Risk of Incident Diabetes and Dysregulated Pre-Existing Diabetes Mellitus in Newly Diagnosed Lymphoma Patients Treated with Steroid-Containing Immunochemotherapy: A Danish Population-Based Study

Abstract Introduction Prednisolone has important potential side-effects, one of which is steroid-induced diabetes mellitus (DM). Due to the exposure to a high cumulative dosage of steroids during first-line treatment, patients with non-Hodgkin lymphoma (NHL) could face increased risk of new onset steroid-induced DM or dysregulation of a pre-existing DM. This nationwide observational cohort study evaluated the risk of new onset DM in lymphoma patients and the impact on pre-existing DM in lymphoma survivors following treatment with steroid-containing regimens. Methods Adult NHL patients (≥18 years) treated with ≥3 cycles of steroid-containing immunochemotherapy, such as R-CHOP(-like) and R-CVP, between 2002 and 2015 were identified in the Danish Lymphoma Register and matched to five random individuals from the general population on birth year, sex, Charlson Comorbidity Index score, baseline DM status (DM or not), and DM duration. NHL patients and matched comparators were followed from start of treatment for the patients until the event of interest (DM, insulin prescription), death, relapse, NHL diagnosis (for matched comparators), or censoring (emigration, missing, or end of study on 31 December 2018), whichever came first. DM was captured by either a diagnosis of any DM (ICD-10 codes: E10-E14) in the Danish National Patient Register or any redeemed anti-diabetic prescription registered in the National Prescription Register (insulin or oral anti-diabetic medicine; ATC A10A or A10B). In the analysis of insulin prescriptions following lymphoma treatment initiation, patients with any redeemed prescription of insulin prior to start of lymphoma treatment were excluded. Time-varying incidence rates (IRs) per 1,000 person years and incidence rate ratios (IRRs) with 95% confidence intervals were estimated using a spline-based Poisson regression approach with two-month time splits and five knots. The Aalen-Johansen estimator was used to compute the cumulative risk of an event treating death, relapse, and NHL diagnosis (in comparators) as competing events. Risk differences at specific time points were calculated using pseudo-observations. Crude and adjusted cause-specific hazard ratios (HR) were obtained using Cox regression. Results A total of 4,703 NHL patients were included in the present study. Median age was 66 years and median follow-up was 8.5 years. Among the NHL patients, 4,325 patients did not have pre-existing DM and were matched to 21,625 comparators without DM. The time-varying IR of DM among comparators was 8-10 cases/1000 person years. The IRR of DM for patients vs comparators was higher for patients in the first year following treatment initiation (maximum IRR: 2.40), lower from 1 to 5 years (minimum IRR: 0.52), and higher from 5 to 10 years (maximum IRR: 1.18) (Fig. 1). The cumulative incidence of DM was higher for NHL patients at six months (0.58 percentage units (%U), p <0.01), but lower at 5 years (-1.17%U, p <0.01) and 10 years (-2.09%U, p <0.01) compared to the matched comparators (p <0.01 for the whole period, Fig. 2). Among the NHL patients, 378 had pre-existing non-insulin dependent DM and were matched to 1,890 comparators. The cumulative incidence difference of any insulin use was higher for patients at 6 months (14.29%U, p <0.01), 5 years (9.95%U, p <0.01), and 10 years (4.61%U, p =0.15) (p <0.01 for the whole period, Fig. 3). However, when events were limited ≥5 prescriptions of insulin, no difference was found (p =0.84 for the whole period). The crude HR for ≥5 prescriptions of insulin was 1.42 [1.10;183] for patients compared to the matched comparators and the HR adjusted for sex, age, and comorbidities was 1.39 [1.08;1.79]. Conclusion In conclusion, patients treated with steroid-containing immunochemotherapy did not experience a higher risk of diabetes mellitus compared to matched comparators beyond the first year. Matched comparators had a higher cumulative incidence of diabetes mellitus after 2 years, which was partly explained by the high competing risk of death in the patient group. NHL patients with pre-existing non-insulin dependent diabetes mellitus had an increased cumulative incidence of any insulin prescriptions; however, the difference was diminished when assessing the risk of at least five insulin prescriptions, suggesting that the impact of steroids on diabetes regulation is limited in time when taking competing risks into account. Figure 1 Figure 1. Disclosures Øvlisen: Abbvie: Other: Travel expenses. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Vestergaard: Novo Nordisk Foundation: Other: Head of Research at Steno Diabetes Center North Jutland funded by the Novo Nordisk Foundation, Research Funding. Jørgensen: Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy; Celgene: Consultancy. Clausen: Gilead: Consultancy, Other: Travel expences 15th ICML ; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee.

