Preconditioning Frailty Phenotype Influences Survival and Relapse for Older Allogeneic Transplantation Recipients.

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST_3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST_3y. Estimates of RMST_3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT_3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT_3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted.

Longitudinal changes in cognitive and physical function and health-related quality of life in older adults with acute myeloid leukemia.

INTRODUCTION: Many older adults with acute myeloid leukemia (AML) do not receive chemotherapy because of physicians' and patients' concern for toxicities and functional decline. This highlights the critical and urgent need to generate knowledge of functional changes following new treatments. MATERIALS AND METHODS: As a part of a pragmatic single-center trial, 59 older adults ≥60 years with AML completed geriatric assessment and health-related quality of life measures before treatment and at one month and three months after chemotherapy initiation. Changes in scores of various geriatric assessment measures were computed by subtracting the baseline score from the one-month and three-month scores for each patient. Established cut-offs were used to determine a clinically meaningful change (improvement or worsening). This study provides results of descriptive exploratory analyses. RESULTS: Patients experienced significant comorbidity burden and a high prevalence of functional impairments before treatment, with 56% of patients having ≥2 comorbid conditions, 69% having abnormal cognitive function (using Montreal Cognitive Assessment), 69% having impaired objective physical function (using Short Physical Performance Battery), and 64% having a positive depression screen (Patient Health Questionnaire-9). Patients (n = 53) received treatment with predominantly low-intensity chemotherapy; six patients received intensive chemotherapy. Among those who completed some or all of the three-month evaluation (N = 43), from baseline before treatment to three months later, cognitive function improved (38.7%) or remained stable (38.7%), objective physical function improved (51.6%) or remained stable (22.6%), and depression scores improved (9.4%) or remained stable (53.1%). Global health status score and role functioning moderately improved by a score of >16. DISCUSSION: An exploratory analysis of our phase 2 trial demonstrated improvement or stabilization of cognitive and physical function and depression score at three months in a high proportion of older survivors of AML, despite a high prevalence of frailty and significant comorbidity burden at baseline. These results demonstrate success of treatment in improving cognitive and physical function and depression score, and, if confirmed in larger studies, should encourage oncologists to offer chemotherapy to older adults with AML. CLINICAL TRIAL REGISTRATION: The study is registered in the ClinicalTrials.gov ID: NCT03226418.

Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia.

INTRODUCTION: Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection. MATERIALS AND METHODS: In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418). In the present report, we demonstrate feasibility of this approach. RESULTS: Broad eligibility criteria and co-management of patients with community oncologists allowed enrollment of 45% of all patients with AML treated at our center during the study period. The median time from enrollment to therapy initiation was two days (range 0-9). Over half of the trial patients had a score of ≥3 on hematopoietic cell transplantation comorbidity index, impairment in physical function (Short Physical Performance Battery), and Montreal Cognitive Assessment. Three fit patients received intensive chemotherapy, whereas other patients received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 3.7% (95% confidence interval [CI] 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). One-year overall survival was 66% (95% CI 60-87%). DISCUSSION: Our data demonstrate the feasibility of integrating geriatric assessment in precision oncology trials to define fitness for intensive chemotherapy. Broad eligibility criteria and academic-community collaboration can expand access to clinical trials.

NCCN Guidelines® Insights: Older Adult Oncology, Version 1.2021.

The NCCN Guidelines for Older Adult Oncology address specific issues related to the management of cancer in older adults, including screening and comprehensive geriatric assessment (CGA), assessing the risks and benefits of treatment, preventing or decreasing complications from therapy, and managing patients deemed to be at high risk for treatment-related toxicity. CGA is a multidisciplinary, in-depth evaluation that assesses the objective health of the older adult while evaluating multiple domains, which may affect cancer prognosis and treatment choices. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines providing specific practical framework for the use of CGA when evaluating older adults with cancer.

Breaking the Age Barrier: Physicians' Perceptions of Candidacy for Allogeneic Hematopoietic Cell Transplantation in Older Adults.

