Unfit Adults Research Articles

Therapy for acute myeloid leukemia in older and unfit adults.

Therapy for acute myeloid leukemia in older and unfit adults.

Decades of Improvement in Cardiovascular Morbidity and Mortality in Leukemia Patients Reversed in 2020: Covid? Novel Agents? Neither?

Introduction: The incidence of many types of leukemia increases with age. Intensive induction chemotherapy containing cytarabine and an anthracycline has been part of the upfront and salvage treatment of AML for decades. Regimens for the treatment of ALL are also often anthracycline-based. Anthracyclines are associated with a significant risk of cardiotoxicity including anthracycline-related left ventricular dysfunction. Comprehensive baseline evaluation of cardiac function and risk may lead to better risk stratification and selection of patients who are best suited to anthracycline-based therapy. With the advent of more effective, yet less chemo-intense regimens for the management of older or unfit adults with leukemia, for example hypomethylator and venetoclax-based combinations, which gained widespread use with their accelerated approval in November 2018, one would hypothesize decreased rates of cardiovascular complications associated with the treatment of adult leukemia. To further investigate this hypothesis, we performed a nationwide analysis for adults age 25 and older with leukemia of all types and their associated cardiovascular disease related mortality. Methods: We utilized the Wide-ranging Online Data for Epidemiologic Research from the CDC. Patients were identified using ICD codes: C91 (Lymphoid leukaemia, C92 (Myeloid leukaemia), C93 (Monocytic leukaemia), C94 (Other leukaemias of specified cell type), and C95 (Leukaemia of unspecified cell type) with an underlying cause of death I00-I99 (Diseases of the circulatory system). Data was reviewed between 1999 to 2020 and included patients who were aged ≥25. We analyzed the age adjusted mortality rate (AAMR) per 100,000 people and stratified the data by sex, race/ethnicity, and geographical location within the USA by census region. Results: There were a total of 19,368 cardiovascular related deaths in leukemia patients between 1999 and 2020. There has been a decreasing trend in overall mortality associated with cardiovascular diseases from 1999 to 2019, falling from 4.6 to 3.9 deaths per 100,000 people, with an annual percent change of -2.89% (Figure 1). Both sexes mirrored this trend, with female mortality rates improving from 3.4 to 2.7 (APC -3.26%) and male rates from 6.5 to 5.6 (APC -3.07%) between 1999 and 2019. In 2020, it was observed that leukemia patients had an increased cardiovascular related mortality: 4.5 AAMR overall, 3.0 AAMR in females, and 6.5 AAMR in males . There was not a statistically significant difference in mortality changes by race (Table 1). Conclusion: Our study reveals a decrease in mortality rates from cardiovascular disease in leukemia patients from 1999 to 2018 followed by a relatively sharp increase noted in 2020. The steady improvements noted from the early 2000s to the 2010s may be attributable to awareness of known toxicities that led to enhanced screening and active monitoring for cardiovascular complications. Electrocardiograms, echocardiograms, and cardiotoxic markers including troponins and natriuretic peptides have served as diagnostic and risk-stratification tools. In 2020 leukemia patients exhibited a sudden increase in mortality across all sub-groups. One may postulate that this is related to COVID-19-related complications/delays in treatment, however, another possible explanation may be incompletely recognized toxicities of novel therapeutics. Interestingly, preclinical data have demonstrated that venetoclax treatment resulted in cardiac damage as evidenced by major changes in histopathology and markedly elevated cardiac enzymes and hypertrophic genes markers. Moreover, a drastic increase in oxidative stress, as well as inflammatory and apoptotic markers, with a remarkable decline in the levels of Bcl-2 has been observed (AlAsmari et al Int J Mol Sci 2022). Clearly, continued monitoring and further exploration is needed to identify the reason or reasons for the noted 2020 phenomenon. Continued data collection in the post-Covid vaccine era is likely to help to further elucidate the reasons for the unexpected uptick in cardiovascular-related morbidity and mortality in our leukemia patients.

Profile of Glasdegib for the Treatment of Newly Diagnosed Acute Myeloid Leukemia (AML): Evidence to Date.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy primarily affecting older adults. Historically, the highest rates of response have been achieved with intensive induction chemotherapy; however, a significant portion of older or unfit adults with AML are unable to tolerate intensive therapy or have chemotherapy-resistant disease, creating a large need for active and less intensive treatment strategies. Glasdegib, an oral inhibitor of the transmembrane protein Smoothened (SMO) involved in the Hedgehog (Hh) signaling pathway, was approved in 2018 for older or unfit adults with AML and attained a role in clinical practice after showing an overall survival (OS) advantage when combined with the established agent low-dose cytarabine (LDAC). Since that time, however, several other highly active lower intensity therapies such as venetoclax plus a hypomethylating agent (HMA) have garnered a dominant role in the treatment of this patient population. In this review, we summarize the role of glasdegib in the current treatment landscape of newly diagnosed AML and discuss ongoing investigations into its role in novel combination therapies.

