FDA Analysis of Survival Outcomes in Older Adults with Relapsed-Refractory Multiple Myeloma (RRMM) Treated with Novel Drug Regimens

Background: Multiple novel therapies have been approved for the treatment of RRMM in recent years, resulting in improvements in progression free survival (PFS) and overall survival (OS). However, clinical trials in MM often enroll only a small proportion of older patients, particularly patients ≥75 years (Kanapuru 2017). Evaluating the impact of novel therapies, especially triplet therapies, in older adults with RRMM from individual clinical trials is challenging due to the small sample size. Furthermore, significant heterogeneity exists among the older adult population with regards to tolerability of anti-myeloma therapy. In newly diagnosed transplant-ineligible patients with MM, evidence from pooled analysis indicates that patients >80 years may be at increased risk for adverse clinical outcomes (Palumbo 2015). We evaluated the prognostic impact of age on survival outcomes in patients with RRMM receiving novel therapies. Methods: Data from 10 clinical trials submitted for approval between 2011-2015 were pooled for this analysis. Participants were grouped according to four age strata: <65, 65-74, 75-80, and >80 years. PFS and OS were calculated using the Kaplan-Meier method (K-M). Within each age stratum, we conducted a subgroup analysis comparing doublet versus triplet regimens. Cox's proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for gender, race, ISS stage, ECOG status, regimen (only for primary age analysis) and prior transplant. Results: In total, 4766 patients were included in the analysis. Forty-seven percent were <65 years, 39% were 65-74 years, 11% were 75-80 years and only 4% were >80 years of age. The percentage of patients with baseline ISS stage III and ECOG 2 was higher in the 75-80 years (31.0% and 11.0%) and >80 years group (32.0%, 19.0%) compared to 65-74 years (24.0%, 8.0%) and <65 years group (22.0%, 6.0%) respectively. K-M plots for PFS and OS and adjusted HR by age is shown below. Estimated median PFS and OS results by regimen type is displayed in Table 1. Adjusted PFS HR (95% CI) for triplet versus doublet regimens was 0.69 (0.60, 0.79), 0.71 (0.61, 0.83), 0.61 (0.46, 0.81), and 0.62 (0.36, 1.05) for <65, 65-74, 75-80 and >80 years respectively. The HR (95% CI) for OS was 0.70 (0.59, 0.83), 0.86 (0.72, 1.02), 0.55 (0.40, 0.77) and 0.98 (0.56, 1.73). Conclusions: Improvement in PFS with novel therapies, including triplet regimens, appears to extend to older adults including patients >80 years of age. No trend in treatment effect for PFS was observed across the age groups. Overall survival was lower in adults ≥65 years of age compared to patients <65 years although results were not significant for patients >80 years of age. Triplet regimens appear to improve survival over doublet regimens; however, a consistent trend across age groups was not observed. The OS results from this analysis must be interpreted with caution due to immature OS data at the time of submission, differential follow-up for individual trials, and small sample size, particularly in patients >80 years of age. Enrolling a representative population of older adults in MM clinical trials is needed to allow for an accurate assessment of outcomes in this population. Furthermore, considering biologic age rather than chronologic age to identify older patients who can benefit from these therapies would serve to further advance treatment in patients with MM. Disclosures No relevant conflicts of interest to declare.

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Chloroquine and Hydroxychloroquine could be an Available Weapons to Treat COVID-19 Associated Pneumonia

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2020/v32i930482 ◽

2020 ◽

pp. 52-60

Author(s):

Nehad J. Ahmed

Keyword(s):

