, can help to explain difficult scientific concepts and to form new theories. We aimed to examine the use of figurative language to describe frailty and to identify themes in the way figurative expressions are used. Understanding how frailty is described figuratively may offer insights for developing useful communication approaches in research settings. Methods: We performed a comprehensive review of editorials in the scientific literature to explore figurative language used to describe frailty in older adults. We categorized themes among the figurative expressions, which may help to inform how to effectively communicate about frailty. Results: We found 24 editorials containing 32 figurative expressions. The figurative expressions conceptualized frailty in six ways: 1) a complex, multifaceted concept; 2) an important issue in health and medicine; 3) indicative of something that is failing or faulty; 4) indicative of fragility; 5) representative of vulnerable, ignored persons; and 6) an opportunity for self-awareness and reflection. Discussion: Our review highlights the heterogeneity in depictions of frailty, which is consonant with the lack of a standardized definition of frailty. We also found a novel aspect to the concept of frailty, which merits attention: frailty characterized as an opportunity for self-awareness and reflection. Figurative language, which often juxtaposes familiar with challenging, complex concepts, can offer insights on issues in frailty research and holds potential as a tool for researchers to improve communication about this important and debated medical condition.

The overuse of medical services is an increasingly recognized driver of poor quality care and high cost. A practical framework is needed to guide clinical decisions and facilitate concrete actions that can reduce overuse and improve care. We used an iterative, expert-informed evidence-based process to develop a framework for conceptualizing interventions to reduce medical overuse.

Secondary central nervous system (CNS) lymphoma is a rare and often fatal complication of non-Hodgkin lymphoma (NHL). Treatment options include radiation therapy, high-dose systemic chemotherapy, intrathecal chemotherapy, and high-dose chemotherapy with autologous stem cell rescue, but outcomes remain poor. Allogeneic blood or marrow transplantation (alloBMT) is widely used in patients with relapsed/refractory systemic NHL. We sought to understand whether a graft-versus-lymphoma effect could maintain remission in CNS disease. We reviewed outcomes in 20 consecutive patients with secondary CNS lymphoma who underwent alloBMT with nonmyeloablative conditioning using fludarabine, cyclophosphamide, and 200 cGy total body irradiation. For graft-versus-host disease prophylaxis, all patients received post-transplantation cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor. With a median follow up of 4.1 years, the median overall survival for the entire cohort was not reached. Median progression-free survival was 3.8 years (95% confidence interval [CI], 5.3 months to not reached). The cumulative incidence of relapse was 25% (95% CI, 5% to 45%), and nonrelapse mortality was 30% (95% CI, 5% to 54%) at 4 years. Of the 5 patients who relapsed, 2 were CNS only, 1 was systemic only, and 2 were combined CNS/systemic. The use of alloBMT in CNS lymphoma merits further investigation.

Bone marrow transplant (BMT) is a curative therapy for patients with hematologic malignancies. However, there is still a high rate of relapse and mortality after BMT. It would be tremendously valuable if we can identify older adults at high-risk for mortality using readily available information. A number of biomarkers are routinely collected during follow-up for clinical care, but this information is seldom used in prediction models. We examined the data from 1011 patients who had BMT at Johns Hopkins between 2013 and 2019. There were 364 death over a median follow-up of 431 days. We considered 4 biomarkers: albumin, hemoglobin, lymphocytes count, and platelets. Biomarker data from one week pre-BMT to 8 weeks post-BMT was used for prediction using a random survival forest model. The model performed quite well and had a 5-fold cross-validated c-index of 0.733 (95%CI: 0.724-0.739). Routine laboratory biomarkers can help identify poorly resilient older BMT patients.

