Impact of Polypharmacy and Potentially Inappropriate Medications Among Older Adults with Blood Cancers

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.

Download Full-text

The Characteristics, Treatment Patterns, and Outcomes of Older Adults with Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-118660 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4463-4463

Author(s):

Mark A. Fiala ◽

Tanya M. Wildes ◽

Mark A. Schroeder ◽

Armin Ghobadi ◽

Keith E. Stockerl-Goldstein ◽

...

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Patient Characteristics ◽

Treatment Patterns ◽

Advisory Committees ◽

Improved Outcomes ◽

Immunomodulatory Drug

Abstract Background: Advances in the treatment for multiple myeloma (MM) have dramatically improved outcomes for younger patients. Older adults, particularly those 80 years of age or older at diagnosis, have seen more modest gains. MM incidence increases with age, and as more of the population is living later into life, the segment of the MM population over 80 will continue to grow. In this study, we sought to better understand the characteristics, treatment, and outcomes of older patients with MM. Methods: We identified all patients diagnosed with MM at age 80 or older in the Surveillance, Epidemiology, and End Results Program (SEER) database from 2007-2013 to determine incidence and outcomes. Subset analysis was then performed on patients included in the SEER-Medicare linked database who were enrolled in Medicare Parts A, B, and D to further explore patient characteristics and treatment patterns. Results: The incidence of MM increases over age, peaking after age 80. The annual incidence for those aged 65-69, 70-74, 75-79, 80-84 and 85+ was 24.4, 32.7, 39.5, 42.8 and 36.4 per 100,000, respectively. Based on 2010 US population estimates, approximately 4,500 new cases of MM were diagnosed annually 2007-2013 in patients age 80 or older. In that period, 8,093 cases, approximately 1,150 per year, were reported to SEER. The estimated median overall survival (OS) of these patients was 14 months (95% CI 13.2-14.8). The estimated relative 12 month survival was 58.9% (95% CI 57.4-60.4) compared to their peers without cancer. Of the 8,093 cases of MM reported to SEER during the study period, 2,385 were present in the SEER-Medicare linked dataset. Of these, 225 were identified as smoldering MM using a previously established algorithm (Fiala, et al, JCOCCI, 2018) and excluded leaving 2,160 for the analyses. The median age was 84 (range 80-100) and 55% were female. 81% were white, 13% black or African-American, and 6% another race. At disease presentation, 22% had claims indicating hypercalcemia, 61% renal failure or chronic kidney disease, 59% anemia, and 34% MM bone involvement. The estimated median OS was 13.4 months (95% CI 12.2-15.1). Only 52% of patients had claims indicating they received systemic MM treatment within 6 months post-diagnosis. Nearly all that did received novel agents; 38% received bortezomib-based treatment, 41% immunomodulatory drug (IMID)-based, and 14% both. The others received antineoplastic chemotherapies such as melphalan or cyclophosphamide. Interestingly, bortezomib utilization increased incrementally from 25% of patients treated in 2007 to 62% in 2013 while IMID utilization declined from 67% to 49%. The median OS of those receiving treatment was 21 months (95% CI 18.5-23.1) compared to 6.3 months (95% CI 5.3-7.3) for those who did not (p <0.0001). MM treatment was associated with a 26% decrease in hazard for death (aHR 0.74; 95% CI 0.67-0.82; p < 0.0001) independent of age, race, gender, poverty, comorbidities, and proxy measures of performance status. Outcomes improved for patients in more recent years; the hazard for death decreased by 3% (HR 0.97; 95% CI 0.94-0.99; p = 0.0096) each year 2007-2013. This can be attributed to increasing treatment rates. In 2007, only 41% of patients received treatment compared to 61% in 2013. After controlling for MM treatment, the year of diagnosis was no longer a significant predictor of survival. Conclusions: The outcomes of patients with MM over 80 years old are still relatively poor; nearly half of the patients do not receive systemic treatment and for those who do the median OS is just 21 months. The population over 80, when MM incidence peaks, is projected to triple over the next few decades. It is imperative that we improve our understanding of the needs of this vulnerable subgroup of patients of MM. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: 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; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

Cognitive Profile of Adults with Sickle Cell Disease - Cluster Analysis

Blood ◽

10.1182/blood-2021-150689 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3120-3120

Author(s):

Maryline Couette ◽

Stéphanie Forté ◽

Damien Oudin Doglioni ◽

Kevin H.M. Kuo ◽

Pablo Bartolucci

Keyword(s):