Clinical Trials ◽

Angiotensin Converting Enzyme ◽

Sample Size ◽

Small Sample Size ◽

Small Sample ◽

Google Scholar ◽

Converting Enzyme ◽

Larger Sample

Aims: This study aims to review the efficacy of chloroquine and hydroxychloroquine to treat coronavirus disease 2019 (COVID-19) associated pneumonia. Methodology: This review includes searching Google scholar for publications about the use of hydroxychloroquinein the treatment of COVID-19 using the words of (Covid-19) AND hydroxychloroquine. Results: Chloroquine and hydroxychloroquine have proven effective in treating coronavirus in China in vitro, but till now only few clinical trials are available and these trials were conducted on a small sample size of the patients. The efficacy of chloroquine and hydroxychloroquine is mainly due to its effect on angiotensin-converting enzyme II (ACE2). Conclusion: The use of chloroquine and hydroxychloroquine could be very promising but more trials are needed that include larger sample size and more data are required about the comparison between chloroquine and hydroxychloroquine with other antivirals.

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Acute Promyelocytic Leukemia In Canada: Poor Outcomes In Older Patients Remain

Blood ◽

10.1182/blood.v122.21.1714.1714 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1714-1714

Author(s):

Matthew D. Seftel ◽

Anna Serebrin ◽

Pascal Lambert ◽

Julie Bergeron ◽

Janeve Everett ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Acute Promyelocytic Leukemia ◽

Older Patients ◽

Early Death ◽

Promyelocytic Leukemia ◽

Survival Outcomes ◽

Younger Patients ◽

One Year

Abstract Introduction Despite widespread use of all-trans retinoic acid (ATRA) in treatment of Acute Promyelocytic Leukemia (APL), recent studies in the US1 and Sweden2 have reported continuing high rates of early death. Patient age has appeared to be an important factor affecting outcomes. We studied the incidence and outcomes in the Canadian APL patients to determine which patients may be at higher risk, and to analyze the success of current management. Methods We used data from the Canadian Cancer Registry, which included all patients diagnosed between 1993-2007. We obtained incidence, Early Death (ED) (death within 30 days of diagnosis), and 1 and 5-year overall survival (OS). This was stratified by age, sex, and time period of diagnosis. Detailed information was obtained on a subset of patients managed at five Canadian leukemia referral centres from 1999 to 2010. Results There were 399 cases of APL diagnosed in Canada between 1993-2007.This accounted for 3.01% of Acute Myeloid Leukemia cases. Incidence (age-standardized to the 1991 Canadian census population) was 0.083/100000. The incidence was greater in the population aged 50 and over, with an incidence rate ratio (IRR) of 2.192 (95% C.I.1.80 - 2.67, p<0.001). ED was 21.8% overall, with a rate over three times higher in older patients as compared to younger patients. The ED rate was 10.6% in younger (<50 years) patients and 35.5% in older (≥50 years) patients. One-year overall survival was 84.1% in younger patients as compared to 52.3% in older adults. The rate of death at one year is nearly three times higher in the older patients. Five-year survival was 54.6%; this was 73.3% in the younger patients (<50), and 29.1% in the older group (≥50 years). There were 131 patients in the leukemia referral centre cohort, who predominantly received tretinoin (ATRA) based therapy. In this population, ED was 14.6%. Two-year OS was 76.5% (95% C.I. 68%-83%). Age over 60 predicted an inferior outcome at 2-years with a hazard ratio of 4.051 (95% CI 1.17-7.57). Conclusions To our knowledge, this is the largest nationwide epidemiologic study of APL. Despite widespread use of ATRA in Canada and low rates of ED reported in clinical trials (often 3-8%), we found that the real survival outcomes of APL were worse than anticipated. However they were similar to those reported recently from other developed counties1,2. The outcomes were much poorer for the older patients with APL. This included a higher rate of early death as well as poorer rates of survival at one, two and five year follow-up times. The ED rates of patients <50 more closely matched rates reported in clinical trials. We compared the survival outcomes of the entire population with APL to a sample of only patients treated at specialized referral centres. Despite receiving care in a specialized tertiary centre, the survival of older patients remained significantly poorer than the younger patients. The incidence of APL was also double in the older population as compared to the younger population. Overall the age-standardized incidence was lower in Canada than has been reported in other countries1,2. This emphasizes that, although APL is a type of AML that does affect younger patients, there is a large and important impact of this disease on older patients. Recent studies in the US and Sweden have also reported higher rates of APL in older populations and poorer rates of survival at various follow up times. Overall the patients with high-risk Sanz scores had the worst survival outcomes. The survival at most time points was slightly higher for patients scored as intermediate-risk compared to those who were in the low-risk category. When arsenic becomes widely available as a first line therapy it will be important to continue population-based analysis to see how this affects outcomes and whether the outcomes are difference in difference age groups or populations. Disclosures: No relevant conflicts of interest to declare.