Despite continuing increases in the use of allogeneic hematopoietic cell transplantation (alloHCT) in older adults, no standardized geriatric assessment (GA) has been established to risk stratify for transplantation-related morbidity. We conducted a survey of transplant physicians to determine perceptions of the impact of older age (≥60 years) on alloHCT candidacy, and utilization of tools to gauge candidacy. This 23-item online cross-sectional survey was distributed to HCT physicians caring for adults in the United States between May and July 2019. Of the 770 invited HCT physicians, 175 (22.7%) completed the survey. The majority of respondents were age 41 to 60 years and male and practiced in a higher-volume teaching hospital. When considering regimen intensity, 29 physicians (17%) stated they would consider a myeloablative regimen for patients age ≥70 years, and 141 (82%) would consider reduced-intensity/nonmyeloablative conditioning for patients age ≥70 years. Almost all (90%) endorsed the need for a specialized assessment of pre-HCT vulnerabilities to guide candidacy decisions for older adults. Most physicians reported that their centers rarely (33%) or never (46%) use a dedicated geriatrician/geriatric-oncologist to assess alloHCT candidates age ≥60 years. Common barriers to performing a GA included uncertainty about which tools to use, lack of knowledge and training, and lack of appropriate clinical support staff. Many alloHCT physicians will consider alloHCT in patients up to age 75 years and not uncommonly in patients older than that. However, the application of tools and domains to assess candidacy in older adults varies widely. Incorporation of a standardized pretransplantation health assessment tool for risk stratification is a significant unmet need.

Health-related and sociodemographic factors associated with physical frailty among older cancer survivors.

OBJECTIVE: The purpose of this study was to examine factors associated with frailty in older cancer survivors. MATERIALS AND METHODS: This is a cross-sectional study using data from the National Social Health and Aging Project (NSHAP) Wave 2, and includes an in-home, nationally representative sample of community-dwelling adults ≥50 years and older from the United States. Frailty score was computed for each individual using a modified 4-point scale based on the phenotypic frailty. Ordinal logistic regression was used to characterize the association between health-related, sociodemographic factors and frailty. RESULTS: Among the 3377 participants, 461 were cancer survivors (answered "yes" to "ever have cancer other than skin cancer"). A final sample of 394 cancer survivors were included: 59 participants (16.1%) were frail, 219 participants were pre-frail (59.8%), and 88 participants were non-frail (24.0%). The univariate analyses showed increasing age (OR 1.48; CI 1.29-1.72; p-value <.001), comorbidities (OR 1.43; CI 1.25-1.64; p-value <.001), depression (OR 1.27; CI 1.19-1.35; p-value <.001) and low mobility (OR 1.55; CI 1.37-1.78; p-value <.001) were associated with frailty. Participants with high self-rated (good/very good/ excellent) physical health (OR 0.18; CI 0.11-0.30; p < .001) and mental health (OR 0.27; CI 0.15-0.50; p < .001) were less likely to be frail. In a multivariate model, frailty was associated with age, self-rated physical health, depression, ability to perform activities of daily living, and mobility (p < .05). CONCLUSION: The findings highlight the importance of incorporating geriatric assessment into cancer survivorship to prevent and delay the progression of frailty.

Geriatric assessment in older alloHCT recipients: association of functional and cognitive impairment with outcomes.

Use of allogeneic hematopoietic cell transplantation (alloHCT) is increasing in older patients with hematologic malignancies. Studies suggest that geriatric assessment (GA), incorporating functional measures such as instrumental activities of daily living (IADL), delineates subtle age-related impairments that enhance risk-stratification. The objective of this multi-institutional retrospective study was to evaluate the prognostic utility of GA metrics collected pre-alloHCT. Eligibility criteria included age ≥50 and pre-alloHCT GA inclusive of at least IADL. Beyond IADL, additional geriatric metrics were collected where available and included Medical Outcomes Study Physical Health score (MOS-PH), Timed Up and Go (TUG), and cognition by Blessed Orientation Memory Concentration (BOMC). Three hundred thirty subjects were included, with a median age of 63 (range 50 to 77). Impairments were frequent: 36% had at least 1 IADL impairment; 14% had TUG ≥13.5 seconds; and 17% had cognitive impairment (BOMC ≥ 7). Median MOS-PH score was 80. IADL and age were not significantly associated with nonrelapse mortality (NRM) or overall survival (OS). In multivariate analysis, only impaired cognition and Hematopoietic Cell Transplant-Comorbidity Index score ≥3 showed an independent association with 1-year NRM (subdistribution hazard ratio [SHR], 2.36; P = .01; and SHR, 2.19; P = .009, respectively). Cognitive impairment independently conferred inferior 1-year OS (hazard ratio, 1.94; P = .01). In a preplanned subgroup analysis in 224 patients aged ≥60 years, cognitive impairment remained the sole GA metric predictive of NRM (2-year NRM: SHR, 2.72; P = .007). These data suggest that cognitive impairment elevates risk of post-alloHCT NRM in older patients.