Cognitive Impairment ◽

Board Of Directors ◽

Cognitive Deficits ◽

Research Funding ◽

Principal Component ◽

Cognitive Profile ◽

Anxiety And Depression ◽

Cognitive Profiles ◽

Advisory Committees ◽

Cluster 2

Abstract Background: Published literature on cognitive functioning in adults with sickle cell disease (SCD) is sparse when compared to children. A few reports describe deficits in processing speed and executive functioning. Some studies suggest that these deficits are more severe in patients with silent cerebral infarcts (SCI). Even in the absence of radiological evidence of ischemic injury, some cognitive deficits have been depicted in adults . We hypothesize that in SCD adults, the cognitive profile varies with the presence of ischemic injury (SCI or overt stroke). The aims of this study were 1) to describe the neuropsychological profiles of SCD adults, and 2) to characterize clusters of patients with similar cognitive profiles. Methods: We conducted a retrospective analysis of all consecutive SCD adults who underwent comprehensive neuropsychological assessment during routine care at the UMGGR clinic at Henri Mondor Hospital, Créteil (France), between January 2017 and April 2021. The Montreal Cognitive Assessment (MoCA) and Hospital Anxiety and Depression Scale (HADS) were used for cognitive disorder, anxiety and depression screening, respectively. The cognitive battery combined standardized neuropsychological tests with established clinical utility and validity. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Principal component analysis was performed. ANOVA was used to compare patients' characteristics between clusters. Results: 80 patients, median age 36.5 [range 19-63] years were included. 40 (50.0%) were male. Genotype distribution was 62 patients (77.5%) with SS/Sbeta 0, 12 (15.0%) with SC and 6 (7.5%) with Sbeta +. On Principal Component Analysis, a 5-factor model presented the best fit (Bartlett's sphericity test (χ²(171)=1174; p<0.001)), explaining 71.8% of the variance in neuropsychological scores. The first factor encompassed tests specifically assessing visual attention/visual organization (right hemisphere). The second included tests for mental/cognitive control (frontal lobe), the third tests of selective inhibition/attention (fronto-parietal), the fourth tests for language/memory (left temporal lobe) and the last referred to shifting skill (sub-cortical loop). On hierarchical classification, 3 different clusters emerged: 32 patients in cluster 1, 32 in cluster 2 and 16 in cluster 3. Cluster 1 had a lower mean educational level (F(2,77) = 15,65; p<0,001). Cluster 1 showed the lowest mean MoCA score (20.0/30.0), relative to cluster 2 and 3 (24.6 and 26.4; p<0.001 and p<0.001, respectively). Cluster 1 patients presented deficits on all five factors. Cluster 2 patients compared to cluster 3 were altered in 4 factors (factors 1-4), but to a lesser extent than cluster 1. Processing speed was slower and some frontal-executive deficits were present in cluster 2 compared to cluster 3. There was no statistical difference between clusters in terms of ethnic origins. There was a trend for the presence of more cerebral vasculopathy in cluster 1 (chi2; p=0.06). Regarding stroke, 70% occurred during childhood in cluster 1, whereas 70% during adulthood in cluster 2, and 100% during adulthood in cluster 3. Conclusions: Overall, these results suggest at least three different cognitive profiles in adults with SCD: 1) few or no cognitive deficits (cluster 3), 2) some cognitive impairment with a sub-cortical cognitive profile (cluster 2) and 3) more global cognitive impairment with cortical/sub-cortical profile and specific deficits of memory, language and constructional praxis, depending on the location of prior overt neurological events (cluster 1). To reduce the long-term cognitive morbidity of SCD, patients can be identified by their distinct cognitive profiles and neurorehabilitation tailored to their unique profile should be applied. The large proportion of childhood stroke in patients with global cognitive impairment in contrast with majority of those with milder to no cognitive impairment having had their stroke in adulthood emphasize the crucial importance of preventing early childhood stroke and implementing early neurorehabilitation. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Kuo: Pfizer: Consultancy, Research Funding; Bluebird Bio: Consultancy; Novartis: Consultancy, Honoraria; Apellis: Consultancy; Alexion: Consultancy, Honoraria; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Bartolucci: Jazz Pharma: Other: Lecture fees; AGIOS: Consultancy; Emmaus: Consultancy; GBT: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Fabre Foundation: Research Funding; Addmedica: Consultancy, Other: Lecture fees, Research Funding.

Download Full-text

Psychological Distress in Young Adults with Acute Myeloid Leukemia Undergoing Induction Chemotherapy

Blood ◽

10.1182/blood-2020-140589 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 17-18

Author(s):

Bethany Lockwood ◽

Areej El-Jawahri ◽

Alison R. Walker ◽

Deborah Russell ◽

Jillian Gustin ◽

...

Keyword(s):

Older Adults ◽

Psychological Distress ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Symptom Burden ◽