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A Naturalistic Study of Driving Behavior in Older Adults and Preclinical Alzheimer Disease: A Pilot Study

Journal of Applied Gerontology ◽

10.1177/0733464817690679 ◽

2017 ◽

Vol 38 (2) ◽

pp. 277-289 ◽

Cited By ~ 8

Author(s):

Ganesh M. Babulal ◽

Sarah H. Stout ◽

Tammie L. S. Benzinger ◽

Brian R. Ott ◽

David B. Carr ◽

...

Keyword(s):

Older Adults ◽

Sample Size ◽

Small Sample Size ◽

Driving Behavior ◽

Driving Performance ◽

Small Sample ◽

Clinical Consequence ◽

Cognitively Normal ◽

Preclinical Ad ◽

One Year

A clinical consequence of symptomatic Alzheimer’s disease (AD) is impaired driving performance. However, decline in driving performance may begin in the preclinical stage of AD. We used a naturalistic driving methodology to examine differences in driving behavior over one year in a small sample of cognitively normal older adults with ( n = 10) and without ( n = 10) preclinical AD. As expected with a small sample size, there were no statistically significant differences between the two groups, but older adults with preclinical AD drove less often, were less likely to drive at night, and had fewer aggressive behaviors such as hard braking, speeding, and sudden acceleration. The sample size required to power a larger study to determine differences was calculated.

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Elderly AML: A Five-Year Retrospective Review on Prognostic Features

Blood ◽

10.1182/blood-2018-99-111418 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5187-5187

Author(s):

Akshay Amaraneni ◽

Jennifer Segar ◽

Trace Bartels ◽

Onyemaechi Okolo ◽

Andrew C Rettew ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Retrospective Review ◽