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Does Addition of Rituximab (R) to BEAM Conditioning Improve Outcomes of Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)?

Blood ◽

10.1182/blood-2019-121347 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 785-785

Author(s):

Deepa Jagadeesh ◽

Navneet S. Majhail ◽

He Yizeng ◽

Kwang Woo Ahn ◽

Carlos Litovich ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

B Cell Lymphoma ◽

Older Age ◽

Disease Stage ◽

Karnofsky Performance Score ◽

Advisory Committees ◽

Significant Difference ◽

The Impact

Introduction: Rituximab-based high-dose therapy (HDT) is frequently prescribed to DLBCL patients (pts) undergoing auto-HCT. However data supporting the benefit of adding R to auto-HCT conditioning are not available. Herein, we report the impact of R-based conditioning on auto-HCT outcomes of DLBCL pts. Methods: Using the Center for International Blood and Marrow Transplant Research registry, 862 adult (≥18 years) DLBCL pts undergoing auto-HCT, between 2003-2017 were included. Analysis was limited to pts receiving BEAM (BCNU, etoposide, cytarabine, melphalan)-based HDT, as R was infrequently used with non-BEAM conditioning regimens. All pts received R-containing chemoimmunotherapy in the frontline setting and had chemosensitive disease prior to HCT. Early chemoimmunotherapy failure (ECitF) was defined as not achieving a complete remission (CR) after frontline chemoimmunotherapy or relapsing within 1 year of initial diagnosis. Primary outcome was overall survival (OS). Secondary outcomes included non-relapse mortality (NRM), relapse, progression-free survival (PFS) and infectious complications within 100 days post-HCT. Results: The study cohort was divided into 2 groups; BEAM (n=667) and R-BEAM (n=195). The baseline characteristics of the 2 cohorts were comparable including age at auto-HCT, disease stage, Karnofsky performance score, extranodal involvement, time from diagnosis to auto-HCT, number of prior therapies, remission status, and ECitF. However, significantly more R-BEAM cohort patients received R as part of last therapy line before auto-HCT (75% vs. 86%; P=0.001). Median follow-up of survivors was 48 (range 1-171) and 64 (range 3-142) months in the BEAM and R-BEAM cohorts, respectively. On univariate analysis, the 4 year cumulative incidence of relapse (41% vs 44%), NRM (11% vs 9%), PFS (48% vs 47%; Figure 1) and OS (58% vs 61%; Figure 2) were similar in the R-BEAM and BEAM groups, respectively (Table 1). On multivariate analysis, no significant difference was seen in OS (HR 0.81; 95% CI 0.81-1.31; P=0.83) or PFS (HR 0.94; 95% CI 0.76-1.18; P=0.61) (Table 1) between the two cohorts. Addition of R had no impact on risk of relapse (HR 0.83; 95% CI 0.65-1.07; P=0.15) or NRM (HR 1.43; 95% CI 0.909-2.26; P=0.12). Variables independently associated with lower OS included older age (HR 3.05; 95% CI 1.81-5.13; P<0.001), not being in CR at auto-HCT (HR 1.67, 95% CI 1.39-2.07; P<0.001) and presence of ECitF (HR 1.52, 95% CI 0.54-3.26; P<0.001). Older age (HR 2.26, 95% CI 1.48-3.45; P<0.0002) and not being in CR at auto-HCT (HR 1.78, CI 1.47-2.14; P<0.0001) were also associated with inferior PFS. There was no significant difference in the 100-day cumulative incidence of bacterial, viral or fungal infections between the two cohorts. Disease relapse was the main cause of death in both BEAM and R-BEAM cohorts (66% vs 55%). Conclusion: In this large registry analysis of DLBCL pts undergoing auto-HCT, adding R to BEAM conditioning had no impact on transplantation outcomes. Older age, absence of CR and ECitF were associated with inferior survival. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Consultancy; Nkarta: Consultancy; Anthem, Inc.: Consultancy; Atara Bio: Consultancy. Sureda:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria; BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Hamadani:ADC Therapeutics: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau.