Background: Inflammation is hypothesized to underlie premature mortality in cancer survivors, yet little is known about the inflammatory proteins and pathways involved. Methods: 474 long-term (≥5 years) older adult survivors of prostate, breast, colorectal, endometrial or bladder cancers in the ARIC study were followed from visit 5 (2011-13) to 12/2018. At visit 5, 580 plasma inflammatory proteins were assayed using the SomaScan platform, a modified aptamer-based assay. We modeled sub-distribution hazards (sHR) of non-index cancer-related death per log2 increase in each protein, adjusting for age, sex, race, years since cancer diagnosis, renal function, anti-inflammatory drug use, and cancer/CVD shared risk factors. We also investigated these proteins with mortality in survivors of the two most common cancers, prostate and breast. To account for multiple testing, we used Bonferroni correction and false discovery rate. Using Ingenuity Pathway Analysis (Qiagen®) and principal components analysis, we identified protein pathways and upstream regulators most strongly associated with mortality. Results: Survivors were 21% Black, 56% male, had a mean age of 77 yrs, and median time since diagnosis of 11 yrs. 95 non-cancer (50% CVD) and 34 non-index cancer deaths occurred in 2740 person-yrs of follow-up. After FDR correction, 49 proteins were significantly associated with risk of death. VEGF sR3, complement C1RL, CD9 antigen, insulin-like growth factor-binding protein 7 (IGFBP7), platelet-derived growth factor D (PDGFD) and interferon-induced protein (IFIT2) were most strongly positively associated, with sHR: 2.1-4.4 per two-fold increase. Transmembrane protein (TMEM230), plasminogen, TNFSF12, APOL1, serum amyloid P-component and von Willebrand factor (VWA2) were most strongly inversely associated, with sHR:0.34-0.42. Only IFIT2 remained significant after Bonferroni correction. Associations of some inflammatory proteins differed by cancer site survived. However, 2 proteins, telomeric repeat binding factor (TERF1) and toll-like receptor (TLR2), were associated with increased mortality in all, prostate, and breast cancer survivors. Proteins associated with mortality were enriched for 5 major signaling pathways - MSP-RON, IL-8, glioma/coagulation, glucocorticoid receptor, atherosclerosis, and hepatic fibrosis, and were activated or inhibited by upstream regulators: SOX7, ERG, MYC, and IL4. Conclusion: Several circulating inflammatory proteins and signaling pathways were associated with premature death in cancer survivors independent of cancer/CVD risk factors. If confirmed, these proteins/pathways may warrant evaluation as potential biomarkers for screening for risk of premature mortality, and possibly as therapeutic targets to prolong lives of cancer survivors. Funding: NHLBI, NCI, NPCR Citation Format: Chinenye C. Ugoji, Keenan A. Walker, Lorraine T. Dean, Alden Gross, Christie M. Ballantyne, Ken Butler, Ron C. Hoogeveen, Corinne Joshu, Thomas H. Mosley, Anna Prizment, A. Richey Sharrett, Adrienne Tin, Ravi Varadhan, Josef Coresh, Elizabeth A. Platz. Circulating inflammatory proteins associated with mortality from causes other than the index cancer in older adult cancer survivors in the atherosclerosis risk in communities study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 903.

Timed sequential therapy (TST) aims to improve outcomes in acute myelogenous leukemia (AML) by harnessing drug-induced cell cycle kinetics of AML, where a second drug is timed to coincide with peak leukemia proliferation induced by the first drugs. We analyzed outcomes in 301 newly diagnosed AML patients treated from 2004–2013 with cytarabine, anthracycline, and etoposide TST induction. Median age was 52 (range 20–74) and complete remission rate 68%. With median follow-up 5.8 years, 5-year DFS and overall survival (OS) were 37% (95% CI 31–45%) and 32% (95% CI 27–38%), respectively. In multivariate analysis, older age, unfavorable cytogenetics, and WBC ≥ 50 × 109/L resulted in worse OS. Among patients not undergoing blood and marrow transplant, a propensity score analysis, which reduces imbalance in baseline characteristics, showed consolidation with TST compared with 1 or more cycles high-dose cytarabine trended toward lower DFS and post-remission survival with hazard ratio (HR) 1.9 (95% CI 0.9–4.0), and 1.6 (95% CI 0.7–3.6), respectively. Our results demonstrate the efficacy and feasibility of TST induction for newly diagnosed patients with AML, with results comparable to that seen in clinical trials with other TST therapies and 7 + 3.