Ptsd Symptoms ◽

Advisory Committees ◽

Clinically Significant

Introduction: Young adults (YAs), ages 18-39 years diagnosed with cancer have distinct physical, developmental, and psychosocial needs that are often unmet during oncologic treatment. In acute myeloid leukemia (AML), a disease affecting both younger and older adults, patients navigate several treatment intensity choices, and with intensive induction chemotherapy are often balancing a chance of cure with a risk of death. Furthermore, YAs with AML can have marked life disruptions with this unpredictable illness trajectory and prolonged induction hospitalization, further conflicting with normal development at this stage. Fundamentally different than solid tumors, we lack an understanding of the YA experience in AML induction compared to their older counterparts. This study explores patient-reported outcomes (PROs) including quality of life (QOL) and physical and psychological symptom burden among YAs undergoing induction chemotherapy. Methods: We conducted a secondary analysis of 160 patients with high-risk AML hospitalized to receive intensive chemotherapy who were enrolled in a randomized control trial of palliative care (PC) intervention versus standard oncology care. Patients with newly diagnosed, relapsed, or refractory AML receiving intensive treatment requiring a 4-6 week hospitalization were enrolled in the study. We used the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu), the Edmonton Symptom Assessment System (ESAS), the Hospital Anxiety and Depression Scale (HADS), and the Post-Traumatic Stress Disorder (PTSD) Checklist to assess QOL, symptom burden, and psychological distress respectively. Assessments were administered at baseline, week-2, and week-4 following initiation of chemotherapy. We used descriptive statistics to compare PROs at baseline between YAs (< 40 years) and older adults. We used linear regression models controlling for PC intervention effect when examining the association between age (YAs versus older adults) and PROs at week-2. We used linear mixed effect models controlling for randomization to the PC intervention to assess the association between age and PROs longitudinally throughout the hospitalization. Results: Of the 160 patients with high-risk AML enrolled in this study, 14 (8.8%) were YAs < 40 years. Demographic characteristics highlight that the majority of YAs had relapsed AML (n=10, 71.4%) and there was a greater presence of racial and ethnic diversity compared to older adults. The baseline mean QOL score for YAs was 110.5 (SD 34.2). Overall, 57.1% (8/14) reported clinically significant anxiety and 50% (7/14) reported clinically significant PTSD symptoms at baseline. Fewer YA patients, 21.4% (3/14) reported clinically significant depression. Evaluation of PROs at week-2 nadir adjusted for randomization to the PC intervention, highlighted a significant lower QOL (β=-18.27; p=0.036), higher anxiety (β=2.72; p=0.048), and higher PTSD symptoms (β=10.34; p=0.007) for YAs compared to older adults. Longitudinal analyses exploring the impact of age on PROs across induction hospitalization demonstrated that YAs had consistently significant higher anxiety (β=3.66; p=0.024) and PTSD symptoms (β=15.64; p<0.001) compared to older adults [Figure 1]. Conclusions: For YAs with AML undergoing induction chemotherapy, anxiety and PTSD symptoms are highly prevalent both at baseline and longitudinally throughout the induction hospitalization. This demonstrates a continued unmet need of the significant psychological distress and intensified hospitalization experience for YAs compared to their older counterparts. Given that distress during induction hospitalization can be predictive of post-treatment outcomes, it is imperative to tailor integrated supportive care and psychosocial interventions for YAs with AML during induction chemotherapy. Disclosures Walker: Geron: Research Funding; Newave Pharmaceuticals: Research Funding. Bhatnagar:KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Predictors of Bleeding in the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study

Blood ◽

10.1182/blood-2019-125292 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 710-710

Author(s):

Alfonso J Tafur ◽

Na Li ◽

Nathan Clark ◽

Sam Schulman ◽

Alex Spyropoulos ◽

...

Keyword(s):

Atrial Fibrillation ◽

Board Of Directors ◽

Research Funding ◽

Factor Xa ◽

Bleeding Risk ◽

Multivariate Model ◽

Thrombin Time ◽

Advisory Committees ◽

Perioperative Bleeding ◽

Active Cancer

Introduction In the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study a simplified, standardized, pharmacokinetic based perioperative interruption scheme was stablished for patients with non-valvular atrial fibrillation taking direct oral anticoagulants (DOACs). The rate of bleeding and thromboembolic outcomes was low, yet better awareness of bleeding predictors will aid the informed decision making for both clinicians and patients. Thus, we aimed to define the factors associated with perioperative bleeding events in the PAUSE cohorts. Methods The standardized interruption scheme is depicted in figure 1. We analyzed bleeding as the composite of major and clinically relevant non-major bleeding (MB/CRNM) according to the ISTH criteria. Putative predictors of bleeding were prospectively collected during the PAUSE recruitment. For patients taking dabigatran the dilute thrombin time was measured from a pre-operative blood sample. A DOAC-calibrated anti-factor Xa level was assessed preoperatively for patients taking factor Xa inhibitors. Continuous numeric variables were reported as means with SD; frequencies were reported when appropriate. We used stratified logistic regression models for analysis. All statistical analyses were performed in R version 3.6.0. Results There were 3007 patients requiring perioperative DOAC interruption, distributed in the apixaban (A) (N = 1,257), dabigatran (D) (N = 668), and rivaroxaban (R) (N = 1,082) cohorts. Characteristics of the patients who developed MB/CRNM are reported in table 1. More than one third of included patients underwent a high bleeding risk procedure. The rates of MB/CRNM were 3.02% in group A, 2.84% in group D, and 4.16% of group R patients from the point of DOAC interruption to 30 days after the procedure. In the univariate analysis, surgery bleeding risk was significantly associated with MB/CRNM (low vs high, OR 0.56, 95% CI 0.36-0.86; p=0.008). Multivariate analysis stratified by region found hypertension (OR 1.81, 95%CI 1.07-3.07; p=0.027), prior bleed or bleed predisposition (OR 1.62, 95% CI 1.02-2.58; p=0.043) were significantly associated with MB/CRNM (table 2); whereas surgery bleeding risk was not significant after adjusting other covariates. Female gender was associated with lower MB/CRNM risk (This result seems to be mainly driven by the rate of CRNM, 2.21% male had CRNM and 1.57% female had CRNM, and the signal disappeared in the model for MB). [Hypertension (OR 3.93, 95%CI 1.40-11.07; p=0.010), active cancer (OR 2.30, 95% CI 1.10-4.81; p=0.026) were significantly associated with MB (table 3)] Aspirin use was more prevalent among males (13.78%) than females (7.75%), but this did not fully explain the gender effect. The model for MB/CRNM had an area under the curve (AUC) of 0.65 (standard error 0.03). Drug level analysis was available for 2541 (84.5%) patients. In the stratified analysis with the DOAC level (>50ng/dL vs £50ng/dL) as a single predictor, there was no significant association with MB/CRNM observed (OR 1.07, 95% CI 0.38-2.96; p=0.902). In the multivariate model, adding DOAC level to the model did not improve the AUC. Discussion A standardized interruption scheme results in low risk of bleeding for patients with atrial fibrillation interrupting DOACs for surgery/invasive procedures. The protocol-defined surgical bleed risk in PAUSE was valid, and selected to numerically higher bleeding rates, but it was not independent predictor of bleeding when the interruption scheme and covariates are accounted for. Hypertension was the only potentially modifiable predictor of perioperative MB/CRNM bleeding. Likely selecting for a frail population, active cancer and hypertension were predictors of MB events. In the exploratory analyses, residual levels did not improve the predictive model. The multivariate model had a low performance and we do not advocate modification of the PAUSE-proposed interruption schema based on these results. The PAUSE trial is the first large scale study enabled to investigate the factors governing perioperative bleed among DOAC-Anticoagulated patients. Nonetheless, we did not have power to analyze DOAC cohorts independently due to the paucity outcomes. Overall, the results strengthen the validity of the PAUSE-proposed DOAC interruption scheme for atrial fibrillation patients who need surgery. Disclosures Tafur: Recovery Force: Consultancy; Janssen: Other: Educational Grants, Research Funding; BMS: Research Funding; Idorsia: Research Funding; Daichi Sanyo: Research Funding; Stago: Research Funding; Doasense: Research Funding. Spyropoulos:Bayer: Consultancy; Ingelheim: Consultancy; Portola: Consultancy; Janssen: Research Funding; Boehringer INgelheim: Research Funding; Janssen: Consultancy. Douketis:Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Portola: Other: Consultant ; Janssen: Other: Consultant ; The Merck Manual: Patents & Royalties; Up-to-Date: Patents & Royalties.