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Sequential Use of Carfilzomib and Pomalidomide in Relapsed Multiple Myeloma: A Multi-Institutional Report from the Canadian Myeloma Research Group (CMRG) Database

Blood ◽

10.1182/blood-2020-142800 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-7

Author(s):

Arleigh McCurdy ◽

Christopher P. Venner ◽

Martha L Louzada ◽

Richard LeBlanc ◽

Michael Sebag ◽

...

Keyword(s):

Multiple Myeloma ◽

Observational Study ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Treatment Initiation ◽

Median Line ◽

Advisory Committees ◽

Two Agents ◽

The Impact

Introduction: The treatment of multiple myeloma (MM) has dramatically improved due to the availability of immunotherapies such as daratumumab (Dara). However, in Canada, myeloma treatments now account for up to 20% of some provincial drug budgets. As Dara may be effective for a prolonged period and is quickly moving into first-line therapy, the Canadian body which provides guidelines to the provincial ministries of health recommended in 2019 against open sequencing of drugs in relapsed MM. Specifically, patients who receive Dara are now only eligible for public funding for either carfilzomib (CAR) or pomalidomide (POM)--but not both-- for relapsed MM. Given the known heterogeneity of myeloma, data gaps regarding the optimal sequencing of the available agents and uncertainly regarding the impact of this new restriction on patient outcomes, we utilized our Canadian national myeloma database to assess the sequencing of these two agents. The goal of our study was to understand the efficacy of these two commonly used treatments in the relapsed setting: 1) POM- after CAR-based therapy and 2) CAR- after POM-based therapy. Methods: We performed a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG-DB), analyzed up to 30/06/2020. The CMRG-DB (formerly Myeloma Canada Research Network Database/MCRN-DB) is a prospectively maintained disease-specific database with over 7000 patients enrolled from 14 academic sites across Canada and includes legacy data collected from 2007. All patients with MM who were treated for relapsed disease with approved regimens using POM after CAR, or CAR after POM were included. Our primary outcomes were overall response rates (ORR) in each respective cohort. Secondary outcomes were progression-free survival (PFS), overall survival (OS), and a landmark OS analysis from treatment initiation with the first of the two agents. Survival was estimated using Kaplan-Meier methods and compared between groups using log rank test. Results: A total of 121 patients were included: 49 treated with POM after CAR, and 72 with CAR after POM. In the POM after CAR group, the median line of treatment was 4th for POM and 3rd for CAR. In the CAR after POM group, the median line of treatment was 4th for POM and 5th for CAR. In 79/121 patients (65%), the two therapies were directly sequential, 40/49 (82%) for the POM after CAR group, and 38/72 (54%) in the CAR after POM group. Baseline characteristics and treatment details are shown in Table 1. The ORR was 51% for patients treated with POM after CAR, and 49% for patients treated with CAR after POM. The median PFS for POM after CAR was 4.93 months (95% CI, 2.76-7.07), and for CAR after POM was 5.36 months (95% CI, 3.75-6.94). The median OS for patients treated POM after CAR was 11.01 months (95% CI, 4.50-19.13), and for patients treated with CAR after POM the median OS was 10.98 months (95% CI, 8.98-19.17) (Figure 1). In a landmark analysis using the time of the treatment initiation with the first of the two agents, the median OS of patients treated with CAR after POM was 37.61 months (95% CI 26.66-46.52) and 25.32 months (95% CI 14.56-41.19) for patients treated with POM after CAR (p=0.1270) (Figure 2). Conclusion: In this real-world observational study we demonstrated that both CAR- and POM-based therapies were effective treatment options for patients with advanced relapsed MM as each produced responses in approximately 50% of patients with a median PFS of about 5 months and median OS of 11 months. These results are comparable to those noted in prospective clinical trials leading to the approval of these agents in this setting. Further, a landmark analysis showed that using both agents sequentially late in the disease course provided reasonable OS outcomes, regardless of the order in which they are sequenced. Finally, as the cost of MM therapy increases, the use of real-world data can help determine the impact of funding decisions on the outcome of patients treated in a publicly funded universal health care system such the one in Canada. Disclosures McCurdy: GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Honoraria; Amgen: Consultancy, Honoraria. Venner:Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria; Celgene, Amgen: Research Funding. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. LeBlanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. Sebag:Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Kotb:Takeda: Honoraria; Merck: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria; Sanofi: Research Funding; Karyopharm: Current equity holder in publicly-traded company; Amgen: Honoraria. Mian:Sanofi: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Stakiw:Roche: Research Funding; Lundbeck: Honoraria; BMS: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Research Funding. Reece:Janssen, Bristol-Myers Squibb, Amgen, Takeda: Consultancy, Honoraria; Janssen, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Otsuka: Research Funding.