Prevalence and effects of polypharmacy on overall survival in acute myeloid leukemia.

Polypharmacy, usually defined as taking ≥5 prescribed medications, increases chances of drug-drug interactions and toxicities, and may harm cancer patients who need multiple chemotherapeutic agents and supportive medications. We analyzed the effects of polypharmacy in overall survival (OS) in acute myeloid leukemia (AML). A total of 399 patients were divided into two groups: patients with polypharmacy (≥5 medications) versus without polypharmacy (<5 medications). Polypharmacy was associated with age ≥60 years, Karnofsky Performance Status of ≤80, hematopoietic cell transplant (HCT) comorbidity index of ≥5, and adverse cytogenetics. Patients with polypharmacy were less likely to receive intensity chemotherapy or HCT. One-year OS of patients with polypharmacy versus those without polypharmacy was 29 vs. 49% (p<.001). Polypharmacy conferred worse OS in patients <60 years (37 vs. 65% at 1 year, HR 1.95, 95% CI 1.21-3.15) but not in patients ≥60 years (26 vs. 27% at 1 year, HR 1.12, 95% CI 0.81-1.57). Thus, polypharmacy has negative impact on OS in AML, particularly among patients aged <60 years.

The underreporting of phase III chemo-therapeutic clinical trial data of older patients with cancer: A systematic review.

PURPOSE: Inspired by the American Society of Clinical Oncology's recommendations to strengthen the evidence base for older adults with cancer, the purpose of this systematic review is to identify the reporting of treatment efficacy and adverse events specific to older adults with cancer in Phase III chemo-therapeutic clinical trials. This review also investigates the frequency with which these data points were reported in the literature to identify gaps in reporting and opportunities to expand the knowledge base on clinical outcomes for older adults with cancer. METHODS: Chemo-therapeutic clinical trial data published from July 1, 2016 to June 30, 2017 was reviewed. Manuscripts (n = 929) were identified based on keyword searches of EMBASE and PubMed. After removal of duplicates (n = 116) and articles that did not meet this study's inclusion criteria (n = 654), 159 articles were identified for review. RESULTS: Reviewed papers were published in 36 different scientific journals and included twenty-five different cancer types. Of the 159 articles, 117 (73.6%) reported age-specific medians and 75 (47.2%) included stratifications of data by age. Treatment efficacy was reported in 96.2% of the articles with 39.9% reporting effectiveness of treatment by age. Reporting of adverse events was included in 84.9% of the articles with only 8.9% reporting these events stratified by age. CONCLUSION: Results suggest inadequate reporting of treatment efficacy and adverse events as well as basic descriptive statistics about the age distribution of study subjects. Conscious efforts are needed to address these deficiencies at every level of planning and conducting clinical trials as wells as reporting outcomes stratified by age. Ultimately, standardized reporting could lead to improved treatment decisions and outcomes for older adults with cancer.

Returning to life activities after hematopoietic cell transplantation in older adults.