Download Full-text

Use of High Dose Cytarabine (HiDAC) for Post-Remission or Re-Induction Therapy Is Safe and Effective in Select Older AML Patients

Blood ◽

10.1182/blood-2021-153143 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4422-4422

Author(s):

Jillian Lykon ◽

Ellen Madarang ◽

Nina Nguyen ◽

Wenhui Li ◽

Sunil G. Iyer ◽

...

Keyword(s):

Older Adults ◽

Febrile Neutropenia ◽

Board Of Directors ◽

Research Funding ◽

Average Dose ◽

Advisory Committees ◽

Poor Risk ◽

Risk Patients ◽

Dose Reductions

Abstract Introduction A standard therapy for fit older adults (≥60 years) with acute myeloid leukemia (AML) being treated with curative intent consists of induction chemotherapy with cytarabine and an anthracycline followed by 1-4 cycles of shorter course post-remission therapy with cytarabine +/- anthracycline. Historically, HiDAC has been reserved for younger patients due to the high incidence of cytarabine-induced neurotoxicity, febrile neutropenia, and hospital re-admissions in older patients (Mayer et al. 1994). In select older adults (e.g., those with good-risk cytogenetic/molecular abnormalities, or requiring reinduction for persistent AML), the risk/benefit for HiDAC may favor its use. Real world evidence is lacking on the safety of full dose HiDAC (total 18 grams/cycle) in fit older adults in the 60-75 age range. Methods We performed a retrospective analysis of AML patients ≥60 years who received at least one cycle of HiDAC, defined as 3g/m2 every 12 hours for 6 doses, either days 1-3 or days 1, 3, 5, as post-remission therapy or primary re-induction (i.e., after failure of primary induction with 7+3 or CPX-351) between July 1, 2014 and May 28, 2021. AML risk was defined by European LeukemiaNet (ELN) guidelines. All patients had daily neurologic exams including prior to each dose of HiDAC and at the beginning of each nursing shift. The primary endpoint was tolerability, defined as average dose per cycle, rate of dose reductions, incidence of febrile neutropenia, cerebellar toxicity, and rate of hospital re-admissions. Secondary endpoints were overall survival (OS), composite complete remission (CCR) for patients treated with HiDAC re-induction, and duration of relapse-free survival (RFS) (from day 1 of treatment) in all patients. Results From July 2014 to May 2021, 34 patients ≥60-years-old were treated with HiDAC at our center. Median age at HiDAC administration was 64 (60-73) [Table 1]. Approximately half the patients were Hispanic and male and almost all (97%) had ECOG performance scores of 0-1. HiDAC was used as post-remission therapy (following 7+3-type induction in 80%) in 25 patients and as re-induction in 14. Eleven patients (32%) were ELN favorable risk, 8 (25%) were intermediate, and 15 (44%) were poor risk. For post-remission therapy, the average total dose of cytarabine per cycle was 16.6 gm/m2 (6-18 gm/m2) and the median number of cycles was 4 (1-4) [Table 2]; 6 patients (24%) required dose reductions, the most common reason being upcoming allogeneic stem cell transplant (n=4). No cerebellar toxicity was observed. Duration of neutropenia was on average 15 days (7-53) in the re-induction group and 7.5 days (1-29) in the post-remission group, with 23 post-remission patients (92%) receiving granulocyte colony stimulating factors (G-CSF). Eleven hospital readmissions occurred, most commonly (73%) for febrile neutropenia. Early mortality rates were low, with one patient on the post-remission arm and one patient on the re-induction arm dying within 30 and 60 days, respectively, both due to sepsis. Median OS was 15.8 months (95% CI 0-31.8) in patients who received post-remission HiDAC, with 44% of patients still alive with a median follow up of 17.2 months (95% CI 7.2-55.8). Favorable risk patients (n=11) receiving post-remission HiDAC had median OS of 15.8 months (95% CI 0-43.1), while intermediate/poor risk patients (n=14) had median OS of 11.3 months (95% CI 9.3-13.2) [p=0.53]. Median OS was 9.8 months (95% CI 2.5-17.1) in patients who received HiDAC re-induction, with 29% of patients still alive with a median follow up of 28.6 months (95% CI 16.6-39.9) [Table 3]. Five patients (36%) achieved CCR after HiDAC re-induction, all of whom went on to receive post-remission HiDAC. Median RFS was 8.5 months for re-induction and 8.8 months for post-remission patients [Table 3]. Conclusions HiDAC (18 grams) can be safely given to select patients over age 60. Critical to tolerability is rigorous screening of "fitness," limiting the upper age receiving HiDAC to 75, ensuring adequate renal function and euvolemia, and advances in supportive care. Encouraging survival outcomes were observed in older adults receiving post-remission or re-induction HiDAC, independent of ELN risk. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

