Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with ...standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular disease (ASCVD) score is a risk stratification tool used by cardiologists to classify patients with a score ≥7.5% as high risk for the incidence of ASCVD events. To date, there are no clinically relevant models that predict the likelihood of ACVE in MM patients treated with K nor are we aware of any protective factors against ACVE. Our study aims to identify factors which can predict and mitigate the incidence of ACVE.
Methods: A retrospective chart review of 372 MM patients who were treated with K between 2011 and 2018 at our institution was performed.Data were summarized using descriptive statistics; Chi-square tests of association and Kruskal-Wallis tests were employed to test for differences across groups, where appropriate. Logistic regression was performed to examine the risk factors associated with ACVE.
Results: Of the 372 patients, 243 (65%) were Durie-Salmon Stage (DSS) III, 70 (19%) were International Staging System (ISS) III; 186 (50%) were men. There were a total of 102 (27%) ACVE and 33 (9%) ≥grade 3 events. The most common ACVE were congestive heart failure (29%), asymptomatic elevations in pulmonary arterial systolic pressure (PASP) (27%), and hypertension (HTN) (16%). Sixty-eight (66%) Caucasians, 14 (14%) African Americans and 17 (17%) Hispanics developed ACVE. Aspirin (ASA) (64%), beta blockers (BB) (51%), calcium channel blockers (CCB) (43%) and statins (37%) were the most common cardiac medications patients were taking at the time of K initiation. Regardless of cardiac history, patients who were taking a CCB had higher odds of experiencing an ACVE compared to patients who were not taking a CCB (CCB + Cardiac history: OR=1.9; CI=1.0-3.7; CCB, no Cardiac history: OR=6.3; CI= 2.1-18.4) (Table 1).
Patients with an ASCVD score ≥7.5% did not have an increased incidence of ACVE but did have an increased incidence of ≥grade 3 vs. grade 1-2 ACVE (100% vs. 78%, p=0.092). Prior cardiac history, including history of HTN, was common (59%) but not associated with incidence or severity of ACVE. Those with type 2 diabetes had a higher rate of ≥grade 3 vs. grade 1-2 ACVE (33% vs. 10%, p=0.004).
Patients on certain CV medications while receiving K-based treatment had a higher incidence of ACVE compared to those not on these medications, including BB (51% vs. 34%, p=0.002), CCB (43% vs. 26%, p=0.002), aldosterone antagonists (AA) (8% vs. 3%, p=0.024) and statins (37% vs. 25%, p=0.022). Patients on ASA were more likely to experience ≥grade 3 compared to grade 1-2 ACVE (78% vs. 53%, p=0.016). ACE inhibitors or angiotensin receptor blockers (ACE/ARB) were not associated with increased incidence or severity of ACVE.
The use of K in relapsed, as opposed to induction setting, was associated with a higher incidence of ACVE (31% vs. 20%, p=0.035). Maximum dose and number of K doses were not associated with ACVE. There was no relationship between PASP elevation and age >75, use of BB, CCB, AA, ACE/ARB, number of K treatments or maximum dose of K.
Factors that were associated with increased odds of ACVE in multivariate analysis included patients who received K in the relapsed setting (OR= 1.7; CI=0.94-3.0) and use of an AA (OR= 4.5; CI=1.4-14.1) (Table 1).
Conclusion: In line with prior studies, 28% of MM patients treated with K at our institution developed an ACVE, with 9% grade 3 or above. Use of CCB and AA were particularly associated with increased risk of ACVE, while use of ACE/ARB were not. ASCVD score ≥7.5% was associated with an increased incidence of ≥grade 3 ACVE in K-treated patients and should perhaps be evaluated as a predictive tool in prospective studies.
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Siegel:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Biran:Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding.
Background: The discovery that gut microbial dysbiosis correlated with prognosis, immune reconstitution and development of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell ...transplantation (allo-SCT) highlights the clinical relevance of the gut microbiome in shaping anti-tumor immune responses. Treatment of allo-SCT patients with antibiotics has recently been associated with increased GVHD mortality (Routy et al. 2017). Based on these studies and the association of distinct gut bacteria with increased efficacy to PD-1 blockade in patients with solid tumors (Derosa et al. 2018), we performed a retrospective analysis to determine if infection treated with antibiotics affected the outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT).