Although the field of frailty research has expanded rapidly, it is still a nascent concept within the clinical specialties. Frailty, conceptualized as increased vulnerability to stressors because of significant depletion of physiological reserves, predicts poorer outcomes in several medical specialties, including cardiology, HIV care, nephrology, and in the behavioral and social sciences. Incorporation of frailty assessment and frailty research into the specialties is hindered by a lack of a consensus definition, by the proliferation of measurement tools, inadequate understanding of the biology of frailty, and lack of validated clinical algorithms for patients who have frailty. In 2015, the American Geriatrics Society, the National Institute on Aging (NIA) and the Alliance for Academic Internal Medicine held a conference for awardees of the NIA sponsored ‘Grants for Early Medical/Surgical Specialists Transition into Aging Research (GEMSSTAR)’1 program to review the current state of the knowledge regarding frailty in the sub-specialties, as well as to highlight key examples of integrating frailty research into the medical specialties. Key research questions to advance frailty research into specialty medicine are proposed.

Demographic studies of mortality often emphasize the two ends of the lifespan, focusing on the declining hazard after birth or the increasing risk of death at older ages. We call attention to the intervening phase, when humans are least vulnerable to the force of mortality, and consider its features in both evolutionary and historical perspectives. We define this quiescent phase (Q-phase) formally, estimate its bounds using life tables for Swedish cohorts born between 1800 and 1920, and describe changes in the morphology of the Q-phase. We show that for cohorts aging during Sweden’s demographic and epidemiological transitions, the Q-phase became longer and more pronounced, reflecting the retreat of infections and maternal mortality as key causes of death. These changes revealed an underlying hazard trajectory that remains relatively low and constant during the prime ages for reproduction and investment in both personal capital and relationships with others. Our characterization of the Q-phase highlights it as a unique, dynamic, and historically contingent cohort feature, whose increased visibility was made possible by the rapid pace of survival improvements in the nineteenth and twentieth centuries. This visibility may be reduced or sustained under subsequent demographic regimes.

Post-transplantation cyclophosphamide (PTCy) can be used for graft-versus-host disease (GVHD) prophylaxis alone or in combination with other agents and is associated with excellent rates of engraftment and acute and chronic GVHD, as well as absence of post-transplantation lymphoproliferative disease. No study has previously evaluated the risk for developing donor-derived malignancy (DDM) in patients who receive PTCy. Giving chemotherapy in the immediate post-transplantation period carries with it a theoretic risk of disturbing the graft at a time of increased hematopoietic stress and causing or accelerating the development of malignancy. From 2000 to 2011, 789 patients underwent allogeneic transplantation and received PTCy at the Johns Hopkins Hospital. There were 4 cases of DDM identified among this large population, which is similar to or below the rate of DDM published in the literature. We found that the estimated cumulative incidence by competing risk analysis of DDM is 1.4% (SE, 1.02%). The use of PTCy does not appear to increase the risk of DDM.