OBJECTIVES: The prevalence of hematopoietic cell transplant (HCT) among older adults with hematological malignancies has more than doubled over the last decade and continues to grow. HCT is an intense process that can impact functional status and health-related quality of life. The objective of this paper is to describe the experience of returning to life activities after HCT in patients 60 years of age and older and the resources required to adapt and cope to limitations in physical, psychological, and cognitive function. MATERIALS AND METHODS: Twenty English speaking adults 60 years and older with hematological malignancy 3 to 12 months post-HCT completed semi-structured interviews. Open-ended questions and probes were guided by the Transactional Model of Stress and Coping to explore adaptive functioning, coping resources, and coping strategies. An integrated grounded theory approach was used to code the textual data to identify themes. The study took place at a tertiary comprehensive cancer center in the Midwest United States. RESULTS: Eight allogeneic and twelve autologous HCT recipients participated in the interviews. Nineteen participants were within 6-12 months and 1 participant was at 3 months post-HCT. Our findings identify the significant role of engaging in life activities and social support in the recovery of physical, psychological and cognitive function. CONCLUSION: Older HCT recipients are an understudied population. They are at high risk for functional decline. Our findings may provide community oncologists and primary care physicians with a context for providing care to older HCT survivors during their recovery.

Screening for cognitive impairment in older adults with hematological malignancies using the Montreal Cognitive Assessment and neuropsychological testing.

OBJECTIVES: The primary objective of the current study is to describe the prevalence and profile of cognitive domains affected in older adults with hematological malignancies evaluated for hematopoietic cell transplantation (HCT) using the Montreal Cognitive Assessment (MoCA) and neuropsychological tests. The secondary objective is to determine if a specific MoCA cut-off score would correlate with the identification of cognitive impairment detected by neuropsychological tests. This would facilitate interpretation of cognitive screening and referral of patients who would likely need further neuropsychological testing. MATERIALS AND METHODS: Fifty-one patients 60 years and older who were evaluated for HCT were assessed using a battery of standardized neuropsychological tests and MoCA. We analyzed Receiver Operating Characteristics (ROC) comparing MoCA scores and four different neuropsychological test criteria for cognitive impairment. RESULTS: The prevalence of cognitive impairment detected by neuropsychological tests was 53 to 70.6% using the criteria for patients with cancer by the International Cancer Cognition Task Force (ICCTF). The following cognitive domains were most affected: language, learning and memory, visuospatial skills, and executive function. MoCA is an appropriate screening test for cognitive impairment. Using the ICCTF criteria, 86 to 100% of patients are correctly classified as having significant cognitive impairment on neuropsychological tests using a cut-off score of 20 or less. CONCLUSION: There is a high prevalence of cognitive impairment identified by neuropsychological tests in older patients with hematological malignancies evaluated for HCT. Identification of an appropriate MoCA cut-off score in this population is important to identify patients who would benefit from further assessment.

Expanding Therapeutic Options for Older Adults: Case-Based Updates in Breast and Lung Cancer.

Oncology care has become increasingly complex, with a dramatic increase in the number of available therapy options. Many newly developed medications have novel mechanisms of action and include targeted therapies and immunotherapy options. These agents typically have unique side effects that differ from more traditional cytotoxic chemotherapy regimens. Older adults represent the majority of patients with cancer and it is important for geriatricians and primary care providers for older adults to have a general understanding of newer agents and novel therapies, in order to aid in decision-making and supportive care strategies during oncology treatment. This review provides a case-based approach to discussing emerging therapeutic treatment options, including targeted therapies and immune-based therapies, in two common malignancies affecting older adults. Incorporation of available evidence of specific novel therapies in older adult populations is discussed. J Am Geriatr Soc 67:1012-1019, 2019.

Frailty in Hematologic Malignancy.

PURPOSE OF REVIEW: Older adults with hematologic malignancy are a growing demographic. Estimating risk of chemotherapy toxicity based on age alone is an unreliable estimate of quality of life, functional capacity, or risk of treatment complications. RECENT FINDINGS: Dedicated geriatric assessment tools can aid the clinician in identifying geriatric syndromes such as frailty, resulting in improved prognostication to decrease morbidity and mortality. Frailty is not synonymous with individual performance status and is dynamic. Establishing the patient goals, values, and preferences is central to the consideration of malignant hematology decision process. Careful considerations of available data on the patient's prognosis based on estimated life expectancy, geriatric assessment data, and age-specific cancer mortality, with and without treatment, can reconcile the risks and benefits. Assessments of frailty can aid the clinical feasibility and burden of the treatment to the patient and family in the context of each patient's unique needs.

Initial therapy for acute myeloid leukemia in older patients: principles of care.

