Measurement and Prevalence of Cognitive Impairment in Older Patients with Hematologic Malignancies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 689-689 ◽  
Author(s):  
Tammy T. Hshieh ◽  
Nolan B. Condron ◽  
Richard M. Stone ◽  
Robert J. Soiffer ◽  
Gregory A. Abel

Abstract Background:Little is known about the frequency of cognitive impairment in older patients with blood cancers, nor how such impairment may contribute to their overall frailty. Understanding the prevalence of impairment is specifically important for this population, because intact cognition is needed to make complex medical decisions, including whether to pursue intensive treatments versus supportive care. We report data from the Older Adult Hematologic Malignancy (OHM) clinic at the Dana-Farber Cancer Institute, which routinely screens patients 75 or older for frailty using tools that incorporate subjective and objective measures of cognition. Methods: Since February of 2015,all patients aged 75 and older who present for initial consultation for hematologic malignancy have been approached for evaluation by a trained clinic assistant. In a 15-minute interview, the assistant uses two parallel methods of screening to characterize the patient as frail, pre-frail or robust. The first employs a "cumulative deficit" approach (Rockwood, 2007) including a 26-item questionnaire adapted from theYale Precipitating Events Project (Searle, 2008), a grip strength test (Gill, 2006), gait speed test (Studenski, 2011), delayed recall section of the Montreal Cognitive Assessment (MOCA; Nasreddine, 2005) and the Clock In Box test, a cognitive impairment screening tool (CIB; Chester, 2011). The second uses a "phenotypic" approach (Fried, 2001), which gives equal weight to the gait speed and grip strength tests, plus three questions about weight loss, energy expenditure and self-reported exhaustion. We also assess two subjective measures of cognition: (1) whether the patient knows why s/he is presenting to the hospital and (2) whether s/he needs help filling out the questionnaire. Results: As of July 1, 2016, 235 of 275 patients approached (85%) agreed to be assessed. Median age was 78 years and 37% were female; 32% were seen in the leukemia clinic, 37% in the lymphoma clinic and 31% in the myeloma clinic. More patients were determined to be definitively frail or robust by the cumulative deficit approach compared with the phenotypic approach, which categorized the majority of patients as pre-frail (Table 1). With respect to cognition, 35.4% of the cohort was found to have probable impairment and 27.3% possible impairment by CIB (Table 2). Fewer patients were found to have probable impairment (18.0%) and possible impairment (19.8%) by MOCA delayed recall. Overall, 18.5% of robust patients had possible or probable cognitive impairment by CIB, and 9.5% by MOCA delayed recall. Nearly 7% of the patients could not explain why they were presenting to the hospital; all of these patients also had probable cognitive impairment and were pre-frail or frail. Moreover, 17% of the total cohort needed assistance completing the questionnaire; half of these had probable cognitive impairment, 43% had possible impairment, and most (92.5%) were pre-frail or frail. The odds of being pre-frail or frail (phenotypic) if cognitively impaired per CIB was 1.89 (95% CI 1.073.34; p=0.03). The odds of being pre-frail or frail (phenotypic) if cognitively impaired per MOCA delayed recall was 1.86 (95% CI 1.02-3.40; p=0.04). Conclusions: Cognitive impairment was prevalent in this cohort of older patients with blood cancers, with between one- to two-thirds of patients testing as probably or possibly impaired using standard measures.A portion of patients who were robust per the brief phenotypic frailty screen were also cognitively impaired, which suggests routinely performing comprehensive frailty screening (cumulative deficit) or adding a cognitive measure such as the CIB. Compared to the phenotypic approach, the cumulative deficit approach, which incorporates specific measurement of cognitive impairment, seemed to result in further discriminaton between patients who were frail versus robust. The CIB test detected more cognitive impairment than the MOCA delayed recall, likely because it assesses both executive function and working memory, whereas the MOCA delayed recall only tests the latter. Taken together, our data suggest that cognitive impairment likely contributes significantly to overall frailty for older patients with blood cancers, and argue for routine testing for such impairment in this patient population. Disclosures Stone: Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jansen: Consultancy; Seattle Genetics: Consultancy; Celator: Consultancy; Agios: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy. Soiffer:Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees.