Myeloid Leukemia ◽

Small Sample Size ◽

Small Sample ◽

Risk Category ◽

Elderly Aml ◽

Acute Myeloid

Abstract Background: Acute Myeloid Leukemia (AML) is a disease of the elderly with a median age of diagnosis of 70 years. Prognosis in this age group is poor, with median overall survival of those undergoing treatment ranging from seven to twelve months. Treatment is difficult for a variety of reasons, including - higher incidence of co-morbid conditions (including frailty and decline in functional status), decreased ability to tolerate infections, socioeconomic considerations, and more aggressive disease phenotype. We present a single-institution retrospective review of acute myeloid leukemia outcomes with respect to these and other variables. Methods: A retrospective chart review was performed on all patients with a new diagnosis of AML from November 2013 through October 2017. Descriptive statistics were performed using excel, inferential statistics including Kaplan-Meier with comparison of survival curves by Logrank test and Cox-proportional hazard regression analysis, and correlation coefficients were performed using MEDCALC statistical software package. Results: Eighty-four AML patients in total were diagnosed with acute myeloid leukemia within the specified time frame, of these, 45 patients were age 65 or older (elderly) and were included in further analysis. Median age of elderly AML patients in this study was 70 years. Six of these patients were diagnosed with secondary AML (having arisen from MDS (N = 4), or other hematologic malignancy (N=2), and two had therapy-related AML. Eight patients had favorable risk disease, 13 intermediate risk, and 24 adverse risk according to ELN 2017 criteria. The median survival of all elderly patients was 322 days. Median survival of elderly AML according to ELN 2017 risk category criteria (Favorable, Intermediate, or Poor) was not reached (mean 880 days), 390 days, and 117 days, respectively (p = 0.0368 by cox hazard regression). Survival was not affected by type of treatment (induction vs hypomethylating agent (HMA); median 579 and 166 days (p = 0.1378) and mean 1552 and 364 days, respectively. This is likely due to small sample size, although survival does appear to favor intensive induction. Survival was not affected by number of medical co-morbidities (p = 0.66), presence of infectious complications (p=0.152), or unplanned hospitalization (p = 0.144). Overall use of clinical trials (N=3) and transplant (N=2) were low, precluding meaningful statistical analysis. However, both patients undergoing transplant exceeded the median OS (579 and 4745 days). Median OS of patients identified as White/Caucasian was greater than those identified as Hispanic/Latino (166 days vs 66 days, respectively), this did not reach statistical significance. Conclusion: Given the limitations of a retrospective review and relatively small sample size, our data shows that the 2017 ELN risk category is the strongest predictor of overall survival. Statistically, those undergoing intensive induction did not have a longer overall survival than those treated with HMAs, highlighting the need for careful selection of induction therapy candidates, and the need for clinical trials investigating other less intense treatment options for patients in this category. Interestingly, number of medical co-morbidities did not influence overall survival, nor did unplanned hospitalizations, presence/absence of significant infections during therapy, or race/ethnicity. Our data suggest an under-utilization of clinical trials and allogeneic hematopoietic stem cell transplant, both of which may serve to improve prognosis. Disclosures No relevant conflicts of interest to declare.

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The relationship between chronic stress, emotion regulation and depressive symptoms in healthy older adults

10.32920/ryerson.14661564 ◽

2021 ◽

Author(s):

Vivian Huang

Keyword(s):

Older Adults ◽

Depressive Symptoms ◽

Sample Size ◽

Chronic Stress ◽

Sex Education ◽

Allostatic Load ◽

Small Sample Size ◽

Small Sample ◽

Community Dwelling ◽

The Relationship

The current study examined the association between chronic stress (measured in allostatic load or AL), ER, and depressive symptoms in a group of community-dwelling older adults. It was hypothesized that chronic stress levels would mediate the relationship between ER and depressive symptoms. A total of 70 older adults aged 60 and older participated in the study. There were no significant associations found in the main analyses between the AL index and depressive symptoms, as well as no significant relationship was found between ER strategies and AL index, after controlling for age, sex, education, and perceived SES. However, perceived stress significantly mediated the relationship between maladaptive ER strategies and depressive symptoms, and the relationship between adaptive ER strategies and depressive symptoms. Given the small sample size and the lack of variability of the AL index, the study would benefit from a larger sample size to clarify the present results.

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Stopping rules for phase I clinical trials with dose expansion cohorts

Statistical Methods in Medical Research ◽

10.1177/09622802211064996 ◽

2021 ◽

pp. 096228022110649

Author(s):

Sean M Devlin ◽

Alexia Iasonos ◽

John O’Quigley

Keyword(s):

Clinical Trials ◽

Sample Size ◽

Dose Escalation ◽

Small Sample Size ◽

Maximum Tolerated Dose ◽

Small Sample ◽

Stopping Rules ◽

Phase I Clinical Trials ◽

Study Protocols ◽

Dose Levels

Many clinical trials incorporate stopping rules to terminate early if the clinical question under study can be answered with a high degree of confidence. While common in later-stage trials, these rules are rarely implemented in dose escalation studies, due in part to the relatively smaller sample size of these designs. However, even with a small sample size, this paper shows that easily implementable stopping rules can terminate dose-escalation early with minimal loss to the accuracy of maximum tolerated dose estimation. These stopping rules are developed when the goal is to identify one or two dose levels, as the maximum tolerated dose and co-maximum tolerated dose. In oncology, this latter goal is frequently considered when the study includes dose-expansion cohorts, which are used to further estimate and compare the safety and efficacy of one or two dose levels. As study protocols do not typically halt accrual between escalation and expansion, early termination is of clinical importance as it either allows for additional patients to be treated as part of the dose expansion cohort to obtain more precise estimates of the study endpoints or allows for an overall reduction in the total sample size.