Older patients with acute myeloid leukemia (AML) frequently have significant comorbidities, geriatric syndromes, and high-risk leukemia that make them susceptible to high early mortality, chemotherapy-related toxicities, and poor long-term survival. The receipt of chemotherapy or hematopoietic cell transplantation is low, and the choices between intensive or low-intensity chemotherapy is often not clear. Geriatric and multidisciplinary interventions targeted to optimize functional status and improve management of comorbidities may enhance chemotherapy tolerance. Comprehensive geriatric assessment, and other integrated risk assessment models have been developed to predict the risk of chemotherapy-related toxicities and survival, and may guide therapy assignment. Development of low intensity but effective therapy is a major need. Deeper understanding of the molecular biology of AML has allowed several novel therapies to enter clinical trials in recent years. Continuation of successful collaboration between several stakeholders will be necessary to build upon the clinical and research improvements made thus far.

Motivating Older Adults with Cancer to Keep Moving: the Implications of Lifestyle Interventions on Physical Activity.

PURPOSE OF REVIEW: The purposes of this review are to describe the unique needs and preferences of older adults with cancer regarding physical activity and to outline the essential characteristics associated with increased physical activity resulting from lifestyle interventions in older adults. RECENT FINDINGS: Functional decline is accelerated in inactive and sedentary older adults. Even a modest increase in physical activity can improve physical function for older cancer survivors. Participation in physical activity is influenced by diverse individual-level factors, behavioral characteristics and skills and social and environmental factors. Thus, programs that are tailored to older adults' preferences provide social support and remove obstacles to participation may be more effective, particularly for older adults with low physical activity and sedentary lifestyle.

Supportive Care in Older Adults with Cancer: Across the Continuum.

Supportive care is an essential component of anticancer treatment regardless of age or treatment intent. As the number of older adults with cancer increases, and supportive care strategies enable more patients to undergo treatment, greater numbers of older patients will become cancer survivors. These patients may have lingering adverse effects from treatment and will need continued supportive care interventions. Older adults with cancer benefit from geriatric assessment (GA)-guided supportive care interventions. This can occur at any stage across the cancer treatment continuum. As a GA commonly uncovers issues potentially unrelated to anticancer treatment, it could be argued that the assessment is essentially a supportive care strategy. Key aspects of a GA include identification of comorbidities, assessing for polypharmacy, screening for cognitive impairment and delirium, assessing functional status, and screening for psychosocial issues. Treatment-related issues of particular importance in older adults include recognition of increased bone marrow toxicity, management of nausea and vomiting, identification of anemia, and prevention of neurotoxicity. The role of physical therapy and cancer rehabilitation as a supportive care strategy in older adults is important regardless of treatment stage or intent.

HSP90 inhibitor, DMAG, synergizes with radiation of lung cancer cells by interfering with base excision and ATM-mediated DNA repair.

Inhibition of heat shock protein 90 (HSP90) leads to inappropriate processing of proteins involved in cell survival pathways. We found that HSP90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), is synergistic with radiation for non-small cell lung cancer cell lines, NCI-H460 and A549. To establish the optimal schedule for this combination, cells were radiated before, after, or simultaneously with DMAG, and survival was scored by clonogenic assay. The sequence of DMAG administration was critical for synergy with radiation, and pretreatment for 16 h led to maximal synergy. Similar radiosensitization was observed in isogenic cells in which expression of wild-type p53 was silenced by RNA interference, although p53 loss rendered cells overall less radiosensitive. The mechanistic basis for synergy was studied by Western blotting, cell cycle analysis, alkaline comet assay, and direct measurement of the activities of key base excision repair enzymes. Regardless of schedule of administration, DMAG led to degradation of proteins involved in activation of cell survival pathways after radiation, which did not explain the differences in the schedule of administration observed in clonogenic assays. In addition to previously reported decrease in activation of ATM, pretreatment with DMAG blocked activation of base excision repair machinery and activity of key enzymes, apurinic/apyrimidinic endonuclease, and DNA polymerase-beta. Similarly, pretreatment with specific apurinic/apyrimidinic endonuclease inhibitor, CRT0044876, reproduced the effects of DMAG. Thus, administration of HSP90 inhibitors before radiation is critical for optimizing their use as radiosensitizers.