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2353-2353
Author(s):  
Stephanie Dubruille ◽  
Cindy Kenis ◽  
Yves Libert ◽  
Michel Delforge ◽  
Catherine Choffray ◽  
...  

Abstract Introduction: Patients "clinically fit" to receive chemotherapy suffering from malignant hemopathies, are an heterogeneous population covering fit and vulnerable patients. Patients with geriatric syndromes and/or irreversible comorbidities are usually excluded from high dose chemotherapy. However, a reliable "frailty score" remains urgently needed to better define the vulnerable population that does not benefit from chemotherapy. In the literature, two clinical (functional decline and Mild Cognitive Impairment (MCI)) and two biological (anemia and inflammation) factors are frequently correlated with poor overall survival (OS) or chemotherapy-related toxicity. Objective: To determine a clinico-biological tool for the screening of vulnerable patients with malignant hemopathies presenting unacceptable chemotherapy-related toxicity or disappointing result defined as a poor OS. Methods: This prospective multicentric study was conducted in the institute 'Jules Bordet' (Brussels) and in the University Hospitals of Leuven (Leuven). A Comprehensive Geriatric Assessment (CGA) was performed to 251 consecutive patients (65-90yrs) with malignant hemopathies admitted to receive chemotherapy. Clinical data, biological parameters and causes of death were extracted from medical records. A screening tool composed of 0 to 4 of the prognostic factors (loss of functional autonomy (Activities of Daily Living scale [ADL]), MCI (Mini Mental State Examination [MMSE]), anemia [hemoglobin] and inflammation [CRP]) was applied to our population. Univariate and multivariate Cox proportional hazards model were used to predict OS. Results: One hundred and eighty two patients were evaluable for all characteristics (NHL, n=105; CLL, n=20; MM, n=26; AML, n=17; ALL, n=6; LMMC, n=3, MDS, n=5). Eighty-three percent had a more favorable prognosis (NHL, CLL or MM) and fifty-five percent have a first diagnosis of cancer. A "frailty" scoring system (range 0-4) was developed, based on items we identified as predictive factors: functional decline (ADL<6, n=94), Mild Cognitive Impairment (MCI) (MMSE<27, n=51), anemia (HB<11g/dl, n=90) and inflammation (CRP≥2mg/l, n=149). The population was stratified into 3 groups: fit (score=0-1, n=56), vulnerable (score= 2, n=60) and "frail" (score= 3 or 4, n=66). The OS was 86% in fit, 60% in vulnerable (hazard ratio (HR)=3.29; 95% CI=1.48-7.33; P=.004) and 41% in "frail" patients (HR=5.87; 95% CI=2.74-12.59; P<.001). Causes of death remain disease-related in a majority of the patients (82%). In our largest group of older patients (NHL, n=105), the frailty scoring was also applied (ADL<6, n=48; MMSE<27, n=29; HB<11g/dl, n=36; CRP≥2mg/l, n=85): the OS was 87% in fit (n=45), 65% in vulnerable (n=31) (HR=2.94; 95% CI=1.11-7.96; P=.034) and 41% in "frail" patients (n=29) (HR=6.61; 95% CI=2.60-16.83; P<.001) and thus reliable in this specific population. Conclusions: In our selected population of patients with malignant hemopathies and particularly in the group of NHL, "clinically fit" to receive chemotherapy, our "frailty score" helps clinician to predict a poor OS. This scoring detects unsuspected "frail" patients who may benefit from palliative care. Further prospective analyses in a larger population, are on going to refine the score in other malignant hemopathies in order to avoid overtreatment in these vulnerable older patients. Disclosures Maerevoet: roche: Membership on an entity's Board of Directors or advisory committees; ARGN-X: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4089-4089
Author(s):  
Tammy T. Hshieh ◽  
Clark Dumontier ◽  
Tim Jaung ◽  
Nupur E. Bahl ◽  
Emily S. Magnavita ◽  
...  