Background: Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are found in approximately 20% of patients with acute myeloid leukemia (AML). Although independent prognostic data are lacking, our program often moves patients with IDH-mutated AML (mIDH) towards allogeneic bone marrow transplant (BMT). Reports on the impact of mIDH on BMT outcomes are conflicting. One study (Quek L, et al. Blood Adv. 2016; 1(3):19320) found improved rates of relapse (RR), relapse free survival (RFS) and overall survival (OS) for patients with mIDH1, whereas another study (Salhotra A, et al. Clin Lymphoma, Myeloma Leuk. 2019 Jul 1;19(7):e400-5) reported higher RR, but no differences in RFS or OS for patients with mIDH1/2. In light of the approved IDH1/2 inhibitors, the role of early BMT for such patients requires additional study. We examined the BMT outcomes of patients with mIDH AML compared to wildtype (wt)-IDH AML. Patients and methods: Patients with AML who underwent a first allo-BMT at Johns Hopkins between 2014 and 2020 and had molecular testing for IDH mutation status were included. Patients were grouped according to IDH mutation status (mIDH versus wt-IDH). Patient demographics, molecular genetics, initial treatment response, and BMT characteristics were compared. Post-BMT RR, RFS and OS were then compared between groups. Multivariate models were used to assess the prognostic significance of mIDH after controlling for co-variates. We also examined the relationship between peri-BMT IDH inhibitor use and IDH mutation status at the time of post-BMT relapse. Results: We identified 109 patients with mIDH AML, 70 (64%) of whom underwent BMT. 210 BMT patients with wt-IDH AML were used as a comparison. Outcomes between patients with mIDH1 and mIDH2 AML were similar and they were combined for all further analyses. Patients with mIDH were generally older (mean age at diagnosis 61 (range 28-75) vs. 54 (range 19-76), p < .001), less likely to have poor-risk cytogenetics, more likely to have a haploidentical donor, and more likely to receive non-myeloablative conditioning (Table 1). mIDH AML was associated with co-mutations in SRSF2 and DNMT3A mutations and less likely to have TET2 and KRAS co-mutations. Patients with mIDH had significantly improved post-BMT RR, RFS and OS compared to patients with wt-IDH (log rank p = 0.04, .01, and .01 respectively, Figure 1). In a multivariate model controlling for ELN risk classification, mIDH was associated with improved OS with a trend towards significance (HR 0.51, 95% CI 0.24 - 1.10, p = 0.085). Recognizing that significant heterogeneity exists within ELN risk groups, we examined the specific components of poor ELN risk classification in each group and found that poor risk in the wt-IDH group was primarily driven by complex karyotypes and TP53 mutations, whereas the ELN poor risk was driven by RUNX1 or ASXL1 co-mutation in the mIDH group. In a model controlling for specific genetic abnormalities (complex karyotype, TP53 mutation, and KRAS mutation) IDH mutation status was not an independent prognostic factor (HR 0.66, 0.34 - 1.28, p = 0.2, Table 2). We also assessed whether improved outcomes might be associated with use of IDH inhibitors in the pre or post-BMT setting. 22 (31%) of the 70 patients with mIDH AML received pre-BMT IDH inhibitors and an additional 4 patients received post-BMT maintenance. Of the 15 patients with mIDH who relapsed post-BMT, 13 had mIDH at the time of relapse. 11 of the 11 patients who had never received an IDH inhibitor had mIDH at relapse compared to 2 of 4 (50%) patients who had received IDH inhibitors (p = .057). Conclusion: In our cohort, patients with mIDH AML had significantly better OS, RFS, and RR following BMT compared to patients with wt-IDH. However, our analyses suggest that IDH mutations are associated with favorable genetic abnormalities and that the differences in BMT outcome are likely attributable to these differing genetic profiles as opposed to the presence of the mIDH. Differences in outcome were specifically driven by a lower prevalence of complex cytogenetics, TP53 mutations, and KRAS mutations amongst mIDH AML and were incompletely captured by ELN risk classification. In addition, the frequency with which post-BMT relapsed AML bears the IDH-mutant clone suggests that incorporation of IDH inhibitors into the peri-BMT setting, as is currently being studied in large randomized trials (NCT03564821, NCT03515512), may further improve outcomes. Disclosures DeZern: Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy. Levis:Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Menarini: Honoraria. Smith:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction: Females are born with a set number of ovarian follicles. Ovarian reserve, defined by the number of primordial follicles, decreases with age. Diminished ovarian reserve (DOR) is a risk factor for shortened reproductive lifespan, infertility and poor assisted reproductive technology outcomes. Young women with sickle cell anemia (SCA) are at risk for DOR1,2. Whether hydroxyurea (HU) use contributes to this risk is not established. Antimullerian hormone (AMH), a biomarker of the ovarian follicle pool, is used with antral follicle count (AFC) and follicle stimulating hormone (FSH), to estimate ovarian reserve. The extent to which AMH corresponds with visualized AFC in SCA, and thus serves as a reasonable surrogate biomarker, is unknown. The purpose of this study was to test the hypothesis that young women with SCA have lower AMH than age and race matched controls and that HU exposure is a risk for DOR. Methods: Subjects from our Adult Sickle Cell Center had ovarian reserve measured on day 3-5 of the menstrual cycle or at any time if on menses-suppressing contraception. We measured serum AMH, FSH, estradiol and AFC by ultrasound. Subjects' demographic, reproductive and SCA treatment history were obtained. HU exposure variables included (1) age at first exposure, (2) use at time of study visit, (3) markers of adherence (MCV and ANC), and (4) refill data. Ferritin was used to assess iron overload. We compared AMH levels in subjects ages 19-25 and 26-31 years to AMH levels in age-matched African American women controls with tubal factor infertility and no chemotherapy exposure, and age-matched levels from the historic Multicenter Study of Hydroxyurea (MSH) cohort2. We then compared subject characteristics by the presence of DOR (AMH 10 - 40IU) or primary ovarian insufficiency (POI), (AMH < 1.1ng/mL and FSH ≧ 40IU). The chi-squared and Mann Whitney U test was used for categorical and continuous variables, respectively, to determine associations with DOR. Results: Sixteen women with SCA participated with a median age of 25.5 years (IQR 21,29), hemoglobin 8.8g/dL (IQR 8,9.2), MCV 96.9fL (IQR 88.6, 101.1), ANC 5.7K/mcl (IQR 3.4, 8.4), and ferritin 857ng/mL (IQR 246, 1957). All had prior HU exposure. The median age at first HU exposure was 17.5 years (IQR 14.5, 21), median months of HU exposure was 23 (IQR 2.8, 38.5). Twelve subjects were taking HU at the study visit and, by refills, 7 took continuous HU in the previous 6-months, median dose 1715mg (IQR 1000, 2000). Lower AMH and AFC was observed in older subjects as expected. AMH was lower in study subjects compared to controls in both age groups: 19 - 25 years [2.48ng/mL (IQR 1.7, 3.4) vs 7.45ng/mL (IQR 6.5, 10.7), p0.05)1. Younger women (19-25yo) had higher median AFC than older women (26-31yo), a difference that was not statistically significant (14(IQR 8, 35) vs 9(IQR 7,12) follicles). Four of 16 subjects had DOR; all four were taking HU and >25yo. In those with or without DOR, there was no difference in median BMI (21.1(20.7, 22.4) vs 24.7 (IQR 20.8, 26.2), hemoglobin (8.7 (IQR 8.4, 8.9) vs 8.8 (7.9, 9.8) g/dL), or ferritin (602 (IQR 131, 1529) vs 875 (IQR 303, 1975). DOR was associated with a lower median AFC (5.5(IQR 4, 7) vs 12 (IQR 9,24) oocytes p=0.04) and higher MCV (112 vs 92fL, p=0.02). Table 1 compares DOR and HU exposure our cohort, the MSH2 and a pediatric cohort1. In all cohorts, some young women exposed to HU have DOR. Conclusions In this pilot study of ovarian reserve in young adult women with SCA, AMH is significantly lower in age- and race-matched controls and levels are similar to an historic SCA cohort. AMH and AFC were both lower in older subjects, suggesting that AMH is a reasonable ovarian reserve marker in SCA. No women had POI. DOR was associated with lower AFC and higher MCV. In young adult women of reproductive age with SCA, taking HU may be a risk for DOR. This data forms the basis for ongoing research on the pathobiological mechanisms and clinical significance of DOR in women with SCA. References 1Pecker, LH et al. Hydroxycarbamide and ovarian reserve in the Multicenter Study of Hydroxycarbamide. British Journal of Haematology. 2020. 2Elchuri, SV et al. The effects of hydroxyurea and bone marrow transplant on AMH levels in females with SCA. Blood Cells Mol Dis. 2015. Disclosures Pecker: Forma Therapeutics: Consultancy. Lanzkron:GBT: Research Funding; HRSA: Research Funding; Ironwood: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; Pfizer: Research Funding; Pharmacy Times Continuing Education: Honoraria; Prolong: Research Funding.