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Broccoli and Helicobacter Pylori: A Systematic Review

Complementary Medicine Journal ◽

10.32598/cmja.10.1.440.1 ◽

2020 ◽

Vol 10 (1) ◽

pp. 2-11

Author(s):

Fatemeh Azizi-Soleiman ◽

◽

Maryam Zamanian ◽

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Helicobacter Pylori ◽

Sample Size ◽

Randomized Clinical Trials ◽

Small Sample Size ◽

Small Sample ◽

Animal Testing ◽

H Pylori ◽

Positive Effect

Objective: Pharmacological treatment of Helicobacter pylori (H. pylori) infection is based on the use of at least two antibiotics with a double dose of proton pump inhibitor which results in antibiotic resistance. Anti-helicobacterial activity of sulforaphane-rich broccoli has been evaluated in laboratory studies. This study aimed to systematically review the conducted randomized clinical trials that have examined the effect of broccoli on H. pylori in humans. Methods: This study is a systematic review of randomized clinical trials on the effect of broccoli on H. pylori. The search was conducted in PubMed, OVID, Web of Science, and Scopus databases using the keywords: Helicobacter pylori, broccoli sprouts, H. pylori, randomized clinical trials, and Brassica, without any time limits for studies conducted until 2019. After excluding duplicates, the titles and abstracts of remained articles were evaluated by two researchers and then the related ones were extracted. Next, their full-texts were examined to select the final articles for review. We included clinical trials and excluded those were in the laboratory or animal testing phases or their full-texts were unavailable. Results: Three studies that had met the inclusion criteria were considered for the review. Overall, neither in the articles that reviewed in the present study nor in the articles that did not enter the review process due to unavailability of their full-texts or having a very small sample size, no clear positive effect of broccoli on inhibiting H. pylori infection in humans had been reported. Conclusion: Due to the lack of optimal results from broccoli consumption for the control of H. pylori infection in humans, it is recommended that longer studies with sufficient sample size and appropriate dose of broccoli along with standard treatment be performed in the future.

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The relationship between chronic stress, emotion regulation and depressive symptoms in healthy older adults

10.32920/ryerson.14661564.v1 ◽

2021 ◽

Author(s):

Vivian Huang

Keyword(s):

Older Adults ◽

Depressive Symptoms ◽

Sample Size ◽

Chronic Stress ◽

Sex Education ◽

Allostatic Load ◽

Small Sample Size ◽

Small Sample ◽

Community Dwelling ◽

The Relationship

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MP35: Acceptability of older patients’ self-assessment in the emergency department (ACCEPTED) – a randomized cross-over trial

CJEM ◽

10.1017/cem.2019.170 ◽

2019 ◽

Vol 21 (S1) ◽

pp. S55

Author(s):

V. Boucher ◽

M. Lamontagne ◽

J. Lee ◽

P. Carmichael ◽

J. Déry ◽

...

Keyword(s):