Abstract Background. Polypharmacy and potentially inappropriate medications (PIMs) are common among older adults with blood cancer and can lead to adverse effects and poor outcomes. Polypharmacy is commonly defined as taking ≥5 or ≥8 medications, depending on the population. PIMs can cause adverse side effects for certain patients, e.g. diphenhydramine and benzodiazepines. We sought to define the prevalence of polypharmacy and PIMs in older adults with blood cancers, and to examine the association between both with cognitive impairment and frailty in this population. Methods. From February 2015 to November 2019, all transplant-ineligible patients ages 75 and older who presented for initial consultation for hematologic malignancy at the Dana-Farber Cancer Institute (Boston, MA) were approached by a research assistant (RA) for a 15-minute screening geriatric assessment. The RA assessed 42 aging-related health deficits using patient-reported and objective performance measures spanning the domains of function, cognition, comorbidity, and mobility. Patients were determined to be frail, pre-frail or robust via two approaches: deficit accumulation approach (Rockwood, JGMedSci 2007) and phenotypic approach (Fried, JGMedSci 2001). Cognition was measured using the delayed recall section of the Montreal Cognitive Assessment (MoCA; Nasreddine, JAGS 2005) and Clock-In-Box test (CIB; Chester, Am J Med 2011). In addition, we collected data via electronic medical record review of all prescribed and over-the-counter medications patients were taking at the time of initial consultation. These data were reconciled and reviewed for quality by two board-certified geriatricians. The geriatricians identified 2 types of PIMs: anticholinergic PIMs per the Anticholinergic Risk Scale (Rudolph, Arch Intern Med 2008) and cancer-specific PIMs per the National Cancer Care Network Medications of Concern (NCCN Older Adult Oncology 2020). For patients recommended for active cancer treatment, the association between polypharmacy and PIMs with frailty was assessed using ordinal logistic regression. The association between polypharmacy and PIMs with cognitive impairment (by MoCA delayed recall and CIB) was assessed using logistic regression. All models controlled for age, gender, and comorbidity (via Charlson Comorbidity Index). Results. In this patient cohort (N=785), 286 (36%) were female with 240 (30%) in the leukemia disease group, 272 (35%) lymphoma and 273 (35%) multiple myeloma. 603 (77%) patients had polypharmacy (≥5 medications) and 421 (54%) were taking ≥8 medications. 201 (25%) patients were taking at least one PIM based on the Anticholinergic Risk Scale (Rudolph) and 343 (44%) based on the NCCN guidelines. Overall, 131 (17%) were frail, 457 (58%) pre-frail and 197 (25%) robust. 541 (69%) patients had Charlson Co-morbidity Index ≥3; 111 (14%) patients had "probable" cognitive impairment by MoCA Delayed Recall and 147 (19%) had "probable" cognitive impairment by CIB. In the 468 (60%) patients on active cancer treatment, there was an association of frailty with polypharmacy defined by a cutoff of ≥8 (adjusted odds ratio [aOR]=2.82, 95% confidence interval [CI] 1.92-4.17), but not ≥5 medications (aOR=1.42, 95% CI 0.91-2.22; Table 1). With each additional medication on a patient's medication list, their odds of being more frail increased by 8% (aOR=1.08, 95% CI 1.04-1.12). With each one-point increase on the Anticholinergic Risk Scale, odds of being more frail increased by 19% (aOR=1.19, 95% CI 1.03-1.39). With each additional PIM based on NCCN guidelines, odds of being more frail increased by 65% (aOR=1.65, 95% CI 1.34-2.04). Polypharmacy and PIMs were not associated with cognitive impairment by either MoCA Delayed Recall or CIB. Conclusion. Polypharmacy and PIMs are prevalent among older patients with blood cancers and are strongly associated with frailty but not cognitive impairment, independent of comorbidity. Increasing number of anticholinergic and especially cancer-specific PIMs have a stronger association with frailty compared to increasing number of medications in general. Our findings highlight that the types of medications contributing to polypharmacy may be more important than number of total medications. This suggests the need for streamlined ways of identifying specific PIMs in practice to deprescribe medications that may be associated with cumulative harm in older adults with cancer. Figure 1 Figure 1. Disclosures Stone: Aprea: Consultancy; Boston Pharmaceuticals: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; OncoNova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Macrogenics: Consultancy; Novartis: Consultancy, Research Funding; Glaxo Smith Kline: Consultancy; Innate: Consultancy; Janssen: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Soiffer: Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Takeda: Consultancy; Jasper: Consultancy; Gilead, USA: Other: Career Development Award Committee; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2609-2609
Author(s):  
Muhned Alhumaid ◽  
Georgina S Daher-Reyes ◽  
Wilson Lam ◽  
Arjun Law ◽  
Tracy Murphy ◽  
...  