Background We previously demonstrated comparable immune reconstitution after HLA-matched sibling (MSD), HLA-matched unrelated (MUD), and HLA-haploidentical (haplo) bone marrow transplantation (BMT) with posttransplant cyclophosphamide (PTCy). Here, we use machine learning algorithms to identify predictive immunologic variables, providing insight for future translational interventions. Methods We assessed 11 pre-transplant factors, 22 immune subsets, and 7 serum markers at day 28 and day 56 post-BMT in 70 patients who engrafted after myeloablative conditioned (MAC) haplo BMT with PTCy (50mg/kg on days +3 and +4), mycophenolate mofetil (days +5-35), and tacrolimus (days +5-180) and 74 patients who engrafted after MAC HLA-matched BMT with PTCy (50mg/kg on days +3 and +4). Classification and regression tree machine based learning with nodal selection was applied to detect risk groups for four outcomes: overall survival (OS), progression-free survival (PFS), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD). Results When compared with cytomegalovirus (CMV) seronegative recipients, CMV seropositive recipients had higher CD3+ T cells, effector memory (EM) CD4+ T cells, T effector memory expressing RA (TEMRA) CD4+ T cells, CD8+ T cells, EM CD8+ T cells, and TEMRA CD8+ T cells at early time points after both BMT platforms (not shown). Pre-BMT disease status and natural killer (NK) cell count at day 28 emerged as predictive variables for survival. Two-year OS and PFS for patients in complete remission (CR) with NK cells >54 cells/µL were 98% and 89%, in CR with NK cells 55 cells/µL, the CuI of aGVHD was 18% in those with CXCL-9 Conclusion Machine learning using immune cellular and soluble markers can be successfully applied to identify risk factors for BMT outcomes. High CD4+ counts and CXCL-9 levels at day 28 predicted aGVHD and high reg3α at day 56 predicted cGVHD. Both CXCL-9 and reg3α represent potential therapeutic targets. Finally, disease status and NK cell counts at day 28 predicted OS and PFS. These data support research to determine what influences NK cell recovery as well as to investigate NK cell therapy for recipients with active disease or for those with poor early NK cell reconstitution.