Download Full-text

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

Blood ◽

10.1182/blood.v128.22.689.689 ◽

2016 ◽

Vol 128 (22) ◽

pp. 689-689 ◽

Cited By ~ 1

Author(s):

Tammy T. Hshieh ◽

Nolan B. Condron ◽

Richard M. Stone ◽

Robert J. Soiffer ◽

Gregory A. Abel

Keyword(s):

Cognitive Impairment ◽

Grip Strength ◽

Board Of Directors ◽

Gait Speed ◽

Older Patients ◽

Hematologic Malignancy ◽

Cognitively Impaired ◽

Advisory Committees ◽

Delayed Recall ◽

Cumulative Deficit

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.

Download Full-text

Evidence of Educational Bias in Cognitive Screening of Adults with Sickle Cell Disease: Comparison of Available Tools and Possible Strategies for Mitigation

Blood ◽

10.1182/blood-2020-143169 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14

Author(s):

Stéphanie Forté ◽

Maryline Couette ◽

Damien Oudin Doglioni ◽

Denis Soulieres ◽

Kevin H.M. Kuo ◽

...

Keyword(s):

Cognitive Impairment ◽

Sickle Cell Disease ◽

Educational Attainment ◽

Board Of Directors ◽

Research Funding ◽

Cognitive Screening ◽

Cell Disease ◽

Advisory Committees ◽

Visuospatial Task ◽

Level Of Education

Background: Cognitive impairment is a dreaded complication of sickle cell disease (SCD) that impacts quality of life, school performance and employment. In 2020, the American Society of Hematology issued a strong recommendation that clinicians supervising the care of adults with SCD conduct surveillance for cognitive impairment using simplified signaling questions (DeBaun, 2020). However, guidance on the optimal screening strategy is lacking and several available tools are biased by language and education. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations (Storey, 2004). In the general elderly population, RUDAS is less biased by education than the Montreal Cognitive Assessment (MoCA) (Naqvi, 2015). Hypothesis: In adults with SCD, performance on the RUDAS is less influenced by educational attainment when compared to the MoCA. Our primary aim was to estimate the prevalence of suspected cognitive impairment using RUDAS and MoCA in adult SCD patients. The secondary aims were to examine for the presence of educational bias and to develop mitigation strategies in case of such a bias. Methods: Study design: cross-sectional study at UMGRR clinic at Henri Mondor Hospital, Créteil (France). Inclusion criteria: out-patients ≥18 years-old; all SCD phenotypes. Exclusion criteria: inability to obtain informed consent and/or follow study instructions. Intervention: Cognitive screening was performed using the RUDAS (translated to French by Philippe Desmarais), MoCA (third alternative version) and an additional visuospatial task of copying overlapping triangles (from the French BEC96 assessment). RUDAS and MoCA scores <28 and <26, respectively, were considered suggestive of cognitive impairment per previous studies (Basic, 2009 and Nasredinne, 2005) and patients were referred for definite neuropsychological evaluation. Survey on demographics and screening for depression and anxiety using Hospital Anxiety Depression Scale (HADS) were completed by the participants. Educational attainment was scored based on the number of years of schooling for the highest completed diploma. Statistical plan: linear regression was performed to identify possible associations between RUDAS, MoCA and social determinants of health. Results: Among the first 45 consecutive adult SCD patients undergoing routine cognitive screening, the median age was 39 (range 19-67). RUDAS and MoCA scores suggestive of mild cognitive impairment were found in 33/45 (73.3%) and 29/45 (64.4%) participants, respectively. There was a strong correlation between both tests (r=0.48, p=0.001). Both RUDAS and MoCA scores increased significantly with increasing level of education (r=0.36, p=0.015 and r=0.39, p=0.007, respectively), but were not significantly influenced by the HADS score. RUDAS and MoCA test items most biased by education were visuoconstructional tasks. Tasks assessing executive functioning and language were also biased in MoCA. Substituting the 3D visuospatial task of the RUDAS by a 2D task reduced the educational bias (r=0.20, p=0.045). Adding 1 point for highest level of education £ 12 years after kindergarten did significantly mitigate the effect of education on the RUDAS but only partially for the MoCA (r=0.23, p=0.131 and r=0.30, p=0.047). Conclusions: Overall, these results suggest there is an educational bias in the neurocognitive screening of adult SCD patients using available tools such as the RUDAS and MoCA. Although RUDAS was less biased overall, visuospatial assessment remained biased. The task often considered more "culture-fair" is still subject to the impact of educational potential (Statucka, 2019). We provide different strategies to mitigate education bias when assessing with RUDAS. Thus, the RUDAS adjusted by the educational level allows to systematically identify SCD patients in need of comprehensive neurocognitive testing. Prospective validation is ongoing. Disclosures Forté: Canadian Hematology Society: Research Funding; Pfizer - Global Medical Grants: Research Funding. Soulieres:Novartis: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Kuo:Pfizer: Consultancy, Research Funding; Celgene: Consultancy; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; Apellis: Consultancy. Bartolucci:Roche: Consultancy; Innovhem: Other; AGIOS: Consultancy; Bluebird: Consultancy; Emmaus: Consultancy; Addmedica: Research Funding; Fabre Foundation: Research Funding; Novartis: Research Funding; Bluebird: Research Funding; GBT: Consultancy; ADDMEDICA: Consultancy; HEMANEXT: Consultancy; Novartis: Consultancy.