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Comparison of Reduced-Intensity Conditioning (RIC) Regimens for Allogeneic Hematopoietic Cell Transplantation (alloHCT) in Non-Hodgkin Lymphomas (NHL)-a Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Blood ◽

10.1182/blood-2019-121849 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 319-319

Author(s):

Nilanjan Ghosh ◽

Sairah Ahmed ◽

Carlos Litovich ◽

Kwang Woo Ahn ◽

Manoj Khanal ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Advisory Committees ◽

Gvhd Prophylaxis ◽

Conditioning Regimens ◽

The Impact ◽

Reduced Intensity

Introduction: Reduced-intensity and non-myeloablative (RIC/NMA) conditioning regimens are frequently used in alloHCT for NHL, because they are associated with decreased non-relapse mortality (NRM) risk in comparison with myeloablative conditioning regimens and allow older patients and patients with comorbidities to receive alloHCT. However, the optimal RIC/NMA regimen in allo-HCT for NHL is not known. Using the CIBMTR database we compared the transplant outcomes between the commonly used RIC/NMA regimens in NHL. Methods: 1823 adult (≥18 years) NHL patients in CIBMTR registry undergoing alloHCT using matched related or unrelated donors, between 2008-2016 were included. Analysis was limited to patients receiving four commonly used RIC/NMA regimens: fludarabine/ i.v. busulfan (6.4mg/kg) (Flu/Bu), fludarabine/melphalan (140mg/m^2) (Flu/Mel 140), fludarabine/cyclophosphamide (Fly/Cy) and Flu/Cy with 2Gy Total Body Irradiation (Flu/Cy/TBI). Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based regimens. Patients who received post transplantation cyclophosphamide for GVHD prophylaxis were excluded. The primary outcome was overall survival (OS). Secondary outcomes included cumulative incidence of NRM, relapse, progression-free survival (PFS) and cumulative incidence of acute and chronic GVHD. Probabilities of OS and PFS were calculated using the Kaplan-Meier estimator. Multivariable regression analysis was performed for GVHD, relapse/progression, NRM, PFS, and OS. Covariates with a p<0.01 were considered significant. Results: The study cohort was divided into 4 groups; Flu/Bu (n=458), Flu/Cy/TBI (n=89), Flu/Mel 140 (n=885) and Flu/Cy (n=391). The baseline characteristics are shown in Table 1. The 4 cohorts were comparable with respect to median patient age, gender, donor type, remission status at alloHCT, and use of prior auto HCT. There was no interaction between NHL histological subtype and type of conditioning regimen. Results of multivariate analysis are shown in Table 2. The Flu/Mel 140 regimen was associated with a higher NRM (HR 1.78, 95% CI 1.37-2.31; p<0.001) when compared to Flu/Bu. Although the risk of relapse with Flu/Mel 140 was lower when compared to Flu/Bu (HR 0.79, 95% CI 0.66-0.94); p=0.007), this did not result in an improvement in PFS. Moreover, the Flu/Mel 140 cohort had an inferior OS (HR 1.34, 95% CI 1.13-1.59; p<0.001) when compared to Flu/Bu. There was no significant difference in terms of OS, PFS, relapse and NRM between Flu/Bu, Flu/Cy and Flu/Cy/TBI. There was no difference in risk of grade 3-4 acute GVHD across the four cohorts and compared to Flu/Cy/TBI, Flu/Mel 140 had a higher risk of chronic GVHD (HR 1.38, 95% CI 1.15-1.65; p<0.001). Four year adjusted PFS was 38% for Flu/Bu, 51% for Flu/Cy/TBI, 39% for Flu/Mel 140 and 35% for Flu/Cy (p=0.07). Four year adjusted OS was 58% for Flu/Bu, 67% for Flu/Cy/TBI, 49% for Flu/Mel 140 and 63% for Flu/Cy (p<0.001). Disease relapse was the most common cause of death across all 4 cohorts. Conclusion: This is the largest analysis comparing the impact of various RIC/NMA conditioning regimens on the outcomes of NHL patients undergoing alloHCT. We report that the choice of RIC/NMA conditioning regimen significantly impacted OS. The most commonly used conditioning regimen, Flu/Mel 140 was associated with a higher NRM and an inferior OS. The Flu/Bu, Flu/Cy, and Flu/CY/TBI conditioning regimens appear to provide comparable OS. Disclosures Ghosh: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; SGN: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Forty Seven Inc: Research Funding; AstraZeneca: Honoraria, Speakers Bureau. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Roche: Honoraria. Hamadani:Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Otsuka: Research Funding; Medimmune: Consultancy, Research Funding; Takeda: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau.