Methods: A list of all MM patients treated at our institution between January 2012 through December 2015 was obtained and 1095 patients were identified. A comprehensive review of the electronic medical record (EMR) of the first 142 who received ASCT was performed. Information was collected from diagnosis to the date of last contact. Baseline characteristics, treatment history, transplant course, antibiotic treatment, and infection severity using common terminology criteria for adverse event (CTCAE) version 4 were reviewed. Prophylactic antibiotics were excluded. Response was measured and defined using the International Myeloma Working Group Criteria. Progression free survival (PFS) and overall survival (OS) were estimated using log rank tests. Cox hazard stepwise regression model examined for multiple factors affecting PFS and OS using the Akaike information criterion.
Results: Of the 142 patients, 93 (65%) were Durie Salmon (DS) III, 20 (14%) were Revised International Staging System (R-ISS) III, 44 (31%) had high-risk cytogenetics, and 76 (54%) were male. The median age at diagnosis was 60. Although there was a similar frequency of DS III (67% vs 61%) and high-risk cytogenetics (35% vs 25%) among patients in the antibiotic and non-antibiotic treated groups, there was an over-representation of R-ISS 3 (19% v 4%) patients in the antibiotic-treated group.
Treatment with antibiotics was associated with decreased median PFS (2.38 vs 6.58 years (yrs), p =0.00003) (Figure 1a) and decreased median OS (7.43 vs 17.39 yrs, p = <0.0001). Fluoroquinolone use compared to no fluoroquinolone use was associated with decreased PFS (1.91 vs 4.09 yrs, p = 0.0001) (Figure 1b) as well as a trend toward decreased OS (7.01 vs 14.23 yrs, p = 0.1). Beta-lactam use compared to no beta-lactam use was associated with decreased PFS (1.74 vs 4.34 yrs, p = <0.0001) (Figure 1c) as well as decreased OS (7.01 vs 17.39 yrs, p = 0.0004). Maximal CTCAE grade of infection throughout the treatment course was a further predictor of decreased PFS-no infection vs CTCAE grade 1/2 vs CTCAE 3/4 (7.49 vs 3.77 vs 1.92 yrs, p = <0.0001) (Figure 2) and OS-no infection vs CTCAE 3/4 (17.39 vs 6.58 yrs, p = <0.0001). (Figure 2).
Multivariate analysis demonstrated progression risk associated with beta-lactam use (HR-2.25, 95% CI, 1.31 - 3.85, p = 0.003), and DSS III (HR-2.28, 95% CI, 1.23 - 4.21, p = 0.009). Multivariate analysis demonstrated increased mortality associated with antibiotic treatment (HR-5.70, 95% CI, 1.34 - 34.29, p = 0.019) and decreased mortality risk with age younger than 65 (HR-0.24, 95% CI, 0.07 - 0.81, p = 0.022). For both PFS and OS, there was no statistical significance demonstrated in multivariate analysis for gender, fluoroquinolone treatment, high risk cytogenetics, R-ISS 3, or CTCAE grade.
Conclusion: In this preliminary study, antibiotic use and infection severity predicted for decreased PFS and OS compared to patients who did not receive antibiotics in MM patients undergoing ASCT. Treatment with at least 2 classes of antibiotics-fluoroquinolones and beta-lactams, predicted for decreased PFS and OS. Multivariate analysis showed increased progression risk with beta lactams and DSS III as well as increased mortality risk with antibiotic treatment and advanced age. The study was limited by its relatively small sample size, retrospective nature, and the high correlation among infection and antibiotic groups that affected the multivariate analysis. Work is underway at our institution to further elucidate the impact of antibiotics on microbial diversity and patient survival.
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Goldberg:COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Biran:Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.
Antiphospholipid syndrome (APLS) is an autoimmune condition that predisposes to venous and arterial thrombosis. Warfarin is the agent of choice for anticoagulation. However, a need for routine ...international normalised ratio (INR) checks and multiple drug interactions are some of the difficulties with warfarin. Currently, there is mixed evidence for and against the use of novel oral anticoagulants (NOACs) for thromboprophylaxis. We present a case report of a patient with APLS on a NOAC for secondary thromboprophylaxis who developed a stroke and discuss current evidence regarding the use of NOACs in patients with APLS. The patient was switched to warfarin for secondary thromboprophylaxis with an INR goal of 2–3. Literature review revealed mixed case reports for and against NOACs for secondary prevention of thrombotic events in patients with APLS. There needs to be further randomised controlled trials to evaluate the efficacy of NOACs for thromboprophylaxis in patients with APLS.