Older patients with ESRD who receive a kidney transplant (KT) may develop post-KT dementia and Alzheimer's disease (AD) associated with their long-standing kidney disease and/or neurotoxic immunosuppressant agents. To investigate this possibility, we studied 40,918 older (aged ≥55 years) KT recipients (January 1, 1999 to December 31, 2011) linked to Medicare claims through the US Renal Data System. We estimated dementia and AD risk (cumulative incidence) and studied factors associated with these sequelae using competing risks models. We estimated the risk of death-censored graft loss and mortality after developing dementia or the AD subtype of dementia, separately, using adjusted Cox proportional hazards models. Older recipients had a 10-year dementia risk ranging from 5.1% for recipients aged 55–60 years to 17.0% for recipients aged ≥75 years; 10-year AD risk ranged from 1.0% to 6.7%, respectively. The strongest predictors for dementia and AD were older recipient age and pretransplant diabetes. The 10-year graft loss risk was 28.8% for those who did not develop dementia and 43.1% for those who did, and the corresponding mortality risks were 55.7% and 89.9%, respectively. Older recipients with dementia had a 1.52-fold (95% confidence interval, 1.39 to 1.68) increased risk of graft loss and a 2.38-fold (95% confidence interval, 2.26 to 2.49) increased risk of mortality. We observed similar results for AD. We conclude that older KT recipients have a high risk of post-KT dementia and AD, and these sequelae associate with a profound effect on patient and graft survival.