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Treatment and Lifestyle Risk Factors for Cardiovascular Disease Post Lymphoma Diagnosis: A Prospective Study in the Modern Treatment Era

Blood ◽

10.1182/blood-2019-127203 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 422-422

Author(s):

Nicholas J Boddicker ◽

Matthew J. Maurer ◽

Melissa C Larson ◽

Cristine Allmer ◽

Susan L. Slager ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Cumulative Incidence ◽

Medical Records ◽

Research Funding ◽

Cardiac Risk ◽

Advisory Committees ◽

Increased Risk ◽

Modern Treatment ◽

New Onset

Background With lymphoma survival rates increasing and a growing population of long-term survivors, the development of cardiovascular disease (CVD) in this patient population is of increasing importance. Anthracyclines are critical in the management of many lymphoma subtypes. However, there is a risk of developing anthracycline-induced CVD. Here, we estimate the cumulative incidence of CVD in adult lymphoma survivors and investigate risk factors associated with post diagnosis CVD. Methods Participants were from the Mayo component of the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence (SPORE). From 2002-2015, the MER offered enrollment to all patients with newly diagnosed lymphoma who are US residents and age >18 years. Participants completed a risk factor questionnaire, and clinical and treatment data were abstracted from medical records. Patients were contacted every 6 months for the first 3 years after diagnosis and annually thereafter to assess disease status, re-treatment and new onset morbidity including CVD. CVD events, including congestive heart failure (CHF), coronary artery disease (CAD), valvular heart disease (VHD), and arrhythmia were identified and validated against medical records. CHF was validated with the Cardiovascular Health Study Criteria and/or the Framingham Criteria. CAD, arrhythmia, and VHD were validated using clinical definitions. We calculated the cumulative incidence of CVD, with death modeled as a competing risk. The association of risk factors and treatments with risk of CVD was estimated using hazard ratios (HR) and 95% confidence intervals (CI) from Cox regression with a competing risk of death. Risk factors included age, sex, diabetes, smoking, body mass index (BMI), and treatment with anthracyclines or radiation therapy. Results The study consisted of 3,063 lymphoma patients after excluding those with chronic lymphocytic leukemia and CVD prior to lymphoma diagnosis. The median age at diagnosis was 59 years (range 18-95), and 56% were males. At a median follow-up was 6.9 years (range 0.8-17.1), 640 patients (21%) had died without CVD and 485 patients self-reported CVD post lymphoma diagnosis, of which 280 (57.7%) were validated. Cardiovascular events included 86 CHF, 78 CAD, 40 VHD, and 164 arrhythmias. The cumulative incidence of CVD (Figure 1) at 5 and 10 years was 6.0% (95% 5.2%-7.0%) and 10.7% (95% CI 9.5%-12.1%), respectively. In multivariable analysis, increasing age (HR=3.93 per 5 years, p<0.001), male sex (HR=1.33, p=0.03), former smoker (HR=1.04, p=0.77), current smoker (HR=1.96, p<0.001), BMI>30 kg/m2 (HR=1.50, p=0.01), and anthracycline treatment (HR=1.49. p<0.001) were all significantly associated with risk of overall CVD, while there was no association with diabetes (HR=0.92, p=0.70) or radiation therapy (HR=1.05, p=0.78) in the multivariable model. Anthracycline use was significantly associated with increased risk of CHF (HR=2.64, p<0.001) and arrhythmia (HR=1.51, p<0.01), but not VHD (HR=0.83, p=0.56) or CAD (HR=1.23, p=0.31) after adjustment for the cardiac risk factors. The number of anthracycline cycles ranged from 0 to 12. 