Download Full-text

Integrating Geriatric Assessment and Genetic Profiling to Personalize Therapy Selection in Older Adults with Acute Myeloid Leukemia (AML)

Blood ◽

10.1182/blood-2019-124375 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 120-120 ◽

Cited By ~ 3

Author(s):

Vijaya R. Bhatt ◽

Christopher Wichman ◽

Zaid S. Al-Kadhimi ◽

Thuy T. Koll ◽

Ann Berger ◽

...

Keyword(s):

Older Adults ◽

Board Of Directors ◽

Geriatric Assessment ◽

Interim Analysis ◽

Research Funding ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Genetic Profiling ◽

Therapy Initiation ◽

Patient Profiling

Introduction: Geriatric assessment can predict the risk of toxicities of chemotherapy in older adults. Genetic risk categories correlate with survival following intensive chemotherapy in AML. Integrating geriatric assessment for patient profiling and genetic profiling of leukemic cells represents an innovative precision medicine approach to personalize therapy selection in older adults with AML. We report results of a pre-planned interim analysis of a pragmatic phase II trial using such strategy that has an overarching goal to reduce early mortality (NCT03226418). Methods: Patients ≥60 years with a new diagnosis of AML underwent geriatric assessment prior to initiation of treatment. Geriatric assessment of physical function, cognitive function and comorbidity burden were used to determine fitness for intensive chemotherapy (Table 1). Additional assessment included Karnofsky Performance Scale (KPS), Patient Health Questionnaire-9 (PHQ-9), and Mini Nutritional Assessment-Short Form (MNA). Genetic profiling for therapy selection relied on karyotyping and followed the 2017 European LeukemiaNet criteria. While available mutation test results were incorporated to risk stratify, the study did not require to wait for the results prior to therapy initiation given an anticipated turnaround time of 1-2 weeks for mutation test results. Therapy selection followed the algorithm demonstrated in Figure 1. Patients with good or intermediate-risk AML received intensive chemotherapy such as 7+3 +/- gemtuzumab or midostaurin if determined to be fit. Patients with high-risk AML received low-intensity chemotherapy such as a hypomethylating agent with or without novel drugs, or CPX 351 if they were fit and met the FDA-approved indications. Patients with organ dysfunction (e.g. creatinine ≥2 mg/dl) and those requiring chemotherapy for other malignancy received low-intensity chemotherapy. Chemotherapy at diagnosis or follow up could be administered in community oncology settings. Patients were followed for assessment of quality of life, functional and oncologic outcomes. Results: Between July 2017-June 2019, a total of 31 patients (including 1 MDS patient considered screen failure) were enrolled. The pre-planned interim analysis results are based on the first 27 AML patients. Baseline characteristics included a median age of 70 years (range 60-84 years), 56% female, 96% white, and a median KPS of 80% (range 60-100%). As presented in Table 1, over half of the patients had ≥3 comorbidities, impairment in objective physical function (short physical performance battery) and Montreal Cognitive Assessment. Additionally, 67% had poor nutritional status (MNA score of ≤11) and 26% had abnormal depression screen (PHQ-9 score of ≥10). Risk categories included adverse (64%), intermediate (16%), and good-risk AML (20%). Patients had one or more of the following mutations: FLT3 ITD (11%), NPM1 (22%), biallelic CEBPA (4%), IDH1 (15%), IDH2 (8%), RUNX1 (15%), ASXL1 (22%), and TP53 (19%). Three patients received intensive chemotherapy; CPX 351 (n=2) or 7+3+ gemtuzumab (n=1). Other patients received decitabine or azacitidine alone (n=16), azacitidine and venetoclax (n=5) or decitabine and midostaurin (n=3). The median time from diagnosis to therapy initiation was 7 days (0-20 days) whereas the median time from enrollment to therapy initiation was 2 days (range 0-9). Mortality at 30 days from diagnosis was 3.7% (95% confidence interval, CI 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). Mortality compared favorably to an unmatched historical cohort of patients ≥60 years treated at our center between 2011-2016, where 30-day mortality was 30% (95% CI 22-40%) and 90-day was 41% (95% CI 32-52%) (Future Oncol. 2019;15:1989-95). Conclusions: Our model to personalize AML therapy selection represents an innovative approach to precision medicine that incorporates both geriatric assessment for patient profiling and genetic profiling of leukemia cells. Geriatric assessment demonstrated high frequency of impairment in objective physical and cognitive function. Patients were able to start therapy within a median of 2 days following enrollment. Pragmatic aspects of the trial included broad eligibility criteria and co-management of patients with community oncologists. Our pre-planned interim analysis data appear promising with lower rates of early mortality compared to unmatched historical controls. Disclosures Bhatt: Pfizer: Consultancy; CSL Behring: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Partner therapeutics: Consultancy; Incyte: Consultancy, Research Funding; Tolero Pharmaceuticals: Research Funding; National Marrow Donor Program: Consultancy. Al-Kadhimi:Celldex Biotech: Other: Stocks; Seattle Genetics: Other: Stocks. Armitage:Oncology Analytics: Consultancy; Partner Therapeutics: Consultancy; Samus Therapeutics: Consultancy; Ascentage: Consultancy; Tesaro bio: Membership on an entity's Board of Directors or advisory committees; Union Pacific: Consultancy. Holstein:GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Gundabolu:Samus Therapeutics: Research Funding; Jazz pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. OffLabel Disclosure: Single agent azacitidine and decitabine as well as decitabine in combination with midostaurin are not approved by the US FDA for acute myeloid leukemia.