Background: Physical frailty is a clinical syndrome associated with aging and manifesting as slowness, weakness, reduced physical activity, weight loss, and/or exhaustion. Frail older adults often report that their major problem is “low energy”, and there is indirect evidence to support the hypothesis that frailty is a syndrome of dysregulated energetics. We hypothesized that altered cellular energy production underlies compromised response to stressors in the frail. Methods: We conducted a pilot study to assess muscle energetics in response to a mild isometric exercise challenge in women (n=30) ages 84-93 years. The frailty status was assessed by a validated physical frailty instrument. Localized phosphorus (P31) magnetic resonance spectroscopy with a 1.5T magnet was used to assess the kinetics of Phosphocreatine recovery in the tibialis anterior muscle following maximal isometric contraction for 30 seconds. Results: Phosphocreatine recovery following exertion, age-adjusted, was slowest in the frail group (mean=189 sec; 95%CI: 150,228) compared to pre-frail (mean=152 sec; 95%CI: 107,197) and nonfrail subjects (mean=132 sec; 95%CI: 40,224). The pre-frail and frail groups had 20 sec (95%CI: -49,89) and 57 sec (95%CI: -31,147) slower phosphocreatine recovery, respectively, than the non-frail. This response was paralleled by dysregulation in glucose recovery in response to oral glucose tolerance test in women from the same study population. Conclusions: Impaired muscle energetics and energy metabolism might be implicated in the physical frailty syndrome.

Allogeneic blood or marrow transplantation (allo-BMT) remains the only treatment for chronic lymphocytic leukemia (CLL) with curative potential. Although post-transplantation cyclophosphamide (PTCy) reduces allo-BMT toxicity by decreasing the risk of graft-versus-host disease (GVHD), its effect on CLL allo-BMT outcomes is unknown. We studied 64 consecutive patients with CLL who underwent nonmyeloablative (NMA) haploidentical allo-BMT at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. In this cohort, the 4-year overall survival was 52% (95% confidence interval [CI], 40% to 68%), and progression-free survival was 37% (95% CI, 26% to 54%). Six patients experienced engraftment failure. PTCy prophylaxis was associated with a modest cumulative incidence of 1-year grade II-IV acute GVHD (27%; %95% CI, 15% to 38%) and %%%2-year chronic GVHD (17%; 95% CI, 7% to 26%). We demonstrate that NMA haploidentical allo-BMT with PTCy is a safe and effective treatment option.

Hematologic malignancies in older people are unlikely to be cured with chemotherapy alone. Advances in allogeneic blood or marrow transplantation (alloBMT), especially nonmyeloablative (NMA) conditioning and the use of haploidentical donors, now make this therapy available to older people; however, long-term outcomes and predictors of success are unclear. We reviewed the outcomes of 93 consecutive patients aged 70 and older (median, 72; range, 70-78), who underwent haploidentical BMT at Johns Hopkins Hospital between 1 September 2009 and 1 April 2018. All patients received NMA conditioning and posttransplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis. The 2-year overall survival was 53%, and 2-year event-free survival was 43%. The 180-day cumulative incidence (CuI) of nonrelapse mortality (NRM) was 14%, and the 2-year CuI was 27%. The 2-year CuI of relapse was 30%. Of 78 patients who were alive and had their weight recorded on day 180, weight loss predicted subsequent NRM (subdistribution hazard ratio, 1.0; 95% CI, 1-1.13; P = .048). In conclusion, haploidentical BMT with PTCy is feasible and relatively safe in septuagenarians. Although early, 6-month NRM was relatively low at 14%, but overall NRM continued to climb to 27% at 2 years, at least in part because of late deaths that appeared to be somewhat age related. Further studies to elucidate predictors of NRM are warranted.

Prior to the introduction of rituximab, primary mediastinal B-cell lymphoma (PMBCL) had high rates of treatment failure with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), prompting the use of consolidative mediastinal radiation or more intensive chemotherapy regimens. Cure rates improved dramatically with rituximab, but mediastinal radiation was still commonly employed with R-CHOP. We performed a retrospective review of patients treated with R-CHOP alone without radiation for PMBCL. Of 43 patients with PMBCL, 16 received R-CHOP alone. High-risk factors included 56% with bulky disease, 75% with elevated LDH, 25% with SVC syndrome, and 13% with stage IV disease. Three-year progression-free survival (PFS) and overall survival (OS) were 93% and 100% respectively. These results suggest that R-CHOP alone has a high cure rate in PMBCL while avoiding the side effects of mediastinal radiation.