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.


2020 ◽  
Author(s):  
Elkin Garcia-Cifuentes ◽  
Felipe Botero-Rodríguez ◽  
Felipe Ramirez Velandia ◽  
Angela Iragorri ◽  
Isabel Marquez ◽  
...  

Abstract Background Traditionally, the identification of cognitive impairment is based on neuropsychological tests and supported with not widely available biomarkers. This study aimed to establish the association between motor function (Gait Speed and Handgrip Strength) and the performance in a global cognitive performance and various cognitive domains. Our secondary objective was to determine a cut-off point for Gait Speed and Handgrip Strength to classify older adults as cognitively impaired. Methods This is a secondary analysis from the SABE Colombia study (Health, Well-Being, and Aging) conducted in 2015. We performed linear regression models, to establish association with motor function, clinical, and sociodemographic variables, and predict the scores of the Mini-mental State Examination and its domains (i.e. orientation, recall, counting, and language). The evaluation of the motor function variables as an instrument to separate cognitively impaired older adults was evaluated by developing a receiving operating characteristic curve (ROC). Results Gait speed was associated with orientation (r2 = 0.16), language (r2 = 0.15), recall memory (r2 = 0.14) and counting (r2 = 0.08). Similarly, handgrip strength was associated with orientation (r2 = 0.175), language (r2 = 0.164), recall memory (r2 = 0.137), and counting (r2 = 0.08). Slow gait had a cut-off point of 0,59 m/s, with an area under the curve (AUC) of 0.629 (0.613–0.646), whereas a weak handgrip strength had an AUC of 0.653 (0.645–0.661), with a cut-off point of 17.50 Kg for separating those older adults with cognitive impairment. Conclusions Gait Speed or Handgrip Strength are similarly associated with cognitive performance, exhibiting the larger associations with orientation and language domains. Gait Speed and Handgrip Strength can be easily performed by any clinician and seems to be useful screening tools to detect cognitive impairment.


Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Regis Peffault De Latour ◽  
Jeffrey Szer ◽  
Austin Kulasekararaj ◽  
Jin Seok Kim ◽  
Caroline I. Piatek ◽  
...  

Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged &gt;65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged &gt;65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or &gt;65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged &gt;65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (&gt;65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged &gt;65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the &gt;65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (&gt;65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 733-733 ◽  
Author(s):  
Dina Okasha ◽  
Amy A Kirkwood ◽  
Mhairi Copland ◽  
Emma Lawrie ◽  
Andrew McMillan ◽  
...  