63.2% of individuals that received anthracyclines received 6 cycles. The 5-year cumulative incidence of CVD for 0, 1-5, 6, and >6 anthracycline cycles was 5%, 6.9%, 7.4%, and 7.7%, respectively. Adjusting for cardiac risk factors, the number of anthracycline cycles was significantly associated with increased risk of CVD (1-5 cycles HR=1.34, p=0.11; 6 cycles HR=1.51, p<0.01; >6 cycles HR=2.04, p=0.03). Furthermore, the number of anthracycline cycles was associated with CHF (1-5 cycles HR=2.82, p<0.001; 6 cycles HR=2.46, p<0.001; >6 cycles HR=5.33, p<0.001) and arrhythmia (1-5 cycles HR=1.31, p=0.27; 6 cycles HR=1.60, p<0.01; >6 cycles HR=1.65, p=0.27). Conclusions In the modern treatment era, the risk of new onset CVD in patients with lymphoma without a history of CVD is approximately 1% per year after diagnosis. Arrhythmia and CHF were the most commonly occurring CVD events in this cohort. Both traditional CVD risk factors and treatment with anthracyclines was associated with an increased risk of developing CVD, and anthracyclines were a risk factor for arrhythmia and CHF in particular. Prevention of CVD in lymphoma patients will need to address both treatment and traditional lifestyle factors. Figure 1 Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding; Celgene: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

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The Effect of Vitamin E on Oxidative Stress Indicated by Serum Malondialdehyde in Insulin-dependent Type 2 Diabetes Mellitus Patients with Retinopathy

The Open Ophthalmology Journal ◽

10.2174/1874364101711010051 ◽

2017 ◽

Vol 11 (1) ◽

pp. 51-58 ◽

Cited By ~ 10

Author(s):

Irini P. Chatziralli ◽

George Theodossiadis ◽

Prodromos Dimitriadis ◽

Michail Charalambidis ◽

Antonios Agorastos ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Vitamin E ◽

Protective Role ◽

Ophthalmological Examination ◽

Significant Difference ◽

Treatment Naïve ◽

Insulin Dependent ◽

The Impact

Background:Several studies have focused on oxidative stress on diabetes mellitus (DM). Our purpose was to investigate the impact of oxidative stress on progression of diabetic retinopathy (DR) in insulin-dependenttype 2DM patients, measuring serum malondialdehyde (MDA), as well as to examine the effect of vitamin E on DR progression in the above-mentioned patients.Methods:Participants in the study were 282 insulin-dependenttype 2DM patients with DR. All participants underwent a thorough ophthalmological examination, so as to grade DR, along with serum MDA measurement. All participants received 300mg vitamin E daily for 3 months and were examined again. Serum MDA pre- and post-intake of Vitamin E was the main outcome.Results:Serum MDA was positively associated with DR stage, while there was a statistically significant difference pre- and post-intake of vitamin E in all DR stages. In a subgroup analysis of patients with proliferative DR, there was a significant difference at baseline between patients who have received prior laser photocoagulation and the treatment naïve patients, while after intake of vitamin E, no statistically significant difference was noticed.Conclusion:Oxidative stress has been found to play significant role in the pathogenesis and progression of DR, while vitamin E seems to reduce MDA levels and subsequent oxidative stress, suggesting that it might have protective role in DR progression.