Change In VO2max And Time Trial Performance To Interval Training Prescribed According To Ventilatory Threshold

Research shows that about 20 % of participants demonstrate no change in maximal oxygen uptake (VO2max) in response to moderate intensity continuous training (MICT) (Bouchard et al 1999) or high intensity interval training (HIIT, Astorino & Schubert 2014). Approximately 50 % of this non-response is hereditary (Bouchard et al 1999) although the other 50 % is unexplored (Mann et al. 2015) and likely related to participants’ habitual physical activity and dietary patterns, sleep, and traits of the training regime. In unfit adults, Wolpern et al. (2015) showed that MICT prescribed according to Ventilatory Threshold (VT) led to lower onset of individual non-response than when prescribed using HR. PURPOSE: To prescribe HIIT according to VT to monitor aggregate and individual responses in both VO2max and time trial (TT) performance. METHODS: Eleven active (age and VO2max = 28.9 ± 7.9 yr and 38.4 ± 4.5 mL/kg/min) men and women performed baseline testing including a VO2max test on a cycle ergometer to determine peak power output (PPO) and ventilatory threshold (Caiozzo et al. 1986). Each subject also performed a 8.2 km cycling TT over three separate trials. Over a 3 wk period, they underwent 9 d of HIIT consisting of 8 – 10 60 s bouts at work rate of 130% VT with a 75 s active recovery period. Training elicited an intensity = 89.2 ± 5.7 %PPO. VO2max and TT were assessed within 96 h after training. Controls (CON) (n=6, age and VO2max = 22.7 ± 2.3 yr and 40.4 ± 8.7 mL/kg/min) consisted of active individuals who completed two sessions of baseline testing separated by 3 wk. RESULTS: Data showed a significant groupXtime interaction for VO2max (38.4 ± 4.5 mL/kg/min to 40.7 ± 4.8 mL/kg/min vs. 40.4 ± 8.7 mL/kg/min to 40.6 ± 8.7 mL/kg/min, p=0.017) and TT (923.1 ± 78.2 s to 899.4 ± 67.2 s vs. 921.2 ± 115.0 s to 924.3 114.4 s, p=0.007) between HIIT and CON. With 2Xtypical error = 0.11 L/min for VO2max and 18.0 s for TT, 63 % of participants showed meaningful increases in VO2max and TT in response to this low dose of HIIT. Two of 11 participants exhibited non-response in both variables. CONCLUSION: These preliminary data show that 9 d of HIIT at 130 %VT significantly increases VO2max and TT performance, but these responses do not occur in everyone. It is possible that the volume or duration of HIIT used is inadequate to promote greater responses in habitually active individuals.

Lower extremity strength, systemic inflammation and all-cause mortality: Application to the “fat but fit” paradigm using cross-sectional and longitudinal designs

BackgroundNo study has applied the “fat-but-fit” paradigm with respect to muscular strength as an index of fitness, despite muscular strength being independently associated with functional ability and mortality. PurposeTo examine the relationship between lower extremity muscular strength, C-reactive protein (CRP), and all-cause mortality among normal weight, overweight and obese individuals. MethodsData from the 1999–2002 NHANES were used (N=2740 adults; ≥50years). CRP values were obtained from a blood sample. Lower body isokinetic knee extensor strength (IKES) was assessed using a Kin Kom MP isokinetic dynamometer. Participant data was linked to death certificate data from the National Death Index to ascertain all-cause mortality status. Participants were classified, based on body mass index (BMI) and strength as: normal weight and unfit (<75th IKES percentile); overweight and unfit; obese and unfit: normal weight and fit (≥75th IKES percentile); overweight and fit; and obese and fit. ResultsIndependent of physical activity and other confounders, compared to those who were normal weight and unfit, unfit overweight (β=.14, p=0.009), unfit obese (β=.33, p<0.001), and obese and fit (β=.17, p=0.008) participants, had higher CRP levels. However, there was no difference in CRP levels between normal weight and unfit participants and overweight and fit participants (β=0.04, p=0.35). Compared to normal weight unfit adults, overweight fit (HR=0.28; 95% CI: 0.11–0.70; p=0.008) adults had a lower hazard rate for all-cause mortality. ConclusionsThese finding suggest that increased lower body strength, independent of physical activity, may reduce premature all-cause mortality and attenuate systemic inflammation among overweight adults.