Abstract In the donor versus no donor analysis of the UKALL12/E2993 trial in adult acute lymphoblastic leukaemia (ALL), there was a significant improvement in overall survival (OS) and reduction in relapse in the donor arm. However the OS benefit did not extend to older patients in whom myeloablative allogeneic hematopoietic cell transplant (alloHCT) related mortality was 35% at 2 years and outweighed the reduction in relapse risk. The overall outcome of older patients in this trial was poor, with patients >40 and 50 years having 23% and 15% 5 year survival respectively. In our current UK National Cancer Research Institute UKALL14 study all patients >40 years in CR, regardless of Philadelphia (Ph+) status and other high risk factors, are considered "high risk" and recommended a reduced intensity conditioned (RIC) alloHCT with a matched sibling (sib) or 8/8 matched unrelated donor (MUD) after a 2 course induction and high dose methotrexate. The primary endpoint is event free survival (EFS). We report here the early outcome of 88 patients with at least day 100 follow up (FU) (median FU 18 months) who received RICalloHCT on trial. Conditioning was with fludarabine 30mg/m2 d -6 to -2, melphalan 140 mg/m2 d -2 and alemtuzumab 30mg d -2 to-1 (MUD) or d-1 (sib). Graft versus host disease (GVHD) prophylaxis was ciclosporin A only. Nine patients did not receive alemtuzumab as per protocol. Multilineage chimerism (MC) and minimal residual disease (MRD) were assessed 3 monthly post alloHSCT. Escalating doses of donor lymphocyte infusions (DLI) were given for T-cell mixed chimerism or MRD, starting dose 1 x 106 CD3 cells/kg, escalating by half log increments every 3 months. Of 511 registered patients, 306 were >40 years old; 127 of those have completed RIC allograft, 88 of whom have sufficient FU to report. Median age was 51.5 years (range 41 to 64). Donor was sib in 24 and MUD in 64 patients, respectively. Median WBC at diagnosis was 7 x 109/l (0.6-557). Forty one of 77 (53%) evaluable patients had high risk cytogenetics, 22 (25%) were Ph+. Twelve of 56 (21%) with MRD data were MRD +ve pre-alloHCT. Post-alloHCT, myeloid engraftment occurred in 86/88 patients at a median of 13 days, 2 had missing data. Acute graft versus host disease (GVHD) occurred at grade 1 in 30 patients (34%) and grade 2-3 in 8 patients (9%). Thirty patients developed chronic GVHD (34% of 87/88 patients surviving to D100), 13 limited and 17 extensive. Of 12 patients who suffered transplant-related mortality (TRM), 6 died of infection (one post-transplant lymphoproliferative disease), 4 of organ toxicity and 2 of GVHD. TRM was not associated with age or donor type. Sixteen patients relapsed at a median time of 317 days (range 110-1034). Of those, 9 (of 15 with data) had high risk cytogenetics (EFS, p=0.38) and 6 (of 11 with data) were MRD +ve pre-alloHCT (EFS, HR 3.35, p=0.047). Twenty seven patients in total received 67 DLI (median maximum dose 3 x 106 CD3 cells/kg): 15 for mixed chimerism, 4 for rising MRD and 8 for both. Five patients (19%) developed post-DLI GVHD at grade 1 (n=4) and grade 2 (n=1). MC data is available for 36 patients receiving alemtuzumab and is shown in figure 1 where dark grey bars represent full and light grey bars mixed chimerism, respectively. DLI are denoted by black dashes. Mixed chimerism was seen in 22 of 36 patients (61%) who received alemtuzumab and so far 26 of 36 have achieved full donor chimerism (median 9 months), 10 after DLI (38%). Figure 2 shows Kaplan Meier curves of OS 76% (64-84, 95% CI) and EFS 68% (55-77)at 18 months. This is the first prospective study of RIC alloHCT in older adults with ALL; these early results demonstrate its feasibility within a large, multicentre trial. T-cell mixed chimerism was common at 1st MC assessment but early data indicate that conversion to full donor chimerism with DLI is a safe and realistic possibility. The impact of mixed chimerism (and pre-emptive DLI) on relapse remain to be evaluated. Severe GVHD and TRM were relatively low, such that the EFS of chemotherapy then RIC alloHCT, albeit with short-term FU, may be higher than expected for chemotherapy alone in this age group. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Copland: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fielding:Amgen: Consultancy, Honoraria.


2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 212-212
Author(s):  
Daniel Ernest Haggstrom ◽  
Marielys Figueroa-Sierra ◽  
Thomas Gregory Knight ◽  
Raghava Induru ◽  
Kim DeRhodes ◽  
...  

212 Background: Comprehensive geriatric assessment (CGA) is a multi-dimensional evaluation which influences medical decisions and predicts toxicity in older cancer patients. CGA pre-allogeneic stem cell transplant patients (ASCT) and repeated post-transplant provides information about treatment and helps to determine which parameters may predict ASCT outcomes. Methods: This was a prospective observational study evaluating 17 older patients with hematologic malignancy with CGA between December 9, 2016 and April 3, 2018 within the Levine Cancer Institute Senior Oncology Clinic. Included were validated measures across domains of cognition, disability, frailty, function and psychologic status. Repeat CGA was performed on surviving patients at least 99 days after ASCT (avg 122 days). Results: Median age was 66 (range 60-75) and the most common diagnosis was AML. There was no notable difference in pre and post-CGA physical and neurocognitive parameters for ASCT survivors (n=8). Within the deceased group (n=9) there was a longer TUG, lower patient-reported KPS, poorer psychological status, grip strength, and social support. Conclusions: There was no notable difference in the physical and neurocognitive CGA parameters before and after ASCT. Although the sample is small, there were notable trends toward lower patient-rated KPS compared to physician-rated KPS, poorer ADL function, slower TUG, and weaker grip strength in those patients who did not survive. CGA may identify older patients with hematologic malignancy who are at risk for worse outcomes post-ASCT.[Table: see text]


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2496-2496
Author(s):  
Alessandra Tucci ◽  
Gerardo Musuraca ◽  
Federica Cavallo ◽  
Vittorio Ruggero Zilioli ◽  
Manuela Zanni ◽  
...  