Download Full-text

Baseline Characteristics and Clinical Outcomes from the Cancer Associated Thrombosis - Patient Reported Outcomes with Rivaroxaban (COSIMO) Trial

Blood ◽

10.1182/blood-2019-126810 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2161-2161

Author(s):

Anthony Maraveyas ◽

Jan Beyer-Westendorf ◽

Agnes Yuet Ying Lee ◽

Lorenzo G Mantovani ◽

Yoriko De Sanctis ◽

...

Keyword(s):

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

Bleeding Event ◽

Select Committee ◽

Advisory Committees ◽

Government Health ◽

Patient Reported ◽

Uk Government ◽

Active Cancer

Background: Patients living with cancer who develop venous thromboembolism (VTE) have a high risk of VTE recurrence, and traditional anticoagulants (low molecular weight heparin [LMWH] or vitamin K antagonists [VKAs]) are associated with significant treatment burdens. Rivaroxaban is a direct oral anticoagulant (DOAC) that may provide a more convenient treatment option for these patients. Methods: The COSIMO study was a multinational, prospective, non-interventional, single-arm cohort study designed to collect real-world data on patient treatment satisfaction and outcomes associated with rivaroxaban treatment following ≥4 weeks of LMWH/VKA therapy for the treatment of acute VTE in patients with active cancer. Here, we report on the secondary objectives, which were to provide descriptive analyses of clinical characteristics and patterns of use of anticoagulant treatment, and to assess the safety and effectiveness of rivaroxaban in this patient population. Results: Overall, 505 patients were enrolled, and the qualifying venous thromboembolic event was deep vein thrombosis (DVT) only in 45.3% of patients, pulmonary embolism (PE) only in 37.2% of patients, DVT with PE in 9.7% of patients, and catheter-associated DVT in 7.5% of patients (Table). The majority of patients had solid tumors (n=449, 88.9%); 56 patients had hematological malignancies. The most common reasons to switch to rivaroxaban were patient preference/quality of life (n=310, 61.4%) and physician decision (n=174, 34.5%). A total of 150 (29.7%) patients were treated with concomitant chemotherapy and 79 (15.6%) received concomitant radiotherapy. Overall, 117 (23.2%) patients discontinued the study: 59 (11.7%) died, 21 (4.2%) withdrew consent, and 17 (3.4%) were lost to follow-up. 80.2% of patients were treated with rivaroxaban for at least 3 months, and most patients (78.6%) received rivaroxaban 20 mg once daily on study entry. Treatment-emergent adverse events (AEs) were reported: 312 (61.8%) patients had an AE (148 [29.3%] serious AEs), and 95 (18.8%) patients had a bleeding event reported, of which 18 (3.6%) patients had an adjudicated major bleeding event. Adjudicated symptomatic and incidental VTE recurrence occurred in 15 (3.0%) and 3 (0.6%) patients, respectively. Adjudicated other site thromboembolic events such as splanchnic or cerebral vein thromboses were symptomatic in 1 (0.2%) patient and incidental in 1 (0.2%) patient. Conclusions: Observed incidence rates of VTE and bleeding events in COSIMO were similar to previous studies of DOACs for VTE treatment in patients with active cancer (Young AM et al. J Clin Oncol 2018;36:2017; Raskob GE et al. N Engl J Med 2018;378:615). Study governance Bayer AG Funding The COSIMO study is funded by Bayer AG and Janssen Pharmaceuticals. Trial protocol number NCT02742623. Registered 19 April 2016. Documented approval from appropriate independent ethics committees/institutional review boards will be obtained for all participating centers prior to study start. Patients were asked to provide signed informed consent forms before joining the study. Few patients have yet completed the study, and so no data are available to share. Acknowledgements Editorial assistance was provided by Kate Weatherall of Chameleon Communications Int. Ltd. with funding from Bayer AG and Janssen Scientific Affairs, LLC. Disclosures Maraveyas: Bristol-Myers Squibb: Honoraria; Bayer AG: Honoraria, Research Funding; Pfizer: Honoraria. Beyer-Westendorf:Pfizer: Honoraria, Research Funding; Bayer HealthCare: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding. Lee:Pfizer: Consultancy, Honoraria; LEO Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Mantovani:Daiichi Sankyo: Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer AG: Honoraria; Fondazione Charta: Consultancy; Pfizer: Honoraria. De Sanctis:Bayer US LLC: Employment, Equity Ownership. Abdelgawwad:Bayer AG: Employment. Fatoba:Bayer AG: Employment. Bach:Bayer AG: Employment. Cohen:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ACI Clinical: Consultancy; CSL Behring: Consultancy; Aspen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lifeblood: Other: advisor to Lifeblood: the thrombosis charity and is the founder of the European educational charity the Coalition to Prevent Venous Thromboembolism; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ONO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Consultancy, Speakers Bureau; TRN: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Temasek Capital: Consultancy; Boston Scientific: Consultancy; Guidepoint Global: Consultancy; Medscape: Consultancy, Speakers Bureau; McKinsey: Consultancy; Navigant: Consultancy; UK Government Health Select Committee: Other: advised the UK Government Health Select Committee, the all-party working group on thrombosis, the Department of Health, and the NHS, on the prevention of VTE; Leo Pharma: Consultancy; GLG: Consultancy; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Download Full-text

Dual Targeting of Ph+ ALL with Dasatinib and ABT-199 (Venetoclax)

Blood ◽

10.1182/blood.v126.23.1329.1329 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1329-1329

Author(s):

Jessica Leonard ◽

Joelle Rowley ◽

Brandon Hayes-Lattin ◽

Jeffrey W. Tyner ◽

Marc Loriaux ◽

...