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Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽

10.1182/blood.v128.22.3306.3306 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3306-3306

Author(s):

Yi L. Hwa ◽

Qian Shi ◽

Shaji Kumar ◽

Martha Q. Lacy ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Mayo Clinic ◽

Cumulative Incidence ◽

Research Funding ◽

Beta Blockers ◽

Multivariable Analysis ◽

Advisory Committees ◽

Risk Of Death ◽

Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Myocardial dysfunction associated with diabetic ketoacidosis in a 5-year-old girl

SAGE Open Medical Case Reports ◽

10.1177/2050313x19847797 ◽

2019 ◽

Vol 7 ◽

pp. 2050313X1984779 ◽

Cited By ~ 3

Author(s):

Amjad Halloum ◽

Shaikha Al Neyadi

Keyword(s):

Diabetes Mellitus ◽

Diabetic Ketoacidosis ◽

Brain Edema ◽

Myocardial Dysfunction ◽

Insulin Dependent Diabetes Mellitus ◽

Inotropic Support ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

Insulin Dependent ◽

New Onset

In this study, we report a case of a 5-year-old girl with new onset of insulin-dependent diabetes mellitus, who presented with severe diabetic ketoacidosis associated with brain edema and severe myocardial dysfunction, needing intubation and inotropic support. To our knowledge, this is the youngest reported case with severe diabetic ketoacidosis complicated with myocardial dysfunction.

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Precollege and New-Onset College Interpersonal Trauma as Predictors of Baseline and Changes in Alcohol Use Disorder Symptoms During College

Journal of Interpersonal Violence ◽

10.1177/0886260519883864 ◽

2019 ◽

pp. 088626051988386

Author(s):

Kaitlin E. Bountress ◽

Daniel Bustamante ◽

Christina Sheerin ◽

Danielle M. Dick ◽

Ananda B. Amstadter ◽

...

Keyword(s):

High Risk ◽

Alcohol Use ◽

Alcohol Use Disorder ◽

Alcohol Misuse ◽

Change Score ◽

Interpersonal Trauma ◽

First Year ◽

Time Period ◽

The Impact ◽

New Onset

College is a high-risk time for interpersonal trauma (IPT) exposure (e.g., physical or sexual abuse/assault), a potent form of trauma exposure. College is also a high-risk time for alcohol misuse, as use begins and increases in adolescence and peaks in the early/mid-20s. In addition, although IPT is associated with alcohol misuse, less clear is whether distal (prior to college) or proximal (during college) IPT impacts alcohol use disorder (AUD) symptoms at the beginning of college and/or changes in symptoms during college. Data were collected from a large, longitudinal study of college students, attending a large public university in the southeast, who had reported lifetime IPT as well as lifetime alcohol use. Participants in the current study were 18.5 years old ( SD = 0.46), primarily female (67.2%), and of diverse racial backgrounds (e.g., 53.4% White, 18.5% Black, 12.7% Asian, 15.4% Other). Latent change score analyses were employed to test the impact of IPT prior to college and IPT during college on initial levels of, and changes in, AUD symptoms during college. Those who experienced an IPT prior to college reported more AUD symptoms at the beginning of college and less changes in AUD symptoms during the first year of college. Those who experienced an IPT in the first 2 and last 2 years of college reported greater increases in symptoms in the first 2 and last 2 years of college, respectively. Findings suggest that prevention and intervention efforts for those who experience an IPT prior to or during college may be useful in reducing AUD symptoms during that time period.