Abstract Introduction: We recently demonstrated in a large multicentre study that sGA can identify fit older patients with aggressive lymphoma able to tolerate first-line intensive treatment with curative intent and to obtain similar results than younger people (Merli at al JCO 2021). Regardless of age, about 40% of patients with aggressive lymphoma are either refractory or will eventually relapse after treatment with curative intent. Salvage platinum-based regimens followed by ASCT in responsive disease is a standard of care to obtain longer second remission. However, in many case series, patients over 65 years are excluded from the transplant approach because of potential severe toxicities of high-dose therapy in older patients. This study was designed to evaluate the feasibility and activity of high-dose treatment followed by ASCT in older FIT patients with R/R aggressive lymphoma selected with a sGA. Methods: Patients with R/R aggressive lymphoma after one line of treatment, aged between 65 and 75, and FIT to sGA were eligible for the study. Salvage treatment could be chosen between R-DHAP, R-ICE or other platinum or gemcitabine-containing regimens and stem cells were mobilized after 1 or 2 cycles. Patients achieving at least partial response after 3 courses and who remained FIT to sGA evaluation were eligible for ASCT and were conditioned with either BEAM or FEAM. Results: From May 2014 to August 2019, seventy-five patients from 16 FIL centres were enrolled and 70 were eligible for the study. Sixty-six of them had a diffuse large B-cell lymphoma, one had follicular 3b, 2 mantle cell and 1 Burkitt histology. Salvage treatment was R-DHAP in 48 patients, R-ICE in seven and gemcitabine or oxalyplatinum containing regimens in the remaining ones. Overall response rate after three courses was 44% (21 complete and 10 partial remission). Among the 39 unresponsive patients, 29 had progressive and 4 stable disease, 2 patients died of septic shock and heart failure during salvage and 4 patients withdrew their consent to ASCT. Four patients relapsed soon after response achievement before undergoing the transplant. ASCT was performed in 27 patients with a median of 5.6 x 10 6 CD34/Kg reinfused. No differences emerged in demographic and clinical characteristics between patients reaching the ASCT timepoint or not (Tab 1a). By intention to treat analysis, 2-y overall survival (OS) and PFS of the entire intention-to-treat population were 65% (95%CI: 50-76%) and 34% (95%CI: 22-46%) respectively, without differences according to age (Tab 1b). After a median of 27 months, 2-y OS was 79% (95CI: 51-86%) and EFS 56% (95CI: 32-75%). Twenty-four patients obtained a complete remission (CR) and 20 of them are in continuous CR after more than 12 months. Three patients progressed 1-8 months after ASCT and died. Most common non-hematologic grade 3-4 adverse events were gastrointestinal (10%) and infectious (8%). Conclusion: This study shows that sGA can identify older patients with R/R aggressive lymphoma who are able to tolerate and can benefit from high-dose therapy and ASCT. The poor response to second-line immunochemotherapy remains the major drawback of this approach since less than 50% of patients could actually receive ASCT. Nevertheless the 2-y survival of 65% in the intention to treat population is remarkable and sets the stage for the evaluation of new approaches such as CAR-T or bispecific antibodies also in older patients. A next step should be to explore the usefulness of sGA in the selection of candidates to these innovative treatments. Figure 1 Figure 1. Disclosures Tucci: Takeda: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo: ROCHE: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Gilead: Speakers Bureau. Zilioli: Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Takeda: Other: travel expenses, accommodation. Merli: EUSA Pharma: Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses. Marcheselli: sandoz: Membership on an entity's Board of Directors or advisory committees. Rossi: Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1091-1091
Author(s):  
Tarek H. Mouhieddine ◽  
Chidimma Nzerem ◽  
Robert A. Redd ◽  
Andrew Dunford ◽  
Matthew Joseph Leventhal ◽  
...  