Keyword(s):

Older Adults ◽

Cell Line ◽

Board Of Directors ◽

Research Funding ◽

Mononuclear Cells ◽

Annexin V ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Treatment of adult Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) remains a challenge. While the addition of the targeted tyrosine kinase inhibitors (TKI) to standard cytotoxic therapy has greatly improved upfront treatment, treatment related mortality in older adults remains high. A novel induction regimen combines the targeted dual Abl/Src TKI Dasatinib (Sprycel, BMS) with a corticosteroid. After the first 21 days of induction the corticosteroids are tapered due to significant toxicities, particularly in older adults. Unfortunately, remaining on TKI monotherapy renders patients susceptible to the development of TKI resistance and thus identifying targeted agents that could enhance the activity of TKIs is urgently needed. Recently a novel and selective inhibitor of BCL-2, ABT-199 (Venetoclax, AbbVie) has shown impressive activity against other lymphoid malignancies including CLL and NHL. Here we describe the pre-clinical and in vivo efficacy of ABT-199 in combination with dasatinib in Ph+ ALL and propose its potential use in future clinical trials. Methods: Drug efficacy in vitro was determined using the Ph+ ALL cell line SupB15, primary Ph+ ALL sample (12-149), the dasatinib sensitive Pre-B ALL cell line RCH and the CML cell line K562. Cells were treated with dasatinib, ABT199 or in combination for 72 hours. Cell viability was assessed with the colorimetric MTS assay and apoptosis was assessed with annexin V staining. Expression of the BCL family proteins BCL-2 and MCL-1 were assessed via immunoblot. Immunodeficient NSG mice were injected with 12-149, then one week later treated with vehicle, 5 mg/kg dasatinib, 5 mg/kg ABT-199, or the combination daily for 5 days each week. Peripheral blood was obtained every 1-2 weeks to assess for engraftment as defined by the presence of >10% human CD45+ cells in the peripheral blood. Once engrafted, mice were euthanized and examined. Mononuclear cells were extracted and assessed for BCL2 and MCL1 expression. Statistical methods were performed using Calcusyn and PRISM. Results: Susceptibility to BCL2 inhibition: Of the dasatinib sensitive cells tested, SupB15 and 12-149 cells were susceptible to ABT-199 while RCH and K562 cells were not. The ALL cells expressed BCL-2 while the CML cell line expressed BCLx. SupB15 expressed low levels of the antiapoptotic protein MCL1 while RCH cells had relatively higher levels. siRNA of MCL-1 rendered the RCH cells sensitive to inhibition by ABT-199. In SupB15 cells, treatment with ABT-199 alone led to upregulation of MCL-1 at 24h which was prevented by the combination of dasatinib + ABT199. Synergy in Ph+ ALL: The calculated IC50 of dasatinib and ABT199 in SupB15 were 8.8nM and 5.9nM, respectively. The IC50 of equimolar combination was 0.42nM, and synergistic with combination index (CI) values between 0.15 and 0.49. Primary Ph+ ALL xenograft cells showed a similar pattern of synergy to the dasatinib + ABT199 combination. Combination treatment also greatly increased apoptosis as measured by Annexin V staining. Xenograft Studies: Animals were treated with a ten-fold lower dose of dasatinib and ABT199 from prior published data. There was no significant difference in time to engraftment or disease burden between vehicle or single agent ABT-199. In contrast, less than one half of the animals treated with dasatinib engrafted by 90 days while none of the animals treated with both dasatinib and ABT-199 engrafted. Most intriguing was the decrease in disease burden as measured by splenic size in the combination group compared to all other groups (P<0.0001, one-way ANOVA). Analysis of BCL-2 family proteins from mononuclear cells isolated from untreated animals confirmed upregulation of BCL-2 and relatively low levels of MCL-1. Animals treated with ABT-199 had greatly upregulated levels of MCL-1, while those treated with dasatinib or the combination did not. Conclusions: The combination of ABT-199 with dasatinib synergistically targets Ph+ ALL cells both in vitro and in vivo, laying the foundation for further evaluation in vivo for adult Ph+ ALL. As demonstrated by others, malignancies that are particularly susceptible to BCL targeting are those which display high BCL-2 expression and a low MCL-1: BCL-2 ratio. Combined targeted therapies may offer the potential for greater and longer responses without the morbidity associated with cytotoxic chemotherapy, particularly in older adults. Disclosures Tyner: Aptose Biosciences: Research Funding; Janssen Pharmaceuticals: Research Funding; Incyte: Research Funding; Array Biopharma: Research Funding; Constellation Pharmaceuticals: Research Funding. Druker:Cylene Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics, Inc (formerly Lorus): Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Novartis Pharmaceuticals: Research Funding; Sage Bionetworks: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Henry Stewart Talks: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncotide Pharmaceuticals: Research Funding; CTI Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Roche TCRC, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.

Download Full-text