Wearable cardioverter defibrillators (WCDs) are external devices capable of continuous cardiac rhythm monitoring as well as automatic detection and defibrillation of potentially life-threatening ...arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF). They are an alternative approach for patients when an implantable cardioverter defibrillator (ICD) is not appropriate. Although treatment with ICD is considered highly effective for the primary and secondary prevention of sudden cardiac death (SCD) in high-risk patients susceptible to VT and VF, patients may still experience psychological difficulties such as fear of shock, avoidance of normal behaviors and reduced quality of life. One of these phenomena is phantom shock (PS), which is defined as a perception of having received a shock with no evidence of recorded defibrillation upon device interrogation. While PS has been reported in the ICD literature, to the best of our knowledge, we present the first known case of WCD-related PS. We also present a review of the current literature to explore the prevalence of PS, the factors associated with its pathogenesis and interventional studies aimed at reducing its occurrence. We highlight this case because PS is considered a phenomenon that few recognize, which should be discriminated from real device shocks before clinicians initiate treatment, device reprogramming or device discontinuation. We describe the psychosocial factors associated with PS to emphasize the importance of managing any associated psychiatric disorders and psychosocial factors both before and after initiation of device treatment.
A 52-year-old woman with a medical history of cervical and thyroid cancer, hypertension, dyslipidaemia, uncontrolled diabetes and heavy smoking was diagnosed with a new metastatic cholangiocarcinoma. ...While undergoing palliative chemotherapy, she developed dysarthria and left-sided weakness. Imaging studies showed multiple bilateral ischaemic strokes. On hospital days 2 and 5, she developed worsening neurological symptoms and imaging studies revealed new areas of ischaemia on respective days. Subsequent workup did not revealed a clear aetiology for the multiple ischaemic events and hypercoagulability studies were only significant for a mildly elevated serum D-dimer level. Although guidelines are unclear, full-dose anticoagulation with low molecular weight heparin was initiated given her high risk of stroke recurrence. She was discharged to acute rehabilitation but, within a month, she experienced complications of her malignant disease progression and a new pulmonary thromboembolism. The patient died soon after being discharged home with hospice care.
Significant progress has been made in our understanding of tumor pathogenesis as a result of the successful generation of many genetically engineered mouse models of human cancers. However, most ...studies of mouse models continue to rely on static, two-dimensional (2D) traditional histological methods, while tumorigenesis is a complex, dynamic and inherently three-dimensional (3D) process. In this thesis, I addressed this limitation by implementing several micro-imaging modalities as powerful tools for the in vivo, 3D and longitudinal characterization of different aspects of tumor progression in two preclinical cancer models. First, I implemented and optimized both high-resolution and high-throughput protocols using Manganese-Enhanced MRI (MEMRI) for the detection and longitudinal imaging of tumors in a Patched-1 (Ptch1) conditional knockout (CKO) model of medulloblastoma. These studies showed that MEMRI is a powerful method for the in vivo detection of the early stages of medulloblastoma and provided the first direct evidence of the distinct tumorigenic capabilities of individual pre-tumoral lesions as they progress to advanced medulloblastomas. Second, I used a genetic imaging approach to non-invasively analyze specific molecular changes underlying vascular development in tumors. For this, I validated a novel targeting system for the in vivo labeling and multimodal molecular imaging of Tie2-expressing blood vessels in mouse melanomas, using ultrasound, near infrared and MRI. The results of this work provide the first evidence for the feasibility of in vivo labeling and 3D longitudinal assessment of spatio-temporal changes in vascular Tie2, from early to advanced tumor stages. Collectively, this dissertation highlights the crucial role of in vivo imaging approaches for the morphological and pathophysiological characterization of tumors. The methodology applied in this work for MEMRI and targeted molecular imaging provides a foundation for future studies about medulloblastoma progression and tumor angiogenesis. In addition, these approaches could potentially be expanded to study other tumor models and diseases, and to inform the design of future preclinical therapeutic studies.
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