Abstract Background: Recent studies have identified clinical and genomic factors contributing to worse clinical outcomes in patients with multiple myeloma (MM). Clonal hematopoiesis (CH) reflects the presence of somatic driver mutations in the blood or marrow of otherwise asymptomatic individuals. Using a variant allele frequency (VAF) cutoff of 2%, we recently reported CH in 21.6% of MM patients at the time of autologous stem cell transplant (ASCT) and found it was associated with shorter overall survival (OS) and progression-free survival (PFS) in those who did not receive maintenance therapy with an immunomodulatory drug (IMiD). However, this finding was based on a single tertiary center and only included MM patients who received ASCT. Methods: We studied a larger cohort of 986 newly diagnosed MM cases. Whole-exome sequencing (WES) data of peripheral blood and bone marrow samples of 986 MM patients (523 transplanted and 463 non-transplanted) from the Multiple Myeloma Research Foundation (MMRF) Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass, NCT0145429) study were analyzed. Both peripheral blood and tumor samples were analyzed to filter out myeloma mutations that could be contaminating the peripheral blood. Given the lower depth of coverage compared to prior targeted sequencing studies, small clones with a VAF below 2% were not detected. Altogether, the WES samples had a total depth of coverage of 117.68X. All data were analyzed using R version 3.5.0 (R Core Team). Results: Among the total cohort, 113 CH mutations were detected in 101/986 (10.24%) patients. CH was detected in 42/523 (8.03%) transplanted patients, compared to 59/463 (12.74%) non-transplanted patients. The most commonly mutated genes were DNMT3A, TET2, ASXL1, PPM1D, and TP53. The median age of the cohort was 63 years (range: 27 - 93), 60% were male, and median follow-up was 3.9 years (95% CI: 3.7 - 4.0). The presence of CH was associated with age (69 vs. 62 years, P &lt; 0.001). As expected, the median age of transplanted patients was lower (60 vs. 67 years) than in the non-transplanted group, which likely explains the higher prevalence of CH detected in the non-transplanted group. CH was associated with recurrent bacterial infections (P = 0.01) and increased cardiovascular disease (P = 0.006), but not with cerebrovascular disease (P = 0.74) or coagulopathies (P = 0.65). There was a trend towards worse PFS in non-ASCT patients with CH who were not treated with IMiDs (1.8 years) compared to non-CH IMiD-treated patients (2.7 years) (P &lt; 0.001). A CH effect on PFS was not detected in ASCT patients. OS was not different in those with or without CH in both ASCT and non-ASCT groups. 8 (0.8%) patients developed a second hematologic malignancy. CH at the time of MM diagnosis was not associated with an increased risk of developing a second hematologic malignancy (P = 0.58). To determine whether CH clones emerged or evolved during treatment, we examined serial samples from 52 patients (36 ASCT patients and 16 non-transplanted patients) with sequential samples. The median time between the first and second time point was 3.1 years (range: 1.0 - 5.4 years). At the first time point, only 3/52 (5.8%) patients had CH, but that number increased to 13/52 (25.0%) at the second time point. Five out of the 13 (38%) were non-transplanted patients. All but 1 patient were exposed to IMiDs. The most common emerging mutated gene was DNMT3A, found in 7 patient samples at the second time point, compared to 2 patients at the first time point. Conclusion: Using WES in a large cohort of newly diagnosed MM patients, we detected CH in 10.2% (VAF ≥ 2%) of patients. CH and non-IMiD treatment confers a shorter PFS in non-transplanted MM patients. However, throughout IMiD-based treatment, MM patients tend to acquire and/or expand previously undetected CH clones, particularly DNMT3A. The clinical significance of this clonal expansion during therapy is yet to be elucidated, and for now, this observation does not yet change clinical management. Figure 1 Figure 1. Disclosures Steensma: Novartis: Current Employment. Ebert: Deerfield: Research Funding; GRAIL: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Skyhawk Therapeutics: Membership on an entity's Board of Directors or advisory committees. Soiffer: NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Gilead, USA: Other: Career Development Award Committee; Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Jasper: Consultancy; Takeda: Consultancy. Sperling: Adaptive: Consultancy. Getz: Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; IBM, Pharmacyclics: Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.


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