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Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽

10.1182/blood-2019-131514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5444-5444

Author(s):

Sæmundur Rögnvaldsson ◽

Ingemar Turesson ◽

Magnus Björkholm ◽

Ola Landgren ◽

Sigurður Yngvi Kristinsson

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Large Population ◽

Diagnostic Delay ◽

Population Based ◽

Lymphoproliferative Disorders ◽

First Year ◽

Advisory Committees ◽

Population Based Study ◽

Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Major Improvement of Invasive Aspergillosis Outcome Is Not Enough to Improve Overall Survival In Allogeneic Hematopoietic Stem Cell Transplant Recipients: Results From a Single-Center Retrospective Analysis

Blood ◽

10.1182/blood.v116.21.1244.1244 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1244-1244

Author(s):

Géraldine Salmeron ◽

Raphaël Porcher ◽

Anne Bergeron ◽

Marie Robin ◽

Regis Peffault de Latour ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Risk Of Death ◽

First Line Treatment

Abstract Abstract 1244 Background. Voriconazole (V) treatment has been shown to improve the 12 week (W) survival rate of hematological patients (pts) with invasive aspergillosis (IA), including recipients of allogeneic hematopoietic stem cell transplants (HSCT). We investigated whether this early survival advantage could translate into a significant increase in overall survival. Methods. We retrospectively reviewed all consecutive pts who received a transplant between Sept. 1997 and Dec. 2008 at Saint-Louis Hospital and were diagnosed as having IA. The temporal origin of the study was the date of IA diagnosis for each patient. Factors associated with survival were analyzed using Cox proportional hazard models. Separate models were estimated for survival up to 12 W and for survival between 12 W and 24 months (M) in pts surviving longer than 12 W. The deaths of pts with and without IA were analyzed with a competing risk framework. Cumulative incidence curves were compared using Gray's tests. Results. Our study examined 89 IA pts. The median follow-up was 70 M (range, 11–130 M). Two pts did not receive any antifungal treatment and were excluded from subsequent analyses. Of the 87 pts, 42 received first-line V and 45 primarily received a lipid formulation of amphotericin B (n=25), amphotericin B deoxycholate (n=10), caspofungin (n=8) or itraconazole (n=2). The primary characteristics of pts with IA and their causes of death, separated by V as first-line treatment, are shown in the table below. The median survival was 2.6 M, and the overall survival at 24 M was 19% (95% CI 12–30 M) (see figure). Overall, the survival rates of the two groups were significantly different (P= 0.010). However, the differences in survival were quite dramatic prior to 10 M, whereas both survival curves became very close after one year. At 18 M, the numbers of surviving pts were almost identical in the two groups [19% (95% CI: 11–34%) in pts who did not receive V as first-line treatment vs. 21% (95% CI 11–38%) in pts who did]. Pts who did not receive V as a first-line treatment displayed a higher probability of dying from IA than those who did (P=0.004), whereas opposite results were found for mortality in pts without IA (P=0.006). The 24-M cumulative incidence of death from IA was 47% (95% CI 31–61%) in the no V group and 19% (95% CI 9–33%) in the group treated with V. The 24-M cumulative incidence of death in pts without IA was 4% (95% CI 7–14%) in the no V group and 27% (95% CI 14–42%) in pts treated with V. The probability of death from another cause, with IA, was similar in both groups (29% vs. 36% at 24 M; P=0.46). After adjusting for donor type, conditioning regimen, progressive GVHD at diagnosis of IA and cumulated steroid dose (mg/kg) in the W preceding IA diagnosis, administration of V as first-line treatment was found to decrease the risk of death during the first 12 W by approximately 70% [HR=0.31 (95% CI 0.16–0.60); P=0.0005]. Conversely, analysis of mortality between 12 W and 24 M failed to identify any significant predictor of risk of death; however, only 24 pts died during this period. Conclusions. The finding that first-line treatment with V, which is associated with a tremendous improvement in IA outcome, does not translate into an increase in overall survival (even in the context of early diagnosis) is striking. Diagnosis of IA following HSCT, whatever the outcome, appears to be a strong marker for poor long-term prognosis. Disclosures: Bergeron: Pfizer: Speakers Bureau, none; Merck: Speakers Bureau, none; Schering: Speakers Bureau, none. Sulahian:Pfizer: Research Funding, non; Merck: Research Funding, none. Ribaud:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, none; Schering: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, none; Gilead: Speakers Bureau, none.

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