Emergency Department ◽

Older Patients ◽

Qualitative Data ◽

Small Sample Size ◽

Statistical Tests ◽

Age Groups ◽

Small Sample ◽

Self Assessment ◽

Use Of Technology ◽

Patient Self Assessment

Introduction: It is recommended that seniors consulting to the Emergency Department (ED) undergo a comprehensive geriatric screening, which is difficult for most EDs. Patient self-assessment using electronic tablet could be an interesting solution to this issue. However, the acceptability of self-assessment by older ED patients remains unknown. Assessing acceptability is a fundamental step in evaluating new interventions. The main objective of this project is to compare the acceptability of older patient self-assessment in the ED to that of a standard assessment made by a professional, according to seniors and their caregivers. Methods: Design: This randomized crossover design cohort study took place between May and July 2018. Participants: 1) Patients aged ≥65 years consulting to the ED, 2) their caregiver, when present. Measurements: Patients performed self-assessment of their frailty, cognitive and functional status using an electronic tablet. Acceptability was measured using the Treatment Acceptability and Preferences (TAP) questionnaires. Analyses: Descriptive analyses were performed for sociodemographic variables. Scores were adjusted for confounding variables using multivariate linear regression. Thematic content analysis was performed by two independent analysts for qualitative data collected in the TAP's open-ended question. Results: A total of 67 patients were included in this study. Mean age was 75.5 ± 8.0 and 55.2% of participants were women. Adjusted mean TAP scores for RA evaluation and patient self-assessment were 2.36 and 2.20, respectively. We found no difference between the two types of evaluations (p = 0.0831). When patients are stratified by age groups, patients aged 85 and over (n = 11) showed a difference between the TAPs scores, 2.27 for RA evaluation and 1.72 for patient self-assessment (p = 0.0053). Our qualitative data shows that this might be attributed to the use of technology, rather than to the self-assessment itself. Data from 9 caregivers showed a 2.42 mean TAP score for RA evaluation and 2.44 for self-assessment. However, this relatively small sample size prevented us to perform statistical tests. Conclusion: Our results show that older patients find self-assessment in the ED using an electronic tablet just as acceptable as a standard evaluation by a professional.

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A Review of Treatment of Coronavirus Disease 2019 (COVID-19): Therapeutic Repurposing and Unmet Clinical Needs

Frontiers in Pharmacology ◽

10.3389/fphar.2020.584956 ◽

2020 ◽

Vol 11 ◽

Author(s):

Po-Lin Chen ◽

Nan-Yao Lee ◽

Cong-Tat Cia ◽

Wen-Chien Ko ◽

Po-Ren Hsueh

Keyword(s):

Clinical Trials ◽

Sample Size ◽

Clinical Evidence ◽

Early Stage ◽

Small Sample Size ◽

Antiviral Agents ◽

Small Sample ◽

Cytokine Release ◽

Mild Disease ◽

Critical Patients

For the initial phase of pandemic of coronavirus disease 2019 (COVID-19), repurposing drugs that in vitro inhibit severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been attempted with overlooked or overestimated efficacy owing to limited clinical evidence. Most early clinical trials have the defects of study design, small sample size, non-randomized design, or different timings of treatment initiation. However, well-designed studies on asymptomatic or mild, or pediatric cases of COVID-19 are scarce and desperately needed to meet the clinical need. However, a trend could be observed based on current clinical evidence. Remdesivir and favipiravir may shorten the recovery time; lopinavir/ritonavir does not demonstrate treatment efficacy in severe patients. Triple therapy of ribavirin, lopinavir, and interferon β-1b showed early viral negative conversion, and the major effect may be related to interferon. Some small sample-size studies showed that interleukin-6 inhibitors may demonstrate clinical improvement; non-critical patients may benefit from convalescent plasma infusion in small sample-size studies; and the role of hydroxychloroquine or chloroquine in the treatment and prophylaxis of COVID-19 remains unclear. Combination therapy of traditional Chinese medicine with antiviral agents (ex. interferon, lopinavir, or arbidol) may alleviate inflammation in severe COVID-19 patients based on small sample-sized observational studies and experts’ opinion. Most of the published studies included severe or critical patients with COVID-19. Combination therapy of antiviral agents and immune-modulating drugs is reasonable especially for those critical COVID-19 patients with cytokine release syndrome. Drugs to blunt cytokine release might not benefit for patients in the early stage with mild disease or the late stage with critical illness. Traditional Chinese medicine with antiviral effects on SARS-CoV-2 and immune-modulation is widely used for COVID-19 patients in China, and is worthy of further studies. In this review, we aim to highlight the available therapeutic options for COVID-19 based on current clinical evidence and encourage clinical trials specific for children and for patients with mild disease or at the early stage of COVID-19.

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