Randomized Study of Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults with Untreated High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) at High Risk of Treatment-Related Mortality

Background: Because of the concern for therapeutic resistance and excessive toxicity or even treatment-related mortality (TRM), many medically unfit patients do not receive AML-directed therapy, although evidence suggests that outcomes are improved if essentially all of these patients are offered some form of chemotherapy rather than given supportive care only. Here, we evaluated the potential value of attenuated doses of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in medically unfit patients with newly diagnosed AML or high-risk MDS (≥10% blasts). In earlier trials, CPX-351 appeared to afford superior outcomes in high-risk AML patients with a wide therapeutic window suggesting that reduced dose treatment may be helpful in this population.Methods: Patients aged ≥18 years with untreated AML or high-risk MDS were eligible if they had a TRM score of ≥13.1, corresponding to an expected TRM (i.e. death within 28 days of treatment initiation) of 31% with standard induction chemotherapy. Bilirubin was to be <2.0 mg/ml because of hepatic excretion of CPX-351, and active infection was an exclusion criterion. Patients were randomly assigned 1:1 to receive CPX-351 at either 32 or 64 units/m2 per dose (previous phase 1 investigations established a maximum tolerated dose of 101 units/m2 per dose) on days 1, 3, and 5 for up to 4 identical induction/re-induction courses. Patients achieving either complete remission (CR) or CR with incomplete platelet count recovery (CRp) could receive up to 4 courses of post-remission treatment with CPX-351 using the same dose on days 1 and 3 only. The primary goal of the study was to estimate whether either the 32 or 64 units/m2 doses were likely to improve TRM rates while keeping the CR rate comparable to historic controls. Specifically, a Bayesian design was used to monitor both response (CR) and toxicity (TRM), with early stopping if the posterior probability was <0.10 that the true TRM rate was <15% (vs. the historical = 31%) or if the posterior probability was >0.90 that the true CR rate with CPX-351 was <30% (historical = 30%).Results: 23 patients, median age 71.1 (range: 53.1-91.1) years, with a median TRM score of 25.7 (range: 13.7-90.0) and a median ECOG performance status of 2 (range: 1-3), were enrolled. Cytogenetic risk was favorable in 1, intermediate in 8, and adverse in 14 (including 3 with insufficient culture growth for analysis), with 9 patients having a monosomal karyotype. 13 patients had secondary disease. Overall, study patients received a median of 1 (range, 1-3) cycles of induction therapy. Among the first 9 patients randomized to 64 unit/m2, 1 CR, 1CRp, and 3 deaths by day 28 occurred. The deaths were due to overwhelming infection in patients presenting with TRM scores of 14.5, 44.4, and 57.9. Because of these 3 deaths, accrual to the 64 units/m2 arm stopped. The 9 patients given 64 units/m2 might have, by chance, been more unfavorable than the large number of historical pts. (n =2,238) used to derive the TRM score. We addressed this possibility by summing the TRM scores in these 9 patients, thus calculating the number of expected deaths by day 28 had these patients received historical treatments, principally 3+7 or higher doses of cytarabine. The number of expected deaths was 3.0, the same as the number observed. Because it met neither the early stopping bound for TRM or lack of CR, the 32 units/m2arm has continued accrual. 14 patients have been enrolled (including 3 who were enrolled without randomization after the higher-dose arm closed). 2 CRs (14.3%) were observed, and 4 patients died early; deaths were related to overwhelming infection in 1 (TRM score of 23.7), and early disease progression in 3 (TRM scores of 23.7, 33.3, and 90.0).Conclusion: This study illustrates the challenge of balancing therapeutic resistance and disease/treatment-related complications in medically unfit adults with AML. Within the constraints of historical controls and an experience limited to 9 patients at the higher dose level, our data suggest that at 64 units/m2, CPX 351 is relatively unlikely to decrease TRM to 15% (from ~30% historically) and increase CR rate to 40% (from ~30% historically) in patients at high risk of TRM. These results present the first attempt at identifying and treating medically unfit patients with CPX-351 and suggest that further adjustments in eligibility and CPX-351 dosing to maximize efficacy and reduce early leukemia-related deaths are needed. DisclosuresOff Label Use: CPX-351 currently has investigational drug status. Louie:Celator Pharmaceuticals, Inc: Employment.

Physical Activity Among Newly Immigrated Latino Adults

Latinos are disproportionately represented among overweight, obese, and unfit adults, putting them at higher risk for compromised health. This study examined weight status and usage of an aerobics program established within a residential complex among a sample of low-income, recently immigrated Latino adults (94 women/53 men). Results demonstrated that most participants were overweight or obese (79%) and physically inactive (59.1%). Results also indicated that while walking was the most common type of physical activity for both men and women, there are significant gender differences in other types of physical activities, in that housework was a more prevalent type of activity for women than men and yard work is a more prevalent activity for men. Furthermore, more women reported going to the exercise class than men while men reported to be more engaged in sports. The finding of this study provided valuable insights on the risk perception of being overweight and its connection to health, as well as useful information about the barriers to the physical activity and preferences for specific physical activities for this population.

Spinning-induced rhabdomyolysis: a case report

Exercise induced rhabdomyolysis has previously been described as occurring in unfit adults or those attempting exhaustive exercise, but is rarely seen in previously fit adults undertaking moderate exercise. This case report describes what we believe to be the first reported case of exercise induced rhabdomyolysis due to the patient completing a 'spinning class' at her local gymnasium. The report also covers diagnosis and management of this condition.